Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Renal interstitial Ca2+ during sodium loading of normotensive and Dahl-salt hypertensive rats.

It is now established that cells in many tissues including renal epithelial cells and perivascular sensory nerves have mechanisms that monitor and respond to the concentration of Ca2+ in the interstitial compartment [Ca2+(ISF)]. We tested the hypothesis that high Na+ intake alters renal [Ca2+(ISF)] and that the response is altered in salt-sensitive hypertensive versus normotensive rats. Male Wistar (W), Dahl salt-resistant (DR), and Dahl salt-sensitive (DS) rats were fed diets containing 0.45% or 8% NaCl for 7 days beginning at 8 to 10 weeks of age. Systolic blood pressure (BP) was measured before and at the end of the 7-day period. During the last 12 h the animals were placed in metabolic cages for urine collection. They were then anesthetized and renal [Ca2+(ISF)] was determined using in situ microdialysis. Feeding 8% NaCl caused a significant increase in systolic BP only in DS. The 8% NaCl also caused a significant increase in renal urinary Na+ excretion in all groups, had no effect on renal Ca2+ excretion in W or DS and significantly increased urinary Ca2+ excretion in DR. When fed 0.45% NaCl, renal [Ca2+(ISF)] was lower in W and DR compared with DS. Feeding 8% NaCl significantly increased [Ca(ISF)] in W, had no effect on this parameter in DR, and significantly decreased [Ca2+(ISF)] in DS ([Ca2+(ISF)] for DS on 0.45% NaCl = 1.89 +/- 0.15 v 8% NaCl = 1.08 +/- 0.07 mmol/L, n = 6 to 12, P <.05). These results indicate that Na+ loading significantly alters renal [Ca2+(ISF)]; that the response of DS is disturbed relative to controls, and are consistent with the hypothesis that Na+ loading can alter cell function by modulating [Ca2+(ISF)].

Serial noninvasive assessment of progressive pulmonary hypertension in a rat model.

Current methods used to investigate pulmonary hypertension in rat models of the disease allow for only one to two measurements of pulmonary artery (PA) pressure in the life of a rat. We investigated whether transthoracic echocardiography can be used to assess the progression of pulmonary hypertension in rats at multiple time points. Serial echocardiographic measurements were performed over a 6-wk period on rats injected with monocrotaline (MCT) or placebo. Development of a midsystolic notch in the PA waveform, a decrease in the PA flow acceleration time (PAAT), an increase in right ventricular (RV) free-wall thickness, and the development of tricuspid regurgitation (TR) were observed as pulmonary hypertension developed. Changes in the PA waveform and PAAT began in week 3 of disease development as the PA systolic pressure (PASP) reached 25-30 mmHg according to right heart catheterization. The RV free-wall thickness increased significantly by week 5 (PASPs 40-50 mmHg). Development of quantifiable TR occurred in week 6 or at PASPs > 65 mmHg. A linear correlation was found between the PAAT and PASP in the range of 30-65 mmHg and between the RV-right atrial pressure gradient (derived from TR velocity) and PASP at pressures >65 mmHg, which enabled a noninvasive estimate of the PASP over a wide range of pressures based on these parameters. These data indicate that transthoracic echocardiography can be used for monitoring the progress of pulmonary hypertension in a rat model.

Normal perivascular sensory dilator nerve function in arteries of Zucker diabetic fatty rats.

BACKGROUND: Type II diabetes in humans is associated with pathology of both the cardiovascular and peripheral sensory nervous systems. Because abnormal vasodilator responses have been reported in animals of type II diabetes and perivascular sensory nerves are a source of vasodilator substances, we tested the hypothesis that sensory nerve-dependent relaxation is abnormal in arteries of the Zucker diabetic fatty (ZDF) rat model of type II diabetes. METHODS: The ZDF rats and genetic controls were studied at 26 weeks of age. Tail-cuff systolic blood pressure (BP) was measured, serum was obtained for chemical determinations, and mesenteric branch arteries were isolated for wire myograph analysis and confocal-based measurement of calcitonin gene-related peptide (CGRP) positive nerve density. RESULTS: No differences in BP were detected. Serum glucose, triglycerides, and cholesterol were significantly elevated in ZDF. Sensory nerve-dependent vasodilation was assessed by measuring relaxation of phenylephrine preconstricted arterial segments to cumulative addition of divalent calcium ion (Ca2+) or capsaicin. Neither Ca(2+)-nor capsaicin-induced relaxation were different in ZDF versus control (maximal ZDF response to Ca2+ = 64% +/- 2% v 59% +/- 4%; ED50 for Ca2+ = 3.7 +/- 0.5 mmol/L v 3.2 +/- 0.5 mmol/L; n = 5, P = not significant [NS]; maximal ZDF response to capsaicin = 68% +/- 9% v 74% +/- 4%; ZDF ED50 = 3.8 +/- 0.5 nmol/L v 9.8 +/- 7 nmol/L; n = 5, P = NS). In contrast, the maximal relaxation response to acetylcholine was impaired in ZDF (maximal ZDF response = 83% +/- 5% v 94% +/- 2%, n = 4, P = .039; ED50 for acetylcholine = 8.1 +/- 2.9 nmol/L for ZDF v 33.5 +/- 18.2; n = 4 per group, P = .086). The CGRP positive nerve density was not different between groups. CONCLUSIONS: Blood pressure, perivascular sensory nerve CGRP content, and dilator function is normal in the ZDF model of type II diabetes, whereas endothelium-dependent relaxation is impaired.