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

Abstract

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.

Figure 1

Hemodynamic effects of CB₁ antagonist SR141716 (3 mg/kg), FAAH antagonist URB597 (10 mg/kg), and anandamide (AEA; 10 mg/kg) in WKY (●) and SHR (○). Drugs were injected at 0 minutes. Values are mean±SEM. *P<0.05 of corresponding baseline values (n=4 to 10 for each condition). HR indicates heart rate.

Figure 2

Representative LV pressure-volume loops from WKY (a, d, g) and SHR (b, c, e, f, h, i) before (blue) and after (red) treatment with indicated agents or their combinations (for doses, see text). Experiments were repeated in 3 more animals in each treatment group with similar results. AEA indicates anandamide.

Figure 3

Effects of URB597 (a); AM251 followed by vehicle (circles) or URB597 (triangles; b), and anandamide (AEA; c) on MAP in normotensive rats (solid symbols) and angiotensin II–induced hypertensive rats (open symbols). Values are mean±SEM. *P<0.05 of baseline values (n=4 to 7 for each condition). Note that AM251 blocks the hypotensive effect of subsequently administered URB597 in SHR (b).

Figure 4

Change in MAP after vehicle (open columns) or 3 mg/kg SR141716 (solid columns) in Dahl salt-sensitive rats fed on 0.12% and 8% salt diet and in Dahl salt-resistant rats on 8% salt diet. Values are mean±SEM. *P<0.05 of baseline values (n=4 to 5 for each condition). Basal MAP after anesthesia was 97±5, 118±6, and 98±4 mm Hg in the 3 groups, respectively.

Figure 5

Hypotensive effect of URB597 (a) or anandamide (b) in SHR is unaffected by VR1 antagonist capsazepine. URB597 or anandamide (10 mg/kg) was injected at 0 minutes and 10 minutes after injection of vehicle (●) or 5 mg/kg capsazepine (○). *P<0.05 of corresponding baseline values. Values are mean±SEM, n=5 to 6 in each group.

Figure 6

CB₁ receptor immunohistochemistry in aorta (a) and Western blot of cardiac CB₁ (b) in WKY and SHR. Values are mean±SE from 4 separate experiments. *P<0.05, WKY vs SHR.

Figure 7

a, Representative ion chromatogram of untreated (blue) and URB597-treated (red) hearts from WKY rats (left) and SHR (right). b, Myocardial anandamide content of untreated and URB597-treated WKY (solid bar) and SHR (open bar; n=4 each group). *P<0.05, WKY vs SHR; #P<0.05 untreated vs URB597-treated rats. c, Western blot of cardiac FAAH (n=3).