Hypertensa Product Information. Indication

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1 Hypertensa Product Information Indication Hypertensa is intended for use in the management of hypertension. Hypertensa is a medical food that must be used under the active or ongoing supervision of a physician. Medical foods are developed to address the different or altered physiologic requirements that may exist for individuals who have distinctive nutritional needs arising metabolic disorders, chronic diseases, injuries, premature birth associated with inflammation and other medical conditions, as well as from pharmaceutical therapies. 1 Hypertension develops from a chronic failure in the autoregulatory mechanisms of blood pressure control to compensate for responsiveness of blood pressure to fluctuations in blood volume and capillary resistance. Overstimulation of sympathetic activity is a contributing factor as are imbalances in levels of vasoactive neuropeptides, hormones, and inflammatory mediators. The autoregulatory mechanisms responsible for blood pressure control are mediated by the activity of neurotransmitters. These mechanisms involve autonomic nervous system activity, vascular endothelial function, cellular responses to inflammation, and hormones that regulate sodium and fluid balance and blood vessel compliance. Several neurotransmitters also have intrinsic vasoactive properties that influence blood pressure. Hypertensa is designed to provide a balance of neurotransmitters, antioxidants, and other ingredients that support the mechanisms that regulate blood pressure. Ingredients Hypertensa is a patented blend of neurotransmitter precursors (L-arginine, choline bitartrate, L-glutamine, and histidine HCl); stimulators of precursor uptake (cinnamon bark); polyphenolic antioxidants (grape seed extract, cinnamon bark, cocoa extract); anti-inflammatory amino acids (Lhistidine, L-glutamine); adenosine antagonists (caffeine, cocoa extract); immunomodulator and antioxidant with anti-inflammatory, anti-apoptotic, and neuroprotective properties (ginseng); and an inhibitor of the attenuation of neurotransmitter production associated with precursor administration (grape-seed extract). The neurotransmitters and neurotransmitter precursors in Hypertensa have been carefully selected based on scientific support for their roles in the synthesis and activity of the neurotransmitters involved in regulation of blood pressure. These roles are summarized in this monograph in the section Scientific Support for Use of Hypertensa in Management of Hypertension. The other ingredients in the formulation are functional components of the Targeted Cellular Technology system. All of the ingredients included in Hypertensa are classified as generally recognized as safe (GRAS) by the United States Food and Drug Administration (FDA). To qualify for GRAS status, a substance that is added to a food, including a medical food, has to be supported by data demonstrating it is safe when consumed in amounts obtained from these foods, as they are typically ingested or prescribed. 1 As defined in the guidelines issued by the Center for Food Safety and Nutrition, United States Food and Drug Administration (FDA). 1 P age Revised 22 Mar 2011

2 Targeted Cellular Technology Hypertensa has been formulated using Targeted Cellular Technology (TCT), an integrated molecular system that facilitates the uptake and utilization of neurotransmitter precursors by target cells within the nervous system. This 5-component patented system consists of: (1) specific neurotransmitter precursors; (2) a stimulus for the neuronal uptake of these precursors by specific neurons; (3) an adenosine antagonist that blocks the inhibitory effect of adenosine on neuronal activity (adenosine brake); (4) a stimulus to trigger the release of the required neurotransmitters from targeted neurons; and (5) a mechanism to prevent attenuation of the precursor response, a well known phenomenon associated with precursor administration. Use of Targeted Cellular Technology improves the metabolic efficiency of neurotransmitter synthesis, thereby reducing the amounts of precursors needed to correct neurotransmitter imbalances. Use of Targeted Cellular Technology also ensures that the appropriate amounts of neurotransmitter precursors are delivered to the target neurons with the appropriate timing. As such, Targeted Cellular Technology synchronizes the availability of the precursor supply with the fluctuating demand for the corresponding neurotransmitters, which is especially important for processes that are regulated by circadian rhythms and are therefore sensitive to the timing of the synthesis and release of neurotransmitters such as acetylcholine, serotonin, nitric oxide, and histamine (1-4). In the cardiovascular system, regulation of vascular tone and platelet aggregation are particularly sensitive to circadian rhythms (5-7). Previous attempts to provide an exogenous source of precursor amino acids and other biogenic amines in the quantities required to support neurotransmitter synthesis for individuals with specific needs necessitated that large amounts of these nutrients be added to the formulations. For patients whose precursor requirements are considerably higher than normal, the amounts of exogenous amino acids needed are not practical to consume on a daily basis. Moreover, ingestion of large quantities of amino acids increases the potential for adverse effects. Metabolic efficiency is also decreased when large amounts of amino acids are delivered to the cells at one time because intestinal membrane transport receptors would be rapidly saturated resulting in a reduction in fractional amino acid absorption and thus attenuation of the tissue response to the supplemental amounts provided. Improving metabolic efficiency in uptake and utilization of neurotransmitter precursors by target neurons using Targeted Cellular Technology allows ingestion of smaller amounts of amino acids to elicit the same response as larger amounts, making daily dosing more feasible and reducing the potential for tolerance. Unlike pharmaceutical products which are not innate components of processes that regulate blood pressure and thus may lose their effectiveness over a relatively short time period, the effectiveness of Hypertensa is not attenuated. Metabolism Hypertensa is a source of amino acids, biogenic amines, and other nutrients for patients with hypertension. These patients require additional amounts of arginine, choline, glutamine, and histidine to restore homeostasis. Under usual physiological conditions, arginine and glutamine are metabolized as nonessential amino acids because endogenous synthesis is adequate to satisfy metabolic demand. When 2 P age Revised 22 Mar 2011

