The endogenous cannabinoid anandamide (arachidonylethanolamide) produces vasorelaxation in different vascular beds. In the present study, we found that anandamide and a metabolically stable analog, methanandamide, produced dose-dependent (10 nM-10 microM) vasorelaxation of approximately 80% in a rabbit aortic ring preparation in an endothelium-dependent manner. Non-endothelium-dependent vasorelaxation was observed to be a maximum of 20-22% at >10 microM methanandamide. The efficacious CB(1) receptor analogs desacetyllevonantradol (10 microM) and WIN55212-2 (10 microM) failed to produce vasorelaxation; however, the endothelium-dependent vasorelaxation evoked by methanandamide was partially (75%) blocked by the CB(1) receptor antagonist SR141716A. The VR(1) vanilloid receptor antagonist capsazepine or the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37) partially attenuated (25%) the vasorelaxation in endothelium-intact preparations and greatly reduced the response in endothelium-denuded preparations. Pretreatment of aortic rings with N(G)-nitro-L-arginine methyl ester completely blocked the methanandamide-, capsaicin-, and CGRP-induced vasorelaxation. Pretreatment of aortic rings with pertussis toxin attenuated the methanandamide-induced vasorelaxation in endothelium-intact aortic rings, indicating the involvement of G(i/o) proteins in the vasorelaxation; however, pertussis toxin treatment failed to block the endothelium-independent response. Thus, in the rabbit aorta, methanandamide-induced vasorelaxation exhibits two components: 1) in endothelium-intact rings, an SR141716A-sensitive, non-CB(1) receptor component that requires pertussis toxin-sensitive G proteins and nitric oxide (NO) production; and 2) in endothelium-denuded rings, a component that is mediated by VR(1) vanilloid receptors and possibly by the subsequent release of CGRP that requires NO production but is independent of pertussis toxin-sensitive G proteins.

The effects of the newly discovered bicyclic prostaglandin, prostacyclin (PGI2), on the pulmonary and systemic vascular beds were investigated in the anesthetized dog. PGI2 decreased systemic and pulmonary arterial pressures in a dose-related manner when injected into the vena cava in doses of 1--30 microgram. Since left ventricular end-diastolic, left atrial, and right atrial pressures were unchanged, and since cardiac output was increased or unchanged, pulmonary and systemic vascular resistances were decreased. PGI2 was 10 times more potent than prostaglandins E1 or E2 in decreasing aortic pressure when injected intravenously, and the effects of PGI2 on the systemic vascular bed were similar when injected into the vena cava or the left atrium. These data indicate that inactivation of PGI2 is minimal in the lung. The stable prostacyclin metabolite, 6-keto-PGF1alpha, had little hemodynamic effects, suggesting that responses to PGI2 were not due to formation of this metabolite. PGI2 produced dose-dependent increases in blood flow in the mesenteric and renal vascular beds. These data demonstrate that PGI2 has marked vasodilator activity in the pulmonary and systemic vascular beds and suggest that prostacyclin is the only known metabolite of arachidonic acid that dilates the pulmonary and systemic circulations.

SUMMARY. To characterize the influences of leukotriene D 4 on regional vascular smooth muscle, effects of leukotriene D 4 on vasomotor tone of canine renal and superior mesenteric arterial rings were determined. Vascular smooth muscle tone was measured with isometric force transducers. After tone had been induced with norepinephrine, leukotriene D«, in concentrations of 10~* M to 10~7 M, produced dose-dependent relaxation of renal and superior mesenteric arterial rings. Leukotriene D 4 -induced relaxation was observed only in those ring preparations in which care had been taken to avoid damaging the Iuminal surface. Acetylcholine (10~7 M) also decreased tone in these same ring segments. Neither acetylcholine nor leukotriene D 4 altered tone of arterial rings after the endothelium had been intentionally disrupted by rubbing with a cotton-tipped applicator. Nitroglycerin (1CT* M) relaxed rings both before and after rubbing the intimal surface. These results demonstrate that leukotriene D 4 possesses the capacity to relax canine superior mesenteric and renal arterial rings in an endothelial-dependent manner. Because relaxation of renal and superior mesenteric arterial rings in response to leukotriene D 4 was not altered after incubation with indomethacin (10~! M), the observed endothelial-dependent relaxation induced by leukotriene D 4 did not appear to be related to release of a cyclooxygenase metabolites). In contrast, FPL 55712 (10~5 M) attenuated the relaxation produced by leukotriene D 4 , suggesting that this response was a receptor-linked consequence. (Circ Res 57: 323-329, 1985)

Influences of leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) on mesenteric and renal blood flow were investigated in the anesthetized dog. Blood flow was measured with noncannulating electromagnetic flow probes, and all agonists were injected as a bolus close arterially. When injected into the superior mesenteric artery, LTC4 (0.1-3.0 ng), LTD4 (0.1-1.0 ng), and LTE4 (1-30 ng) produced dose-dependent decreases in blood flow in absence of a change in mean arterial pressure. When compared with intestinal vasoconstrictor responses caused by angiotension II, which was most active, and norepinephrine, which was least active, the leukotrienes were intermediate between these two well-known vasoactive hormones. LTD4 was more active than LTC4, and both were considerably more active than LTE4. In contrast to the intestine, injection of leukotrienes (1,000 ng) into the kidney resulted in little to no change in renal blood flow or mean arterial pressure, but mesenteric flow decreased 10-15 s later. Administration of indomethacin (5 mg/kg iv) did not alter mesenteric vasoconstrictor responses produced by LTD4. However, mesenteric vasoconstrictor responses to prostaglandin (PG)D2 were reduced after indomethacin, whereas renal vasodilation caused by PGD2 was unaffected. These results demonstrate that LTC4, LTD4, and LTE4 differentially affect blood flow in the intestine and kidney and suggest that if circulating levels of leukotrienes are increased, blood flow would be expected to be diverted away from the intestine. These data are thus compatible with the hypothesis that leukotrienes may participate in regulation of peripheral regional blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Medical SciencesUnusual pulmonary vasodilator activity of 13,14-dehydroprostacyclin methyl ester: Comparison with endoperoxides and other prostanoids ( Contributed by Josef Fried, September 12,1977 ABSTRACT Microsomes from stomach fundus and blood vessels transform the endoperoxide, PGH2, into a newly discovered unstable substance, PGI2, that relaxes arterial stri4s and inhibits platelet aggregation. 13,14-Dehydro-PGI2 methyl ester, a newly synthesized, stable PGI2 analog, was found to have potent vasodilator activity in the feline and simian pulmonary vascular bed. The PGI2 analog decreased lobar arterial perfusion pressure in the intact cat and monkey. Because pulmonary blood flow was held constant and left atrial pressure was unchanged, the decrease in perfusion pressure reflects a decrease in pulmonary vascular resistance. The dilator response was unusual in that it persisted for 10-12 min, whereas the response to PGEI, the only other vasodilator prostaglandin in the mature animal, persisted for only 1-2 min. The dilator response to the PGI2 analog was enhanced when pulmonary vascular resistance was increased. This substance had less effect on cardiac output and aortic pressure than PGEI, whereas it was a more potent pulmonary vasodilator. These data demonstrate that prostacyclin-like substances possess novel vasodilator activity in the pulmonary circulation and suggest a therapeutic use in the treatment of pulmonary hypertensive diseases.