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 n m ), neither 5‐HT (10 −8 to 10 −4 m ) nor 5‐carboxamidotryptamine (5‐CT; 10 −8 to 3 × 10 −4 m ) caused relaxations like those observed with methacholine. Both 5‐HT and 5‐CT further increased the tone of the vessels, with pD 2 values of 7.1 and 7.9, respectively. 3 In the absence of U46619, both 5‐HT (10 −7 to 3 × 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 (pD 2 ) of the agonists was: α‐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). Responses 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 × 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 × 10 −3 m ) did not significantly affect responses to 5‐HT or 5‐CT, but almost eliminated those to tyramine. Cocaine (3 × 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‐HT 2 , 5‐HT 3 or 5‐HT 4 type. The pharmacological properties of this receptor most closely resemble those described for the heterogeneous 5‐HT 1 ‐like category.