ANALYSIS OF THE 5-HT RECEPTORS MEDIATING CONTRACTIONS IN THE RABBIT ISOLATED RENAL-ARTERY

1 Using a number of agonist and antagonist compounds, we have attempted to characterize the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT) in the rabbit isolated renal artery. 2 In vessel segments precontracted with the thromboxane-mimetic agent, U46619 (100 nM), neither 5-HT (10(-8) to 10(-4) M) nor 5-carboxamidotryptamine (5-CT; 10(-8) to 3 x 10(-4) M) caused relaxations like those observed with methacholine. Both 5-HT and 5-CT further increased the tone of the vessels, with pD2 values of 7.1 and 7.9, respectively. 3 In the absence of U46619, both 5-HT (10(-7) to 3 x 10(-3) M) and 5-CT (10(-7) to 10(-3) M) contracted the rabbit renal artery, but with reduced potencies. The contractions to 5-HT were reproducible and the rank order of potency (pD2) of the agonists was: alpha-methyl-5-HT (5.7), sumatriptan (5.3), 5-HT (5.1), 8-hydroxy-2(di-n-propylamino)tetralin (5.0), 5-CT (4.7) and 5-methoxytryptamine (4.3). 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, flesinoxan and RU 24969 elicited either only small contractions or none at all. 4 The contractile effect of 5-HT was unaffected by MDL 72222 (10(-6) M) and metergoline (10(-8) and 10(-7) M), was weakly antagonized by ketanserin and phentolamine (pK(B):6.6 and 6.8, respectively), but was effectively antagonized by methiothepin (pK(B):8.6). Response to 5-CT and sumatriptan were affected by ketanserin, phentolamine and methiothepin similarly to 5-HT-induced responses. 5 Ketanserin was ineffective against noradrenaline-induced contractions, which were antagonized by phentolamine with a pK(B) of 7.3. The pK(B) values of phentolamine against 5-HT, 5-CT or sumatriptan were about half a log unit lower than against noradrenaline. 6 In vascular preparations treated with cocaine (3 x 10(-5) M), the potency (pK(B)) of phentolamine as an antagonist of the responses to noradrenaline (7.6) and 5-HT (6.7) did not differ significantly from the values in untreated preparations. However, the difference between the pK(B) values of phentolamine against the two agonists was now about one log unit. 7 Pretreatment of the vascular strips with 6-hydroxydopamine (1.5 x 10(-3) M) did not significantly affect responses to 5-HT or 5-CT, but almost eliminated those to tyramine. Cocaine (3 x 10(-5) M) slightly potentiated noradrenaline-induced contractions, but did not significantly affect those induced by 5-HT. 8 These data suggest that: (i) 5-HT receptors mediating vasodilatation are not present in the rabbit renal artery smooth muscle or endothelium; (ii) the contractile effect of 5-HT does not involve the release of noradrenaline from sympathetic nerve stores; (iii) the 5-HT receptor in the rabbit renal artery is not of the 5-HT2, 5-HT3 or 5-HT4 type. The pharmacological properties of this receptor most closely resemble those described for the heterogeneous 5-HT1-like category.