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 (pKB: 6.6 and 6.8, respectively), but was effectively antagonized by methiothepin (pKB: 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 pKB of 7.3. The pKB 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- I M), the potency (pKB) 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 pKB 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- 3M) did not significantly affect responses to 5-HT or 5-CT, but almost eliminated those to tyramine. Cocaine (3 x 10- 5M) 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.