1 The effects of 5-hydroxytryptamine (5-HT) were studied in vitro on proximal and distal portions of canine interventricular and circumflex coronary arterial strips. 5-HT produced concentrationrelated contractions in the proximal portion whether contracted previously with KCl or not. These responses were still present after either chemical sympathetic denervation or release of noradrenaline induced by K+-free salt solution. In contrast, the distal portions of coronary arteries did not respond to 5-HT. 2 Concentration-response curves to 5-HT exhibited a classical hyperbolic shape with a calculated Hill-coefficient of approximately 1. 3 Methysergide and phentolamine but not morphine shifted to the right and depressed the maximum of the dose-response curves to 5-HT. 4 It is concluded that the contractions produced by 5-HT in the proximal portion of the interventricular and circumflex coronary arteries are not due to the release of endogenous noradrenaline. The vessels appear to possess separate receptors for 5-HT and noradrenaline and the 5-HT responses belong to neither the M nor the D type.

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Existing models used to study the mechanism of action and antagonism of tachykinergic effects on intestinal contraction and secretion suffer from technical problems and have not been fully characterized using specific tachykinin antagonists. Contraction of ileal segments by substance P, colonic circular muscle by beta-alanine-neurokinin A, and longitudinal muscle by senktide were used as models for neurokinin-induced contraction in the guinea-pig. Guinea-pig colonic epithelial tissue was stimulated by substance P and senktide to assess NK1- and NK3-mediated secretion. Using these models the potency of therapeutically useful compounds was determined. NK1 and NK2 activation directly contracted smooth muscle, while NK1-mediated secretion was nerve-mediated. NK3 stimulation of contraction and secretion was neurally mediated, involving cholinergic nerves and 5-HT release. NK1-mediated contraction and secretion were antagonized by SR140333 (pD'2 = 9.29 and pKb = 8.53); NK2-mediated contraction was antagonised by SR48968 (pD'2 = 8.35) and NK3-mediated contraction and secretion were antagonized by SB223412 (pKb = 8.97 and 8.79). The mixed antagonist MDL103392 blocked NK1- and NK2-mediated contraction with pKb values of 7.92 and 6.71 respectively and NK1-mediated secretion with a pKb value of 6.57. This data characterizes existing tachykinin antagonists, and should orientate the development of improved compounds as therapies for intestinal disease.

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