3 needs are altered by increased demand to support the metabolic adjustments needed to maintain blood pressure, the usual rate of synthesis is no longer sufficient and these nutrients become conditionally essential, requiring that supplemental amounts be consumed. Histidine has also been considered a nonessential amino acid for adults because blood levels can be maintained by breakdown of skeletal muscle and hemoglobin; however, there is no evidence of de novo histidine synthesis in mammalian tissues and thus an exogenous supply is important, especially during times of increased need, to preserve muscle mass and plasma hemoglobin concentration. Glutamine. Glutamine is synthesized in virtually all tissues by the addition of an amino group to glutamate (Figure 1). As a carrier of amino groups, glutamine is involved in the disposal of nitrogenous waste from protein catabolism in urea, in the transfer of amino groups for synthesis of nonessential amino acids, and in the synthesis of purine and pyrimidine bases for production of nucleic acids. Glutamine also has neurotransmitter activity at the N-methyl-D-aspatate (NMDA) receptor sites in the brain. In addition, it is deaminated to regenerate glutamate, the major excitatory neurotransmitter of the central nervous system and a precursor of GABA, the major inhibitory neurotransmitter of the central nervous system. Figure 1. Competing Pathways of Glutamine Metabolism When glutamine intake is not sufficient to meet increased demands, the endogenous supply is depleted thus compromising synthesis of nucleic acids and other compounds that are synthesized by glutamine transfer of amino groups. The increased demands for this amino acid will deplete the available supply of glutamate thus decreasing substrate for synthesis of arginine and of glutathione (γ-glutamylcysteinylglycine), a potent cellular antioxidant which protects cell membranes from damage 3 P age Revised 22 Mar 2011

4 by reactive oxygen species. Hypertensa improves metabolic efficiency by providing supplemental glutamine to satisfy demands while conserving the glutamate tissue pool. Arginine. The metabolic pathways which generate arginine are also normally sufficient to ensure an adequate supply of this amino acid. Endogenous arginine synthesis occurs primarily in the kidney and to a lesser extent in the liver which recycles citrulline to arginine in the urea cycle (Figure 2). Hepatic arginine is utilized locally and therefore does not contribute significantly to plasma concentrations; however, because it can be synthesized in the urea cycle from metabolites of glutamine and glutamate, arginine is not considered an essential amino acid. Arginine is a precursor of the neurotransmitter nitric oxide which functions as a vasodilator, immunomodulator, and intercellular/intracellular messenger. In addition, arginine is a precursor of polyamines, urea, and the high-energy storage compounds creatine and creatine phosphate (Figure 2). When the demand for nitric oxide is increased, the synthesis of these compounds is compromised by depletion of arginine reserves. To compensate for the decreased supply of arginine available to competing pathways, glutamine and glutamate can be metabolized to provide ornithine which is then utilized to regenerate arginine in the urea cycle. Consequently, when arginine intake is insufficient for a prolonged period, the tissue pool of glutamine/glutamate will eventually be depleted. Figure 2. Competing Pathways of Arginine Metabolism Since vascular function is dependent on nitric oxide synthesized from arginine, an increased demand for this neurotransmitter will increase the need for supplemental arginine to prevent depletion of the arginine tissue pool. Hypertensa improves metabolic efficiency by ensuring that sufficient arginine is available 4 P age Revised 22 Mar 2011

5 to meet the need for increasing production of nitric oxide without compromising demands for arginine by competing pathways. Choline. The requirement for choline is dependent on the extent of the demand for acetylcholine and is thus increased by metabolic pathways associated with increased cholinergic activity. Acetylcholine is produced from choline in an acetylation reaction catalyzed by choline acetyltransferase with acetyl coenzyme A (CoA) as the acetyl group donor. (Figure 3). Figure 3. Biosynthesis of Acetylcholine Under usual metabolic conditions, the primary source of choline for acetylcholine synthesis is the hydrolysis of the membrane phospholipid phosphatidylcholine (lecithin) which serves as a reservoir of choline to meet short-term needs for the neurotransmitter. When the demand for acetylcholine exceeds the amount of choline that can be supplied by the membrane pool, dietary choline becomes an increasingly more important source to maintain levels of acetylcholine (Figure 4). Hypertensa provides additional amounts of choline to meet the increased needs for acetylcholine when demand is increased over prolonged periods. By supplying an exogenous source of choline, Hypertensa prevents the depletion of membrane phosphatidylcholine, thus preserving the structural integrity of the cell. 5 P age Revised 22 Mar 2011

