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Abstract-The hypotensive mechanisms of N-(2-hydroxyethyl) nicotinamide nitrate Nicorandil) were studied in anesthetized dogs. Intravenous injections of SG-75 (0.03-1 mg/kg) decreased systemic blood pressure (SBP) and increased peripheral (coronary, renal, mesenteric and femoral) blood flow (PBF) dose-dependently.The duration of the PBF increase, however, was much shorter than that of the SBP decrease. When peripheral vascular beds were perfused by means of a pump under a constant perfusion pressure near the SBP, the duration and magnitude of the SBP decrease and the PBF increase were equal. In doses of 0.03-0.3 mg/kg i.v., SG-75 did not significantly affect pulse pressure, heart rate, aortic blood flow, left ventricular pressure (LVP) and LVdP/dt max. Intra-arterial injections of SG-75 (0.003-1 mg) increased coronary, renal, mesenteric and femoral blood flow dose-dependently, without affecting SBP and cardiac function. In heart-lung preparations the drug (0.1-2 mg) did not cause cardio depression. No hypotensive effect was observed following the adminis tration of SG-75 (3 mg) into the cisterna magna. The results indicate that the hypotensive effect of SG-75 may be due mainly to its peripheral mechanisms, relating to vasodilation.

1. Contractions to 5-hydroxytryptamine (5-HT) and histamine of longitudinal muscle from the isolated ileum of the tree shrew (Tupaia), guinea-pig and rat were investigated by constructing doseresponse curves and studying the effects of various antagonists. 2 In the Tupaia and rat ileum the contraction to 5-HT was reduced by methysergide but not affected by tetrodotoxin (TTX), morphine, hexamethonium (C6) or atropine. The response of guineapig ileum to 5-HT was not significantly inhibited by methysergide or C6, but was blocked by TTX, morphine and atropine.3 Histamine-induced contraction of Tupaia and guinea-pig ileum was antagonized by diphenhydramine but not by TTX, morphine, C6 or atropine. Histamine was almost without effect on the rat ileum.

Abstract-Tolerance to N-(2-hydroxyethyl)nicotinamide nitrate (SG-75) and nitroglycerin (NTG) was studied in rats with regard to the blood pressure responses in vivo and thoracic aorta strip preparations in vitro. Tolerance to the blood pressure response to SG-75 or NTG was observed with con secutive subcutaneous administrations of high doses of SG-75 or NTG, three times a day and the tolerance was time-and dose-dependent.In strips of the aorta incubated for 30 min with SG-75, sensitivity to challenging doses of SG-75 remained unchanged, but in the preparations incubated with NTG, the response to challenging doses of NTG was greatly decreased. SG-75 developed no cross tolerance to NTG. In in vivo experiments, SG-75 developed only slight tolerance, but in the in vitro experiments, unlike NTG, induced no tolerance.

Abstract--The mode of actions of' 5-hydroxytryptamine (5-HT) and its derivatives, tryptophan (14)), 5-hydroxytryptophan (5-HTP) and 5-hydroxyindole acetic acid(5-HIAA) vas studied on the isolated, blood-perfused small intestine and isolated ileum strip of rats.In the isolated, blood-perfused intestinal preparations, 5-HT and 5-HTP injected into the superior mesenteric artery caused a monophasic fast contraction, while TP and 5-HIAA had no effects on the intestine. The contractile responses to 5-HT and 5-HTP were abolished by tetrodotoxin (TTX), hexamethoitium (C5) and morphine, but were resistant to blockade of either atropine, methvsergidc or phentolamine.On the other hand, in the ileum strip preparations, 5-HT contracted the ileum, but its derivatives had no effects on the ileum. TTX, C,;, morphine and atropine failed to prevent the contractile response to 5-HT, whereas methysergide effectively antagonized the response. The present results indicate that 5-HT acts by exciting intramural neuronal elements or by directly contracting the smooth muscle of the intestine.5-HTP seems to act in the same manner as 5-HT.5-Hydroxytryptamine (5-HT) has been shown to contract smooth muscle of the isolated intestine by a direct action on the muscle fibres or by an indirect effect through excita tion of the intrinsic network of nerves (1-5). These findings, however, were obtained in isolated intestinal preparations bathed in physiological salt solutions. In view of this, it was considered that recordings of response of the intestinal smooth muscle with an intact blood supply may reveal features of the intestinal musculature.In the present experiments, we perfused the isolated small intestine of the rat through the superior mesenteric artery with blood from a donor, using a cross-circulation technique. This method enabled injection of drugs into the superior mesenteric artery and We could observe simultaneously vascular and muscular responses of the intestine.Our objective herein was to determine whether comparable information about the actions of 5-HT and its derivatives could he obtained from isolated, blood-perfused small intestine and from isolated ileum strips of the rat. MA I"ERIALS AND M1 THODSMale Sprague-Dawley rats were used.Isolated, 1,/crcnl perJuse~l.enrall intestinc: Donor rats (550-750 g) were anesthetized with pentobarbital sodium (65 mg/kg i.p.). The animal was placed on a table maintained by a