urb-597 and Hypertension

Our study aimed to examine the effects of hypertension and the chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on vascular function and the endocannabinoid system in spontaneously hypertensive rats (SHR). Functional studies were performed on small mesenteric G3 arteries (sMA) and aortas isolated from SHR and normotensive Wistar Kyoto rats (WKY) treated with URB597 (1 mg/kg; twice daily for 14 days). In the aortas and sMA of SHR, endocannabinoid levels and cannabinoid CB

Topics: Acetylcholine; Amidohydrolases; Animals; Aorta; Arachidonic Acids; Benzamides; Carbamates; Endocannabinoids; Essential Hypertension; Hypertension; Male; Mesenteric Arteries; Nitroprusside; Polyunsaturated Alkamides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Cannabinoid; Vasoconstriction; Vasodilation

Hypertension is one of the most common cardiovascular diseases in the world and is associated with oxidative stress. The aim of this study was to examine the effect of the chronic administration of the fatty-acid amide hydrolase inhibitor (URB597-[3-(3-carbamoylphenyl)phenyl]

Topics: Amidohydrolases; Animals; Benzamides; Carbamates; Disease Models, Animal; Erythrocyte Membrane; Hypertension; Lipid Peroxidation; Male; N-Acetylneuraminic Acid; Oxidative Stress; Rats; Rats, Inbred SHR

Hypertension is accompanied by oxidative stress, which can be modified by the functioning of the endocannabinoid system playing a prominent modulatory role in the brain. The present study tested whether chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl) phenyl]N-cyclohexylcarbamate (URB597) to rats with primary hypertension (SHR) can modify redox balance and consequently brain phospholipid metabolism. Experiments were conducted using SHRs and normotensive control Wistar-Kyoto rats treated by intraperitoneal injection with URB597 for 14 days. The biochemical parameters were assayed in the rats' brains. Inhibition of FAAH activity by URB597 resulted in an increase in anandamide and GPR55 receptor levels, as well as a decrease in CB

Topics: Animals; Arachidonic Acids; Benzamides; Brain; Carbamates; Disease Models, Animal; Endocannabinoids; Hypertension; Injections, Intraperitoneal; Male; Malondialdehyde; Oxidation-Reduction; Phospholipids; Polyunsaturated Alkamides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, G-Protein-Coupled

The effect of chronic administration of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate (URB597), inhibitor of fatty acid amide hydrolase (FAAH) that hydrolyzes anandamide, on cross-talk between endocannabinoid system, oxidative status and pro-inflammatory factors in the liver of spontaneously hypertensive rats (SHRs) was investigated.. Experiments were conducted using SHRs and normotensive control Wistar-Kyoto rats treated by intraperitoneal injection with URB597 for 14 days. The biochemical parameters were assayed in the rat's livers.. In conclusion, long-term chronic administration of URB597 to SHRs by altering interactions between endocannabinoid and redox systems enhances some liver metabolic disturbances observed in hypertension.

Topics: Amidohydrolases; Animals; Benzamides; Carbamates; Endocannabinoids; Enzyme Inhibitors; Fatty Acids; Hypertension; Lipid Metabolism; Male; NF-kappa B; Oxidation-Reduction; Phospholipids; Rats; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Hypertension is a civilization disease leading to remodeling and damage of blood vessels, impaired renal function and premature death. The aim of this study was to compare the effect of chronic administration of URB597, the FAAH (fatty acid amide hydrolase) inhibitor, to rats with primary (SHRs) and secondary (DOCA-salt hypertensive rats) hypertension on electrical and physicochemical properties of kidney cells membranes. Changes in the electrical charge of the membrane may affect the cell functions. The electrical properties of the kidney cells (surface charge density, zeta potential) were measured by electrophoresis. Qualitative and quantitative composition of the membrane (phospholipids and proteins) was determined by HPLC and lipid peroxidation product (4-hydroxy-2E-hexenal; 4-HHE) level was examined by GCMSMS, while the sialic acid content was measured by resorcinol method. In rats with primary hypertension (SHR) and secondary hypertension (DOCA-salt), changes in electrical properties (increase of electric charge and zeta potential) and membrane composition (increase in sialic acid and protein concentration and decrease in phospholipid level) of kidney cells are observed in comparison to control animals. Greater changes were observed in DOCA-salt hypertensive rats. Changes in membrane properties caused by URB597 depend on the type of hypertension. The administration of URB597 to rats with primary hypertension partially prevents changes in the electrical properties (electrical charge, zeta potential) of the membrane caused by hypertension as well as in the sialic acid and proteins content. However, there is no reduction in oxidative stress, assessed by the level of 4-HHE, which may affect the metabolic function of the kidneys. URB597 administered to rats with DOCA salt does not prevent, but rather intensifies, changes caused by hypertension in the kidney. In conclusion, URB597 given to individuals with hypertension, particularly with secondary hypertension, enhancing some disturbances in electric and physicochemical properties of kidney cells observed in hypertension what may lead to additional kidney disorders. Therefore, further researches are necessary.

