anandamide and Hypertension--Portal

Endocannabinoids may participate in the homeostasis of arterial pressure. Recently, anandamide, the most extensively studied endocannabinoid, has been proposed as a key mediator in the peripheral arterial vasodilation of cirrhosis.. To determine if circulating levels of anandamide are related to the extent of the peripheral arterial vasodilation, the severity of portal hypertension and the degree of liver and renal dysfunction of patients with cirrhosis.. Plasma levels of anandamide and several systemic, portal and renal hemodynamic parameters were determined in 18 patients with cirrhosis and eight healthy subjects (control group).. Plasma levels of anandamide were elevated in patients compared to the control group (P<0.05), nevertheless, no differences between patients with ascites and well-compensated patients were found. There was no correlation between anandamide concentration and arterial pressure, cardiac output and systemic vascular resistance, Child-Pugh's score, portal pressure, renal vascular resistance, plasma renin activity or plasma aldosterone concentration.. Circulating levels of anandamide are increased in cirrhotic patients. However, this elevation was unrelated to the extent of arterial vasodilation, the severity of portal hypertension or the degree of hepatic and renal dysfunction. Although a local hormonal action cannot be excluded, our results do not support a relevant contribution of this system in the hemodynamic disturbance of cirrhosis.

Topics: Arachidonic Acids; Cannabinoid Receptor Modulators; Endocannabinoids; Female; Glomerular Filtration Rate; Humans; Hypertension, Portal; Liver Cirrhosis; Male; Middle Aged; Polyunsaturated Alkamides; Stroke Volume; Vascular Resistance

The endogenous cannabinoid anandamide causes hypotension and mesenteric arteriolar dilation. A detailed analysis of its effects on systemic and portal venous hemodynamics had not yet been performed. We assessed the effects of anandamide (0.4-10 mg/kg) on systemic and portal hemodynamics with and without prior treatment with various antagonists. The specific antagonists used included SR-141716A, N(omega)-nitro-L-arginine methyl ester, indomethacin, and nordihydroguaiaretic acid. Anandamide produced a dose-dependent decrease in mean arterial pressure due to a drop in systemic vascular resistance (SVR) that was accompanied by a compensatory rise in cardiac output. Anandamide also elicited an increase in both portal venous flow and pressure, along with a decline in mesenteric vascular resistance (MVR). Pretreatment with 3 mg/kg SR-141716A, a CB(1) antagonist, prevented the decline of SVR and MVR from the lower dose of anandamide. Antagonism of nitric oxide synthetase, cyclooxygenase, or 5-lipoxygenase did not prevent the systemic nor the portal hemodynamic effects of anandamide. Furthermore, the use of R-methanandamide, a stable analog of anandamide, produced similar hemodynamic effects on the mesenteric vasculature, thereby implying that the effects of anandamide are not related to its breakdown products. Anandamide produced profound, dose-dependent alterations in both the systemic and portal circulations that could be at least partially blocked by pretreatment with SR-141716A.

Topics: Animals; Arachidonic Acids; Blood Pressure; Calcium Channel Blockers; Cannabinoids; Cardiac Output; Cyclooxygenase Inhibitors; Endocannabinoids; Enzyme Inhibitors; Heart Rate; Hypertension, Portal; Indomethacin; Liver Circulation; Male; Masoprocol; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Piperidines; Polyunsaturated Alkamides; Portal Vein; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Splanchnic Circulation