6 Figure 4. Sources of Acetylcholine Histidine. The need for histidine is also dependent on dietary intake because this amino acid cannot be synthesized endogenously, thus the amount consumed determines the amount available for competing pathways of utilization. Histidine is a precursor of histamine which is synthesized and released by neurons and immunocytes. Increased needs for histidine can be met temporarily by release of the amino acid from hemoglobin and skeletal muscle protein. The specific results of histamine activity are dependent upon the particular tissue receptor subtype which is activated. Hypertensa provides histidine to meet increased needs for histamine while preserving hemoglobin levels and skeletal muscle mass. Dosage The recommended dose of Hypertensa is 2 capsules taken 3 times daily. An additional dose may be taken if needed. As with any medical food, the best dosing protocol should be determined by a physician based on assessment of individual needs. The effects of Hypertensa are confined to constricted blood vessels, thus abnormal dilatation of vessels does not occur and the possibility of overdose is low. There are no known interactions between Hypertensa and any medications including sildenfil sulfate, or any herbal supplements. Patients taking pharmaceutical agents to treat hypertension should initially maintain their current dosage of these medications. Hypertensa should be added to the regimen under supervision of a physician with regular monitoring of clinical status. The response to Hypertensa can occur within 15 minutes of the first dose. The maximal effect of Hypertensa will accumulate within 2 weeks from the initiation of therapy. The patient can be monitored in the office after the first dose is taken to observe changes in blood 6 P age Revised 22 Mar 2011

7 pressure. Therapeutic doses of anti-hypertensive medications taken with Hypertensa may be modified as indicated by clinical response. The addition of Hypertensa to the treatment regimen may allow the dosage of these drugs to be reduced with a reduction in drug-related side effects. The amounts of each ingredient consumed at the recommended doses of Hypertensa are presented in Table 1. Table 1. Hypertensa Composition Ingredient mg/kg body weight 1 L-arginine L-glutamine L-histidine L-leucine L-cysteine Choline bitartrate Whey protein hydrolysate Cocoa extract (8% theobromine) (fruit) Cinnamon Ginseng Caffeine Grape seed extract (20% polyphenol) Dosing range of 2 capsules taken 3 times daily Side Effects and Contraindications As with any amino acid therapy, headache, nausea, or dry mouth may be experienced in some people after beginning treatment with Hypertensa. These symptoms are mild and temporary, and readily managed by increasing fluid intake. The development of side effects with use of Hypertensa can be minimized by careful titration of the dosage. All of the ingredients in Hypertensa are regularly consumed in amounts normally found in foods, therefore development of an adverse reaction to Hypertensa is not expected. Hypertensa is contraindicated in patients who may be hypersensitive to any component of an arginine-containing preparation. Hypertensa contains L-arginine which has been associated with side effects when consumed as a single-dose supplement. These effects are not observed at the low levels of 7 P age Revised 22 Mar 2011

8 arginine in Hypertensa or when consumed from formulations containing other amino acids such as Hypertensa. A 2-capsule dose of Hypertensa contains 126 mg of L-arginine provided in a balanced formula with other amino acids and dietary factors and therefore may be safely taken 2 to 3 times daily. Side effects specific to oral supplementation with L-arginine have been reported at doses between 3 and 100 g/d, approximately 12 to 400 times the amount provided in Hypertensa in the recommended daily dose (126 mg/2 capsules) (8). L-arginine is generally well-tolerated at intakes of up to 15 g/d. The most common adverse reactions have been observed at the range of intakes between g/d and include nausea, abdominal cramps, diarrhea, and vomiting. Some patients may experience symptoms at lower doses. Most of the side effects associated with L-arginine supplements have been reported at single doses >9 g (>140 mg/kg), particularly when consumed in regimens where total daily doses amount to >30 g/d. L-arginine supplements must not be taken alone by patients testing positive for HIV-1 infection, but may be consumed by these patients in combination with other amino acids and dietary factors as provided in Hypertensa. Long-term safety studies have not been conducted with L arginine. Because it may stimulate growth hormone production, pregnant women and nursing mothers should avoid L-arginine supplementation. Individuals with renal or hepatic failure should also exercise caution with the use of supplemental L-arginine. Oral supplements of arginine and citrulline can increase local nitric oxide production in the small intestine which may be harmful under certain circumstances. Abbreviations and Definition of Terms The definitions for the abbreviations and terms referenced in this monograph are summarized in Table 2. Table 2. Abbreviations and Definitions of Terms Term/Abbreviation Definition Angiotensin Antioxidants Baroreceptor Reflex cgmp Cardiovascular Control Center Chemoreceptors Vasoactive peptide involved in long-term blood pressure control by renal mechanisms; also found in the brain where it is involved in short-term blood pressure control through modulation of sympathetic activity and/or blunting of baroreceptor feedback to the brainstem Molecules or enzyme systems that inhibit injury to cells from reactive oxygen or nitrogen species Normalizes blood pressure primarily through parasympathetic-mediated effects on cardiac output involving mechanoreceptor activation; modified by circulating angiotensin II Cyclic guanidine monophosphate; a cellular messenger which initiates neurotransmission, relaxation of vascular smooth muscle cells, hemodynamics, and cellular metabolism; activated by nitric oxide through stimulation of guanylyl synthase Nuclei located in the medulla where information regarding blood volume and vessel diameter is integrated Receptors located in the carotid sinus, aortic arch, and other large arteries in the neck and thorax which respond to changes in blood gases and ph, and to binding of vasoactive peptides 8 P age Revised 22 Mar 2011