Topics: Amidohydrolases; Animals; Benzamides; Carbamates; Cell Membrane; Chromatography, High Pressure Liquid; Desoxycorticosterone Acetate; Disease Models, Animal; Enzyme Inhibitors; Hypertension; Kidney; Lipid Peroxidation; Male; N-Acetylneuraminic Acid; Phospholipids; Rats; Rats, Inbred SHR; Rats, Wistar

Recent interest in the use of cannabinoids as therapeutic agents has revealed the involvement of the endogenous cannabinoid system (ECS) in the regulation of the cardiovascular system in hypertension. Abnormalities in glucose metabolism and insulin action are commonly detected in hypertensive animals. Thus, potential antihypertensive drugs should be investigated with respect to modulation of glucose homeostasis. Therefore, the aim of the present study was to evaluate the effects of the ECS activation after chronic fatty acid amide hydrolase inhibitor (URB597) administration on plasma glucose and insulin concentrations as well as parameters of myocardial glucose metabolism in the deoxycorticosterone acetate (DOCA)-salt hypertensive rats, an animal model of secondary hypertension.. Hypertension was induced by DOCA (25mg/kg) injections and addition of 1% NaCl in the drinking water for six weeks. Chronic activation of the ECS was performed by URB597 (1mg/kg) injections for two weeks. We examined fasting plasma levels of insulin (ELISA), glucose and intramyocardial glycogen (colorimetric method). Expressions of glucose transporters (GLUT1, 4) and selected proteins engaged in GLUT translocation as well as glucose metabolism were determined using Western blotting.. Hypertension induced hypoinsulinemia with concomitant lack of significant changes in glycemia, reduced intramyocardial glycogen content and increased pyruvate dehydrogenase (PDH) expression in the cardiac muscle. Importantly, chronic URB597 administration in the hypertensive rats increased insulin concentration, elevated plasmalemmal GLUT1 and GLUT4 expression and concomitantly improved myocardial glycogen storage.. Chronic administration of fatty acid amide hydrolase (FAAH) inhibitor has potential protective properties on myocardial glucose metabolism in hypertension.

Topics: Animals; Benzamides; Blood Glucose; Carbamates; Desoxycorticosterone Acetate; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 4; Glycogen; Hypertension; Insulin; Ketone Oxidoreductases; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar

The interaction between the endocannabinoid and ROS signaling systems has been demonstrated in different organs. Inhibitors of fatty acid amide hydrolase (FAAH), the key enzyme responsible for degradation of the endocannabinoid anandamide, are postulated to possess anti-hypertensive potential. Here, we compared the effects of hypertension and chronic FAAH inhibition by URB597 on the endocannabinoid system and redox balance in spontaneously hypertensive rats (SHR) and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. Enhanced oxidative stress and lipid peroxidation were found in both hypertension models. Hypertension affected cardiac and plasma endocannabinoid systems in a model-dependent manner: anandamide and 2-arachidonoylglycerol levels decreased in SHR and increased in DOCA-salt. Cardiac CB

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Carbamates; Desoxycorticosterone Acetate; Endocannabinoids; Glycerides; Heart; Hypertension; Male; Myocardium; Oxidation-Reduction; Oxidative Stress; Polyunsaturated Alkamides; Rats, Inbred SHR; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Topics: Amidohydrolases; Animals; Benzamides; Carbamates; Desoxycorticosterone Acetate; Disease Models, Animal; Gene Expression Regulation; Heart; Hypertension; Injections, Intraperitoneal; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Xanthine Oxidase

There is significant evidence that the endocannabinoid system (ECS) takes part in the regulation of the cardiovascular system in hypertension. It is quite well established that hypertension causes several changes in the heart metabolism, but it is still unknown whether the ECS affects this process. Therefore, we investigated the influence of prolonged ECS activation on myocardial lipid metabolism in deoxycorticosterone acetate (DOCA)-salt hypertensive rats by chronic fatty acid amide hydrolase (FAAH) inhibition.. We examined the uptake and oxidation of palmitic acid during the heart perfusion as well as intramyocardial and plasma lipid contents using gas liquid chromatography. Total, plasmalemmal and intracellular expressions of selected proteins were estimated by the Western blot technique. Moreover, the left ventricle's morphology, including myocardial vessels density, was measured using immunohistochemistry.. We demonstrated that hypertension induced cardiomyocytes and myocardial blood vessels hypertrophy, followed by a reduction in myocardial palmitate oxidation. Interestingly, prolonged activation of the ECS in the normotensive rats induced cardiomyocyte enlargement and intensified fatty acids metabolism. We have also shown that FAAH inhibition improved morphology of coronary blood vessels and only partially maintained its effect on lipid metabolism in the DOCA-salt hearts (i.e. elevated plasma and intramyocardial TAG contents as well as plasmalemmal FAT/CD36 and total FATP1 expressions).. This study revealed that chronic FAAH inhibition has no protective effects on the heart lipid metabolism in hypertension.

