Increased contractile response to 5‐hydroxytryptamine1‐receptor stimulation in pulmonary arteries from chronic hypoxic rats: role of pharmacological synergy

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Abstract
5‐Hydroxytryptamine (5‐HT)1‐receptor‐induced contraction is enhanced, or uncovered, by elevated vascular tone in many arteries including pulmonary arteries. In hypoxia‐induced pulmonary hypertension, the endogenous tone of pulmonary arteries is elevated and this may contribute to increased 5‐HT1‐receptor‐induced contraction. Here we investigate the influence of vascular tone induced by endothelin‐1 (ET‐1), neuropeptide Y (NPY), KCl, 4‐aminopyridine (inactivator of Kv channels, 4‐AP) or the calcium ionophore A23187 on contractile responses to the 5‐HT1‐receptor agonist 5‐carboxamidotryptamine (5‐CT) in small muscular pulmonary arteries from control rats and rats exposed to chronic hypoxia. The influence of the nitric oxide synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) was also studied. These conditions were chosen to mimic those that influence pulmonary vascular tone in hypoxia‐induced pulmonary hypertension. In control rat small pulmonary arteries, only high concentrations of 5‐CT (>1 μM) induced vasoconstriction. Tone induced by NPY, 4‐AP and A23187 had no effect on responses to 5‐CT whilst responses to 5‐CT were increased by ET‐1‐ and KCl‐induced tone. In the presence of L‐NAME these responses to 5‐CT were enhanced further. Responses to 5‐CT were enhanced 3 – 4 fold in small pulmonary arteries from hypoxia‐exposed, pulmonary hypertensive rats and neither L‐NAME nor increasing tone with NPY, 4‐AP, A23187, ET‐1 or KCl had any further effect on responses to 5‐CT. The results suggest that inhibition of nitric oxide synthase combined with KCl‐ or ET‐1‐induced vascular tone potentiates responses to 5‐HT1‐receptor‐induced contraction in pulmonary arteries in a synergistic fashion and this mimics the effects of chronic hypoxic exposure. British Journal of Pharmacology (2001) 134, 614–620; doi:10.1038/sj.bjp.0704273

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