9 Term/Abbreviation Definition and other substances which are synthesized and released by the neurons involved in control of blood pressure. Cholinergic Cytokines Endothelium Essential Hypertension Excitatory Neurotransmitters Glutamatergic Glutathione Inflammatory mediators Inhibitory Neurotransmitters Mechanoreceptors Neuromodulators Neuropeptides Neurosteriods Neurotransmitters Neurons that synthesize, package, and release acetylcholine Class of inflammatory mediators which control the transcription of inos protein and thus the production of nitric oxide in the presence of inflammation; vasoactive peptides A layer of cells lining the vascular lumen which produces nitric oxide; a highly active regulatory organ which senses and assesses the hemodynamic, humoral, and inflammatory signals in the blood to which it is constantly exposed and responds to these signals by secreting factors that affect vessel tone and structure Disease characterized by chronic elevations in systolic and diastolic blood pressures; generally characterized by increased blood volume and sympathetic-mediated elevation in total peripheral resistance Molecules released from presynaptic cells at terminal nerve endings which transmit action potentials to adjacent neurons by depolarization of postsynaptic cell membranes resulting in a decreased stimulus threshold for firing which increases the frequency and rate of transmission of action potentials Neurons that synthesize, package, and release glutamate Potent cellular antioxidant synthesized from glutamate, cysteine, and glycine which sequesters nitric oxide by forming adducts which extends its half-life and prevents its oxidation to damaging reactive nitrogen species such as peroxynitrate Serum proteins and cellular products released from activated inflammatory cells (lymphocytes, leukocytes, platelets) and damaged tissues which modulate the inflammatory response, e.g, cytokines and prostaglandins Molecules released from presynaptic cells at terminal nerve endings which transmit action potentials to adjacent neurons by hyperpolarization of postsynaptic cell membranes resulting in a increased stimulus threshold for firing which decreases the frequency and rate of transmission of action potentials Receptors located in the carotid sinus, aortic arch, and other large arteries in the neck and thorax activated as part of the baroreceptor reflex; detect increases in blood volume or pressure due to stretching of vagal nerve fibers in the vessel wall Neurotransmitter, neuropeptides, and other molecules including neurosteriods which influence neurological function Polypeptides which function as neurotransmitters but are more widely diffused and have longer-lasting effects; may also function as hormones, e.g., prolactin, vasopressin Progesterone, testosterone, aldosterone and their derivatives which are synthesized in both the central and peripheral nervous systems; may influence neurotransmitter activity as allosteric modifiers of neurotransmitter receptors or through regulatory effects on neuroendocrine and metabolic processes Amino acids, biogenic amines, and other molecules that facilitate communication between the peripheral nervous system, spinal cord, and brain by generating a series of action potentials 9 P age Revised 22 Mar 2011

10 Term/Abbreviation Definition which are transmitted between neurons NMDA receptor NOS Ornithine Peripheral Vascular Resistance Peroxynitrate Prostacyclin Prostaglandins S-nitrosoglutathione Vasoconstrictor Vasodilator Targeted Cellular Technology N-methyl-D-aspartate; subfamily of glutamatergic receptors which require a co-agonist for activation Nitric oxide synthase; catalyzes the synthesis of nitric oxide from arginine; expressed as one of three isoforms: neuronal (nnos) and endothelial (enos) which are constitutive and inducible (inos) which is induced by specific mixtures of cytokines Intermediate of the urea cycle which can be utilized to regenerate arginine; product of glutamate metabolism State of smooth muscle cell contraction which can be adjusted to increase or decrease blood flow through capillary beds: vasodilation increases blood flow and vasoconstriction decreases blood flow Highly reactive and damaging nitrogen free radical species produced by the combining of nitric oxide with superoxide anions Prostaglandin I 2 ; a primary regulator of vascular tone and tissue perfusion; considered to be the most important physiological modulator of vascular tone; functions by reducing systemic vascular resistance secondary to peripheral vasodilation Inflammatory mediators synthesized from 20-carbon fatty acids by cyclooxygenases;,may have proinflammatory (omega-6 fatty acids) or anti-inflammatory (omega-3 fatty acids) effects depending on the initial fatty acid substrate Adduct formed between nitric oxide and glutathione which extends the half-life of nitric oxide by preventing formation of reactive nitrogen species Substance that promotes contraction of smooth muscle cells within the vascular endothelium which increases peripheral vascular resistance by constricting blood vessels Substance which promotes relaxation of smooth muscle cells within the vascular endothelium that results in a decrease in peripheral vascular resistance by dilation of blood vessels A patented process that facilitates endogenous production, uptake, and utilization of neurotransmitter precursors Mechanism of Action Hypertensa has been formulated to provide a balance of neurotransmitters with well-defined roles in the mechanisms of blood pressure control. Blood pressure is a function of cardiac output (heart rate/stroke volume) and total peripheral resistance which are regulated by the coordinated activities of the sympathetic and parasympathetic nervous systems. Under resting conditions, the dominant neural influence on blood pressure is the parasympathetic nervous system which slows heart rate and decreases cardiac output. The autoregulatory response to changes in blood pressure is a function primarily of the sympathetic nervous system which mainly acts through adjustments in peripheral resistance (9-10). The effects of the sympathetic nervous system on peripheral resistance are mediated by changes in the contractility of arteriolar smooth muscle cells which adjust the flow of blood through the capillary beds, 10 P age Revised 22 Mar 2011