Topics: Amidohydrolases; Animals; Benzamides; Blood Pressure; Carbamates; Chromatography, Gas; Chromatography, Liquid; Coronary Vessels; Desoxycorticosterone Acetate; Disease Models, Animal; Endocannabinoids; Fatty Acids; Hypertension; Lipid Metabolism; Male; Myocardium; Myocytes, Cardiac; Rats; Rats, Wistar

The endocannabinoid system has been suggested to be up-regulated in hypertension. Fatty acid amide hydrolase (FAAH) is the main hydrolytic enzyme for the encocannabinoid anandamide. The aim of our study was to examine the age-specific influence of the chronic administration of the FAAH inhibitor URB597 on blood pressure (BP), heart rate (HR) and cardiac and renal hypertrophy in hypertensive rats during two critical periods for the development of hypertension.. Experiments were performed on uninephrectomised 4 (younger) and 6-7 (older) weeks old rats rendered hypertensive by a high salt diet and deoxycorticosterone acetate (DOCA) injections and on normotensive animals (unilateral nephrectomy only). URB597 1mg/kg or its vehicle were injected twice daily for 2 weeks.. The DOCA-salt procedure caused comparable increases in BP (but not HR) in both age groups and more strongly increased cardiac and renal hypertrophic indices in younger than in older animals. Chronic URB597 administration reduced BP and HR in older but not in younger rats. In contrast, the inhibitor diminished the cardiac and renal hypertrophy in younger but not in older animals. URB597 did not affect body weight gain, and food and water intake in normotensive or hypertensive rats.. Two weeks of URB597 administration to DOCA-salt hypertensive rats caused an age-specific reduction in BP, HR and cardiac and renal hypertrophy and did not affect the body weight, and water and food intake. Thus, caution should be taken during studies of FAAH inhibitors because of their potential age-specific effects.

Topics: Amidohydrolases; Animals; Benzamides; Blood Pressure; Carbamates; Desoxycorticosterone Acetate; Heart; Heart Rate; Hypertension; Hypertrophy; Kidney; Male; Rats; Rats, Wistar

This study examined whether the fall in blood pressure (BP) induced by the chronic inhibition of fatty acid amide hydrolase (FAAH) by URB597 in deoxycorticosterone acetate (DOCA-salt) hypertensive rats correlates with endocannabinoid-mediated vascular changes.. Functional studies were performed in isolated endothelium-intact aortas and small mesenteric arteries (sMAs) using organ bath technique and wire myography, respectively.. In the DOCA-salt rats, methanandamide-stimulated relaxation was enhanced in sMAs or diminished in aortas. Its vasorelaxant effect in sMAs was sensitive to the antagonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1), capsazepine, in normo- and hypertensive animals and to the antagonist of the cannabinoid CB1 receptors, AM6545, only in DOCA-salt rats. Cannabinoid CB1 receptors were up-regulated merely in DOCA-salt sMAs. URB597 decreased elevated BP in DOCA-salt rats, medial hypertrophy in DOCA-salt aortas. In sMAs it reduced FAAH expression and restored the augmented phenylephrine-induced contraction in the DOCA-salt rats to the level obtained in normotensive controls. In normotensive rats it diminished endothelium-dependent relaxation and increased phenylephrine-induced contraction.. The study showed the protective role of cannabinoid CB1 receptors in DOCA-salt sMAs. Reduction in BP after chronic administration of the FAAH inhibitor URB597 in DOCA-salt hypertensive rats only partially correlates with structural and functional changes in conductance and resistance vessels, respectively. Caution should be taken in studying cannabinoids and FAAH inhibitors as potential therapeutics, because of their vessel- and model-specific activities, and side effects connected with off-target response and activation of alternative pathways of anandamide metabolism.

Topics: Amidohydrolases; Animals; Aorta; Arachidonic Acids; Benzamides; Blood Pressure; Capsaicin; Carbamates; Desoxycorticosterone Acetate; Dose-Response Relationship, Drug; Drug Interactions; Hypertension; Male; Mesenteric Arteries; Morpholines; Phenylephrine; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Sodium Chloride; Vasoconstriction; Vasodilation

Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis.

