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

Abstract

1. 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-HT(1)-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 K(v) channels, 4-AP) or the calcium ionophore A23187 on contractile responses to the 5-HT(1)-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 N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM) was also studied. These conditions were chosen to mimic those that influence pulmonary vascular tone in hypoxia-induced pulmonary hypertension. 2. In control rat small pulmonary arteries, only high concentrations of 5-CT (>1 microM) 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. 3. 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. 4. The results suggest that inhibition of nitric oxide synthase combined with KCl- or ET-1-induced vascular tone potentiates responses to 5-HT(1)-receptor-induced contraction in pulmonary arteries in a synergistic fashion and this mimics the effects of chronic hypoxic exposure.

Figure 1

Effect of increasing vascular tone with neuropeptide Y (NPY, n=6), 4-amidopyridine (4-AP, n=6), the calcium ionophore A23187 (n=6) and the nitric oxide synthase inhibitor N^ω-nitro-L-arginine methyl ester (L-NAME, 100 μM, n=7) on contractile responses to 5-carboxamidotryptamine (5-CT, control: n=12) in control rat isolated small muscular pulmonary arteries. Responses are shown as the percentage response to a contraction to 50 mM KCl. Data is shown as means±s.e.mean. n=number of rats.

Figure 2

Effect of increasing vascular tone with endothelin-1 (ET-1, n=8) and KCl (n=9), ET-1 plus the nitric oxide synthase inhibitor N^ω-nitro-L-arginine methyl ester (L-NAME, 100 μM, n=6) and KCl plus L-NAME (n=8) on contractile responses to 5-carboxamidotryptamine (5-CT, control: n=12) in control rat isolated small muscular pulmonary arteries. Responses are shown as the percentage response of a contraction to 50 mM KCl. Data is shown as means±s.e.mean. n=number of rats. Control data shown is as for Figure 1.

Figure 3

Responses to 5-carboxamidotryptamine (5-CT) in control (n=12) and chronic hypoxic (n=6) rat isolated small muscular pulmonary arteries. Responses are shown as the percentage response of a contraction to 50 mM KCl. Data is shown as means±s.e.mean. n=number of rats.

Figure 4

Effect of increasing vascular tone with the nitric oxide synthase inhibitor N^ω-nitro-L-arginine methyl ester (L-NAME, 100 μM, n=6), endothelin-1 (ET-1, in the presence (n=6) and absence (n=6) of L-NAME), KCl (in the presence (n=6) and absence (n=6) of L-NAME) on contractile responses to 5-carboxamidotryptamine (5-CT, control: n=6) in chronic hypoxic rat isolated small muscular pulmonary arteries. Responses are shown as the percentage response of a contraction to 50 mM KCl. Data is shown as means±s.e.mean. n=6 rats. Control data shown is as for Figure 3.