11 thus modifying the degree of tissue perfusion with subsequent effects on cardiac output (10). The diversity of sympathetic innervation of various tissues such as the brain, heart, lungs, kidneys, and gastrointestinal tract allows for regional variations in blood flow which enable these organs to autoregulate their blood supply (9, 11). Neurological involvement in short-term blood pressure regulation. The neural network of the brain plays a significant role in both the short- and long-term regulation of blood pressure (12). Short-term regulation involves the activation of chemoreceptors and mechanoreceptors located in the carotid sinus, aortic arch, and other large arteries in the neck and thorax. Chemoreceptors respond to changes in blood gases and ph as well as to binding of vasoactive peptides and other substances which are synthesized and released by the neurons involved in neurogenic control of blood pressure (12-13). Mechanoreceptors, which are activated by the stretching of nerve fibers in the vessel walls, detect increases in blood volume or pressure as part of the baroreceptor reflex. Although the this reflex is generally a mechanism for normalizing blood pressure over the short-term, disturbances in mechanisms of long-term blood pressure control can reset the baroreceptors to maintain a higher level arterial pressure which contributes to the establishment of hypertension (14). The baroreceptor reflex normalizes blood pressure primarily through parasympathetic-mediated effects on cardiac output (15). Vagal (parasympathetic) stimulation from mechanoreceptor activation increases the discharge rate of neural impulses which are transmitted to the cardiovascular control center in the medulla where information regarding blood volume and vessel diameter is integrated (14). Parasympathetic output from the cardiovascular control center slows heart rate causing a reduction in cardiac output which decreases blood volume and prevents a rise in blood pressure. The reduction in sympathetic-mediated vascular tone that accompanies the increase in parasympathetic activity relaxes smooth muscle cells in the peripheral vasculature which favors vasodilation (16). Arteriole dilation increases blood flow through the capillary beds by decreasing peripheral vascular resistance whereas venodilation decreases blood flow by the pooling of blood in the venous reservoirs which decreases venous return. Both of these vascular responses to decreased sympathetic-mediated vasomotor tone complement the parasympathetic-mediated effects on heart rate resulting in a reduction in cardiac output and contraction of blood volume that prevent a rise in blood pressure. Neurological involvement in long-term blood pressure regulation. In contrast to the vascular mechanisms that regulate blood pressure over short periods of time, long-term blood pressure control is achieved primarily by renal mechanisms, most notably by the renin-angiotensin system which adjusts blood volume by effecting changes in renal reabsorption of sodium and water (13). Although this hormonal system was originally described in the kidney, it has also been identified in the brain with an important role in neural control of blood pressure. Overactivity of the brain renin-angiotensin system adversely influences blood pressure through peripheral effects on renal reabsorption mechanisms as well as through central nervous system effects on control of sympathetic activity and/or blunting of baroreceptor feedback to the brainstem. The increased activity of the renin-angiotensin system in the brain has been linked to the increase in sympathetic activity associated with essential hypertension. 11 P age Revised 22 Mar 2011

12 Sympathetic and parasympathetic activity in essential hypertension. Primary or essential hypertension is a disease with a multifactorial etiology that is expressed as chronic elevated systolic and diastolic blood pressures. The early stages of the pathophysiology of the disease are generally characterized by increased blood volume, but sympathetic-mediated elevation in total peripheral resistance is also a common feature of the disease regardless of the initiating factors (17). The normal sympathetic response to a temporary increase in blood volume is an increase in tissue capillary blood flow which decreases arterial blood volume and thus prevents a rise in blood pressure. When the sympatheticmediated response to an increase in blood volume is blunted, peripheral resistance must eventually be increased to prevent excessive capillary blood flow through the tissues. This compensatory peripheral vasoconstriction will be sustained until blood volume can be restored to normal levels by renal mechanisms that increase sodium and fluid excretion. The subsequent failure to readjust vascular tone after cardiac output has been restored is one of the mechanisms that has been proposed to explain the effect of expanded blood volume on the establishment of essential hypertension. Essential hypertension may also develop in response to disturbances in neural mechanisms within the cardiovascular control centers of the brain which keep vascular tone elevated despite adjustments in blood volume and cardiac output (11, 18). Overstimulation of sympathetic nerve fibers which sustains elevations in peripheral resistance can be attributed to defects in regulation of sympathetic nervous system activity by neurotransmitters. Chronic exposure of blood vessels to the mechanical stress of tonic contraction leads to hypertrophy and hyperplasia of smooth muscle cells in the endothelial layer and fibromuscular thickening of the intima causing permanent narrowing of the vessel lumen (18-21). Endothelial injury also stimulates the release of inflammatory mediators which increase vascular permeability and exacerbate thickening of the vessel walls. As a consequence, vascular compliance is decreased and endothelial function is impaired, thus preventing vascular tissue from responding quickly to the changes in sympathetic activity needed to regulate blood flow, restore cardiac output, and normalize blood pressure (18). Hypertensive vascular injury. Hypertensive injury to blood vessels has multiple effects that weaken the regulatory mechanisms involved in control of blood pressure. These effects consist of alterations in vascular structure and compliance as well as decreased bioavailability of nitric oxide and increased levels of oxidative stressors which also contribute to further endothelial damage (18-19, 22-25). Vascular injury caused by chronic high blood pressure is exacerbated by inflammation of the blood vessel walls laying a foundation for impaired endothelial function. Hypertensive injury is also typically accompanied by imbalances in hormones that regulate sodium and fluid balance and thus prevent the reduction in blood volume that would eventually allow vascular tone to return to normal (26). Mechanism of neurotransmitter activity. Neurotransmitters and neuropeptides are the key modulators of the autoregulatory processes that stabilize blood pressure. These molecules function as mediators of sympathetic nervous system activity, the inflammatory response, and the activation and release of hormones involved in fluid/electrolyte balance and autonomic nervous system function (27). Neurotransmitters are amino acids, biogenic amines, or amino acid derivatives which function as mediators of physiological responses to physical, chemical, or electrical stimuli. Neurotransmitters are 12 P age Revised 22 Mar 2011

