Pentolinium

Abstract: Antagonists of nicotine have been used in an attempt to resolve the continuing controversy about the role of nicotine as the primary reinforcer in cigarette smoking. Mecamylamine, an antagonist which readily penetrates to the central nervous system, increased the rate of cigarette smoking by about 30% in laboratory tests; this was accompanied by reduced blood pressure, impaired performance of a digit symbol substitution test, improved hand steadiness, and by dysphoria. The increased smoking may be regarded as self-titration with nicotine, an interpretation which receives some support from results obtained with pentolinium, an antagonist with predominantly peripheral actions. In the doses used, pentolinium did not affect smoking rate, blood pressure, or hand steadiness, but it impaired digit symbol performance and induced dysphoria. The different results with mecamylamine and pentolinium support previous evidence that the action of nicotine in the central nervous system has a small but clearly demonstrable role as a primary reinforcer of the smoking habit.

Abstract: The isolated vas deferens of the guinea-pig contracted when stimulated transmurally with parallel wire electrodes. These contractions persisted in concentrations of hexamethonium, pentolinium, nicotine and mecamylamine which at the same time abolished the responses to hypogastric nerve stimulation. Procaine and lignocaine in local anaesthetic concentrations abolished the responses to transmural stimulation but potentiated the contractions produced by added noradrenaline. Guanethidine and bretylium in concentrations specific for adrenergic neurone blockade abolished the contractions due to transmural stimulation without impairing the responses of the muscle to added noradrenaline or acetylcholine. In contrast, high concentrations of the adrenergic-blocking agents phentolamine and dihydroergotamine were needed to block the contractions due to transmural stimulation; these concentrations also blocked the response to added noradrenaline but simultaneously reduced the responses to added acetylcholine or potassium chloride. Preparations from guinea-pigs previously treated with reserpine at first responded normally to transmural stimulation; thereafter the contractions diminished progressively but were never abolished. Hyoscine and atropine produced a small decrease in the response to transmural stimulation when present in concentrations up to 1×10-5 and a larger decrease only in concentrations of 1×10-4 or greater. Hemicholinium produced a small decrease of the contractions due to transmural stimulation in concentrations up to 1×10-4; concentrations of 5×10-4 present for 1 hr produced only a slightly greater reduction in response. These experiments show that when the guinea-pig vas deferens is removed without the hypogastric nerve and stimulated transmurally by the method described, contractions are produced mainly by excitation of postganglionic adrenergic nerves.

Abstract: 1. Conscious Long Evans rats, chronically instrumented for cardiovascular measurements, were challenged with i.v. bolus doses of glyceryl trinitrate (40 nmol kg-1), acetylcholine (1.2 nmol kg-1), bradykinin (3.2 nmol kg-1), or endothelin-1 (0.25 nmol kg-1). Under control conditions these doses produced similar falls in mean arterial blood pressure (glyceryl trinitrate, -20 +/- 3 mmHg; acetylcholine, -24 +/- 2 mmHg: bradykinin, -21 +/- 3 mmHg; endothelin-1, -25 +/- 3 mmHg), associated with renal, mesenteric and hindquarters vasodilatations (except for endothelin-1 which caused mesenteric vasoconstriction). 2. In the presence of NG-nitro-L-arginine methyl ester (L-NAME, 10 mgkg-1), a potent inhibitor of nitric oxide biosynthesis and endothelium-dependent vasorelaxation in vitro, the hypotensive responses to glyceryl trinitrate, acetylcholine, and endothelin-1 were increased, although that to bradykinin was not. However, comparing the differences between the response to glyceryl trinitrate and that to any other agonist in the absence and presence of L-NAME showed that there were relative attenuations of the hypotensive responses to bradykinin and endothelin-1, but not to acetylcholine, in the presence of L-NAME. 3. This comparative analysis showed that the renal and hindquarters vasodilator responses to bradykinin and endothelin-1 were attenuated in the presence of L-NAME, but the renal, mesenteric and hindquarters vasodilator responses to acetylcholine were not. However, when L-NAME was administered in the presence of pentolinium, captopril and the vasopressin V1-receptor antagonist, d(CH2)5[Tyr-(Et)]DAVP, (to abolish baroreflex and neurohumoral mechanisms), there was attenuation of the renal and mesenteric vasodilator effects of acetylcholine relative to those seen with glyceryl trinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)