Cardiac and carotid vascular effects of 5-hydroxyttyptamine-related drugs in the pig

There exists now an extensive literature dealing with the nature of the 5-HT receptors involved in 5-Hf-induced cardiovascular effects. For example, 5-Hf-induced tachycardia is notoriously species-dependent and is mediated, directly or indirectly, either by 5-Hf,-like (cat), 5-Hf2 (rat, dog) or 5-Hf, (rabbit, dog) receptors, or by tyramine-like (guinea-pig) or unidentified mechanisms (pig, Helix aspersa) (see Saxena, 1986; Saxena and Villalon, 1990a; 1991). In marked contrast, little is known about the nature of the myocardial receptors involved in 5-Hf-induced positive inotropic effects (Kaumann et al., 1990a,b ). Therefore, Chapters 7 and 8 of the present thesis deal with the mechanism(s) and characteriaation of the 5-Hf receptor type involved in the positive chronotropic effects induced by 5-Hf and some indole- and benzamide derivatives in the pentobarbitone anaesthetized pig, whereas in Chapter 9 an attempt was made to delioeate the receptor involved in the positive inotropic effect by 5-Hf in the same species. On the other hand, it is has been demonstrated that 5-Hf,-like receptors mediate hoth the constriction of porcine cephalic arteriovenous anastomoses and the dilatation of arterioles induced by 5-Hf and some 5-Hf,-like receptor agonists, including the antimigraine drug sumatriptan (Saxena et al., 1989; Saxena and Villalon, 1990a; Den Boer et al., 1991); however, it has not yet been fully identified which specific 5-Hf, receptor subtype (5-HflA, 5-Hf16, 5-Hf1c or 5-Hf10) is involved in such effects (Born et al., 1989a,b; Saxena and Villalon, 1990a). For this reason in Chapter 10 of this dissertation we have further attempted to study the possible involvement of 5-Hf lA• 5-Hf,., 5-Hf1c and/or 5-Hf10 receptors in the distribution of common carotid artery blood flow into arteriolar (nutrient) and arteriovenous anastomotic (non-nutrient) parts in the pig by using indorenate~ a tryptamine derivative with antihypenensive properties (Hong et al., 1978; Hong, 1981) as well as a high affinity for the 5-Hf 1A binding site (Dompert et al., 1985; Hoyer et al., 1985). Ketanserin. methiothepin and metergolioe were used as potential antagonists. Finally, in view of the involvement of cranial arteriovenous anastomoses constriction as a possible mechaoism for antirnigraine action (see Saxena and Ferrari, 1989). the last part of the present dissertation is devoted to the analysis of the effects of dihydroergotamine (an established antimigraine drug). and S9977 (a potential antimigraine drug) on the distribution of the porcine total common carotid artery blood flow (Chapter 11), and accordingly, highligbts the possible mechanisms that migbt explain the action of the antimigraine drugs