13 released from storage vesicles in presynaptic neurons in response to action potentials at the distal nerve endings where they bind to receptors on postsynaptic neurons (Figure 5). Neurotransmitter binding alters the resting membrane potential of postsynaptic neurons generating an action potential which is transmitted to the terminal ending of the neuron where the sequence of electrochemical events is repeated until the signal reaches specific processing centers in the brain. The same mechanism of neurotransmittermediated electrochemical events is involved in transmission of output from the brain to target effector tissues or organs, and in transmission of signals originating within different regions of brain over the internal circuits between these regions. Figure 5. Neurotransmitter Activity in Presynaptic and Postsynaptic Neurons The rate of signal transmission between presynaptic and postsynaptic neurons in the central and peripheral nervous systems is dependent on the chemical nature of the neurotransmitter involved (28). Excitatory neurotransmitters released from presynaptic nerve terminals depolarize postsynaptic cell membranes which lowers the stimulus threshold for firing and increases the frequency and rate of transmission. Inhibitory neurotransmitters have the opposite effect of hyperpolarizing postsynaptic membranes which raises the stimulus threshold and decreases the frequency and rate of transmission. Although neurotransmitters can be classified as excitatory or inhibitory based on the primary effects they have on resting membrane potentials, these classifications do not always predict the response of the effector tissue or organ. Excitatory neurotransmitters can suppress a response by activation of inhibitory mechanisms and inhibitory neurotransmitters can activate a response by suppression of these mechanisms (29). Imbalances caused by deficiencies in one or more of the excitatory and inhibitory neurotransmitters, or changes in their binding affinities to postsynaptic receptors, will determine the intensity and duration of the signals transmitted (29-30). General roles of neurotransmitters. The effects of the neurotransmitters which modulate the central nervous system pathways that regulate blood pressure involve the tonic excitatory and inhibitory activities of nitric oxide, acetylcholine, glutamate, and histamine (31). Nitric oxide was identified as the original endothelium-derived relaxing factor which functions as a signaling molecule with significant roles in the regulation of smooth muscle cell contractility and vasomotor tone (32-35). It is considered the most 13 P age Revised 22 Mar 2011

14 important neurotransmitter involved in regulation of blood pressure based on observations that inhibition of its activity will initiate a sequence of events resembling all of the characteristics of volume-dependent essential hypertension, a feature that has not been observed for any other neurotransmitter (35-36). In addition to nitric oxide, other neurotransmitters, endothelium-derived substances, and metabolic endproducts (e.g., adenosine) relax vascular tone and promote vasodilation (24, 32). These effects are opposed by endothelium-derived contracting factors such as angiotensin II, vasoconstrictor prostanoids, endothelin-1, and superoxide anions (37). A balance between the endothelium-derived relaxing and contracting factors modulates the responsiveness of vascular smooth muscle tone to changes in blood volume and pressure whereas imbalances between these factors can contribute to the pathophysiology of essential hypertension (24, 38). Acetylcholine is an endothelium-dependent agonist which promotes relaxation of vascular smooth muscle cells (18, 35). It is the primary neurotransmitter of the sensory and motor circuits of the autonomic nervous system and a sympathetic neurotransmitter in specific vasculatures (11, 39). It exhibits both excitatory and inhibitory effects in the sympathetic nervous system and excitatory effects in all parasympathetically-innervated tissues except cardiac smooth muscle where it acts as an inhibitory neurotransmitter which decreases heart rate. Vasodilatory responses to acetylcholine are mediated in part through endothelium-derived relaxing factors, hyperpolarizing factors, and contracting factors (15). Glutamate is the major excitatory neurotransmitter of the central nervous system with widely distributed receptors in the brain which are concentrated in areas of high cholinergic activity. Under conditions where glutamatergic activity is inhibited, acetylcholine-mediated transmission is stimulated and cholinergic receptors in the hypothalamus are upregulated (40). Histamine is also an excitatory neurotransmitter which functions in both the central and peripheral nervous systems eliciting effects that vary with the specific type of histaminergic receptor expressed (41). Neuropeptides. In addition to the classic neurotransmitters, a number of neuropeptides are involved in the regulation of blood pressure with varying effects on central and peripheral nervous system activities. At least 16 naturally-occurring peptides which function as vasoconstrictors or vasodilators have been identified including cytokines and hormone-releasing factors (42). Many of these peptides are present in nerve cells and nerve terminals that supply the systemic and pulmonary blood vessels and the heart, and are released locally where they function in a manner similar to those neurotransmitters involved in regulation of vascular tone, local and regional blood flow, arterial blood pressure, and cardiac function. At least some of these vasoactive peptides may mediate and/or modulate arterial hypertension by involvement in these activities. Among the neuropeptides and other vasoactive peptides which function as nonconventional mediators of mechanisms that regulate blood pressure are angiotensin II, vasopressin, endothelins, cytokines, vasoactive intestinal peptide, glucocorticoids, and aldosterone (43). These peptides not only have direct effects on vessel contractility and diameter but they also modulate the activities of the classic neurotransmitter/neuropeptide-transmitting systems. Endothelins, cytokines, and vasopressin also have direct effects on the central nervous system which influence blood pressure as do corticotrophin-releasing 14 P age Revised 22 Mar 2011