Topics: Amidohydrolases; Animals; Benzamides; Carbamates; Catalase; Desoxycorticosterone Acetate; Endocannabinoids; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Glutathione Transferase; Hypertension; Liver; Male; Monoacylglycerol Lipases; Phospholipases A2; Rats, Wistar; Reactive Oxygen Species; Receptor, Cannabinoid, CB1; Superoxide Dismutase

This study was performed to examine whether hypertension affects the sympathetic transmission to resistance vessels of pithed rats via inhibitory presynaptic cannabinoid CB1 receptors and whether endocannabinoids are involved in this response.. We compared uninephrectomised rats rendered hypertensive by high salt diet and deoxycorticosterone acetate (DOCA) injections with normotensive animals (uninephrectomy only). Experiments were performed on vagotomised and pithed animals. Increases in diastolic blood pressure (DBP) were induced four times (S1-S4) by electrical stimulation or phenylephrine injection.. Electrical stimulation (0.75Hz, 1ms, 50V, 5 impulses) of the preganglionic sympathetic nerve fibres innervating the blood vessels more strongly increased DBP in normotensive than in DOCA-salt rats. Phenylephrine (0.01μmol/kg) induced similar increases in DBP in both groups. The cannabinoid receptor agonist CP55940 (0.01-1μmol/kg) did not modify the rises in DBP induced by phenylephrine. However, it inhibited the electrically stimulated increases in DBP, more strongly in DOCA-salt than in normotensive animals (maximally by 50 and 30%, respectively). The effect of CP55940 was attenuated by the CB1 antagonist AM251 (3μmol/kg). AM251 enhanced the neurogenic vasopressor response during S4 by itself in hypertensive rats only. URB597 (3μmol/kg), which inhibits degradation of the endocannabinoid anandamide, did not modify the electrically stimulated increases in DBP.. The function of inhibitory presynaptic CB1 receptors on sympathetic nerves is enhanced in DOCA-salt hypertensive rats. Thus, the CB1 receptor-mediated inhibition of noradrenaline release from the sympathetic nerve fibres innervating the resistance vessels might play a protective role in hypertension.

Topics: Animals; Benzamides; Blood Pressure; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Carbamates; Desoxycorticosterone Acetate; Hypertension; Male; Nephrectomy; Phenylephrine; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Presynaptic; Sodium, Dietary; Sympathetic Nervous System

Oleamide is an endocannabinoid-like, fatty acid amide with structural similarities to anandamide. The cardiovascular effects of anandamide are enhanced in hypertension and we have now examined how hypertension affects responses to oleamide. Vasorelaxant responses to oleamide were significantly (P<0.001) enhanced in aortic rings from spontaneously hypertensive rats (SHRs), such that the maximal relaxation to oleamide was 40.3 ± 3.5%, compared to 15.7 ± 3.9% in normotensive Wistar Kyoto (WKY) controls. The augmented responses to oleamide in SHR arteries were unaffected by either inhibition of nitric oxide synthase (300 μM l-NAME) or fatty acid amide hydrolase (1 μM URB597) and independent of cannabinoid CB(1) receptors or the endothelium. The enhanced responses to oleamide were opposed by pre-treatment with capsaicin (such that R(max) was reduced to 9.8 ± 1.5%) and this occurred independently of TRPV1 receptor and sensory nerve activity, as the TRPV1 antagonist capsazepine (1-5 μM) and the cation channel inhibitor ruthenium red (10 μM) had no effect on the responses to oleamide. However, inhibition of cyclooxygenase (10 μM indomethacin) enhanced the responses in the WKY aortae, such that the responses were comparable to those in the SHR. The results suggest that the cyclooxygenase pathway has a role in modulating vasorelaxation caused by oleamide in normotensive aortae and that this is lost in hypertension, possibly as an adaptation to the increase in blood pressure.

Topics: Amidohydrolases; Animals; Aorta; Benzamides; Biomimetic Materials; Cannabinoid Receptor Modulators; Capsaicin; Carbamates; Cyclooxygenase Inhibitors; Endocannabinoids; Endothelium, Vascular; Hypertension; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester; Oleic Acids; Rats; Receptor, Cannabinoid, CB1; TRPV Cation Channels; Vasodilator Agents

The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined.. We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds.. Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB(1) receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide].. These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB(1) receptor-mediated mechanisms in the actions of anandamide.

Topics: Acute Disease; Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzoxazines; Blood Pressure; Cannabinoids; Carbamates; Consciousness; Endocannabinoids; Hindlimb; Hypertension; Infusions, Intravenous; Injections, Intravenous; Male; Morpholines; Naphthalenes; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Renal Circulation; Splanchnic Circulation; Vascular Resistance; Vasodilation

Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension.. In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats.. We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.

Topics: Amidohydrolases; Angiotensin II; Animals; Arachidonic Acids; Benzamides; Benzyl Compounds; Blood Pressure; Camphanes; Carbamates; Dronabinol; Endocannabinoids; Endothelium, Vascular; Hypertension; Male; Models, Cardiovascular; Myocardial Contraction; Myocardium; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Up-Regulation; Vascular Resistance; Vasodilation; Ventricular Function, Left