5-HYDROXYTRYPTAMINE RECEPTORS MEDIATING VASOCONSTRICTION IN PULMONARY-ARTERIES FROM CONTROL AND PULMONARY HYPERTENSIVE RATS

1 We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasocon striction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile resp onses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agon ist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1+2-receptor antagonist) a nd ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel select ive 5-HT1D receptor antagonist) on 5-HT-mediated responses were also s tudied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP](i)) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP](i)) we re determined and we assessed the degree of inherent tone in the vesse ls under study. 2 5-HT was most potent in the resistance arteries. pEC (50) values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistan ce arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum respo nse of, 5-HT was increased in all the arteries removed from the chroni c hypoxic (CH) rats. In CH rats the pEC(50) values were 5.9 +/- 0.2, 6 .3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 3 5%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vesse l from the control rats whilst 5-CT did contract the resistance arteri es. In the CH rats, however, they both contracted the resistance arter ies (responses to sumatriptan were small) (pEC(50): 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC(50): sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmon ary artery (pEC(50): 6.0 +/- 0.3). 3 Ketanserin (1 nM-1 mu M) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pK(b) values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-1 mu M) inhibited responses to 5-HT in the first branch (estimated pK(b) value: 7.8) and main pulm onary artery. In CH rats, the estimated pK(b) values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery wer e 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contract ions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pK(b) values of 7 and 9.5, respectively. In control ani mals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pK(b) values for GR55562 were 6. 5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 4 Large pulmonary arteries from c ontrols demonstrated inherent tone and this was increased three fold i n the CH rats. The resistance arteries from controls demonstrated litt le inherent tone though this was enhanced in those from the CH rats. 5 [Cyclic AMP](i) was 259 +/- 23 pmol mg(-1) protein in the pulmonary a rtery branches removed from control rats and decreased to 192 +/- 11 p ml mg(-1) protein in the CH rats (P < 0.01, n = 8). [Cyclic GMP](i) al so decreased in the pulmonary artery branches (from 550 +/- 15, contro l to 462 +/- 31 pmol mg(-1) protein in CH vessels, n = 8, P < 0.01) an d in the main pulmonary arteries (from 566 +/- 33, control to 370 +/- 25 pmol mg(-1) protein in CH vessels, n = 8, P < 0.001). No changes in either [cyclic AMP](i) or [cyclic GMP](i) were observed in the resist ance arteries. 6 The results suggest that the increased vasoconstricto r response to 5-HT in CH rat pulmonary arteries is due to an increase in 5-HT2A-receptor mediated contraction combined with an increase in r 5-HT1B-like receptor-mediated contraction. An increase in vascular ton e and decreased levels of [cyclic GMP](i) in the large pulmonary arter ies may contribute to the observed increase in activity of r5-HT1B-lik e receptors.