1 We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT, agonist), and sumatriptan (5-HTID-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT, ±2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HTID receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cycic monophosphate ([cyclic AMP]j) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]j) were determined and we assessed the degree of inherent tone in the vessels under study.2 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 + 0.1, 5.3 + 0.1, 5.0 + 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 + 0.2, 6.3 +0.2, 6.4 + 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4+0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +0.2; 5-CT, 5.4 +0.2). 5-CT also caused a contraction in the main pulmonary artery (pECmo: 6.0+0.3). 3 Ketanserin (1 nM-l gM) caused a competitive antagonism of the 5-HT response in all vessels tested.In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-l giM) inhibited responses to 5-HT in the first branch (estimated pKb value: 7.8) and main pulmonary artery. In CH rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contractions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pKb values of 7 and 9.5, respectively. In control animals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pKb values for GR55562 were 6.5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 6 The results suggest that the increased vasoconstrictor 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 r5-HTIB-like receptor-mediated contraction. An increase in vascular tone and decreased levels of [cyclic GMP]i in the large pulmonary arteries may contribute to...