15 hormone, thyrotropin-releasing hormone, natriuretic peptides, and adrenomedullin (12). The endothelins, a family of 21-amino acid peptides produced primarily in the endothelium, are among the strongest vasoconstrictors that have been identified and have been implicated in vascular diseases of several organ systems (44). Neurosteriods. Another class of molecules that influence neurotransmitter-mediated effects on blood pressure is the neurosteroids comprising progesterone, testosterone, aldosterone, and their derivatives which are synthesized by both the central and peripheral nervous systems. Neurosteroids may modify neurotransmitter activity by acting as allosteric modifiers of neurotransmitter receptors such as the glutamatergic NMDA receptors or as regulatory molecules that modify neuroendocrine and metabolic processes (45). The activities of enzymes involved in the synthesis of neurosteroids are finely tuned by various neurotransmitters and neuropeptides suggesting that some of the central effects of these hormones are related to neurotransmitter-mediated systems that regulate their production such as the hypothalamicpituitary-adrenal (HPA) axis. Neurotransmitter roles in blood pressure homeostasis. The neurotransmitters and neuropeptides which have significant roles in blood pressure homeostasis are released by neurons in several regions of the brain (10, 13, 43). The blood pressure response to stimulation of these neurons is determined by the balance between inputs from excitatory and inhibitory neurotransmitters (12, 29). Experimental data have shown that slight disturbances in blood pressure due to alterations in blood volume lead to marked changes in the rates of neurotransmitter release within various brain structures (43) Prolonged activation or inhibition of specific neurotransmitter/neuromodulator pathways frequently results in long-lasting disorders in regulatory systems of blood pressure control (12). Central mechanisms of blood pressure control can be modulated by interactions with peripheral neuromodulators. Blood levels of vasoactive peptides are monitored by the brain in circulation through the circumventricular organs which lack a blood brain barrier (14). Adjustments in plasma concentrations of neurotransmitters and hormones ensure an appropriate level of sympathetic-mediated vasomotor tone (15). Changes in circulating levels of angiotensin II in the area postrema close to the baroreceptor nucleus can influence baroreceptor input and subsequent vascular responsiveness to short-term pressure changes (14). Release of angiotensin II within the brain activates angiotensin receptors in the cerebral vasculature which promotes endothelial synthesis of nitric oxide. Diffusion of nitric oxide from the cerebral vasculature across the blood-brain barrier alters the activity of neurons in the cardiovascular control center (15). It also triggers a vascular-brain signaling mechanism which allows angiotensin II released in the brain to bypass the blood brain barrier and influence blood pressure control through peripheral effects on renal fluid volume and capillary resistance (14). Other hormones synthesized peripherally and transported in the blood to the brain can also alter central nervous system activity by binding to receptors outside the blood brain barrier. Vascular endothelial dysfunction. Increasing evidence suggests that vascular tone is dependent on the health of the endothelium, a monolayer of cells lining the vascular lumen which have been implicated as both a mediator and target of hypertension (35, 38, 46). The vascular endothelium is a highly active 15 P age Revised 22 Mar 2011

16 regulatory organ which senses and assesses the hemodynamic, humoral, and inflammatory signals from circulation and responds to these signals by secreting factors that affect vessel tone and structure (47). The vascular endothelium also has protective roles as a metabolic barrier and as a barrier to diffusion of vasoconstrictor substances, and as a secretory source of paracrine hormones. Impaired endotheliumdependent vasomotor control has been documented in hypertension, as well as in hypercholesterolemia, atheromatosis, diabetes, and reperfusion damage (48). In patients with hypertension, endotheliumdependent relaxation is impaired in the aorta and carotid artery as well as in the cerebral and mesenteric arterioles and coronary arteries (26). Endothelial dysfunction is a major factor in the autoregulatory failure underlying the establishment of essential hypertension (23). Increased peripheral resistance, tissue ischemia, and cardiovascular complications have been associated with impaired function of the vascular endothelium (23, 44). Impaired endothelial function often precedes vascular dysfunction and exacerbates its effects on the progression of hypertension (48). Changes in endothelial function have a prognostic value in predicting cardiovascular events in hypertensive patients, and improvements in function have been associated with decreased morbidity and mortality in this disease (22-23, 35, 44, 47, 49). A number of factors are involved in the pathophysiology of endothelial dysfunction in hypertension (23). The primary defect appears to be an alteration in agonist-induced endothelium-dependent vasodilation with impairment in the tonic release of nitric oxide secondary to the hypertension (26). Continuous exposure to mechanical forces has been associated with morphological and functional changes in the vascular endothelium in both experimental and human hypertension (23). Although subtle and distinct functional defects in endothelial function are present in hypertension, not all vascular beds are similarly affected and not all defects are caused by the same mechanisms (44). The anatomical integrity of the endothelium is a requisite for vascular smooth muscle cell responsiveness to relaxing factors such as acetylcholine and nitric oxide and to (48, 18). The production and release of nitric oxide is decreased by damage to the endothelium as are other endothelium-derived factors including prostacyclin (PGI 2 ), a major regulator of vascular tone and tissue perfusion (37-38). Prostacyclin, which is regarded as the most important physiological modulator of vascular tone, functions through reducing systemic vascular resistance secondary to peripheral vasodilation (38). While the vasodilatory effects of prostacyclin are similar to those of nitric oxide, they are not additive as inhibition of the activity of one can be completely compensated for by increased activity of the other (36). The vasodilatory properties of prostacyclin differ from those of nitric oxide in that they are independent of the endothelium and thus are observed in the absence of endothelial cells. Inhibition of cyclooxygenase activity restores nitric oxidemediated vasodilation in patients with essential hypertension, indicating that cyclooxygenase-dependent constrictor substances can impair nitric oxide production in this disease. Oxidative damage. Oxidative stress caused by the accumulation of superoxide anions is involved in the pathogenesis of hypertension. Increased activity of cyclooxygenase, the controlling enzyme in prostaglandin synthesis, generates large amounts of superoxide (50). Damage to the vascular endothelium caused by oxidative stress interferes with normal vascular function which is exacerbated by decreased endothelial synthesis and release which reduces the availability of nitric oxide. Endothelium-derived 16 P age Revised 22 Mar 2011

17 nitric oxide is also rapidly inactivated by accumulation of superoxide radicals which combine with nitric oxide to form peroxynitrate, a highly reactive nitrogen species (51). Formation of peroxynitrate not only decreases the availability of nitric oxide, but also maintains a high level of oxidative stress (22). Superoxide and other free radicals can also be generated from increased activity of proinflammatory enzyme systems such as xanthine oxidase, NADH/NADPH oxidase, and myeloperoxidase due to chronic inflammation associated with vascular injury caused by chronic elevations in blood pressure. Angiotensin II can decrease the availability of nitric oxide by increasing superoxide production through activation of NAD(P)H oxidase. Endothelial function as therapeutic target. Endothelial dysfunction is a primary therapeutic target in the treatment of hypertensive disease (22). Factors that promote vasorelaxation, inhibit vasoconstriction, reduce production of free radicals, or support other mechanisms that protect against vascular injury improve endothelial function (52). Angiotensin-converting enzyme inhibitors which prevent the conversion of renin to angiotensin and thus decrease levels of angiotensin II, have been shown to reverse endothelial dysfunction. The results of a number of trials indicate that therapeutic interventions which modulate the synthesis and release of both renin and angiotensin and the balance between these peptides influence the processes which control vascular remodeling (46). The effectiveness of therapeutic interventions that lower blood pressure through increasing the bioavailability of nitric oxide depends on the efficiency with which these interventions increase nitric oxide production and/or decrease superoxide production in the endothelium (24). Endothelial function is improved by supplementation with the nitric oxide precursor L-arginine (48). Scientific Support for Use of Hypertensa in Management of Hypertension The use of Hypertensa in the management of hypertension is supported by experimental and clinical data which have identified specific roles for each ingredient in the mechanisms that regulate blood pressure. A balanced production of nitric oxide, acetylcholine, histamine, and glutamine/glutamate are needed to modulate autonomic nervous system activity, vasomotor tone, inflammatory processes, and the hormonal regulatory responses that impact heart rate, cardiac output, blood volume, blood flow, peripheral vascular resistance, and endothelial function. The effectiveness of Hypertensa in the nutritional management of hypertension is supported by an extensive body of experimental and clinical data demonstrating specific roles for each ingredient in regulation blood pressure. Hypertensa is formulated with the optimum balance of amino acids and antioxidants to support mechanisms involved in blood pressure control using Targeted Cellular Technology to control the timing of the release of these ingredients. Neurotransmitter activity in vascular tissue. Presynaptic receptors for acetylcholine (muscarinic), histamine (H2), prostaglandins, adenosine (A1), dopamine (DA2) and opioids (53), and are expressed by vascular tissue, thus it can be considered a neuroeffector organ of the sympathetic nervous system. Sympathetic stimulation promotes either inhibitory or excitatory responses in vascular tissue depending upon the particular ligand, underscoring the importance of a balance in neurotransmitters to achieve an appropriate response to various stimuli. Treatment of a variety of clinical conditions, including 17 P age Revised 22 Mar 2011