Acute hypoxia modulates 5-HT receptor density and agonist affinity in fetal and adult ovine carotid arteries

Abstract

In light of recent observations that receptor-ligand binding and coupling are physiologically regulated, the present study examined the hypothesis that the direct effects of hypoxia on vascular contractility involve modulation of pharmacomechanical coupling via changes in agonist affinity and/or receptor density. Because the direct effects of hypoxia on vascular smooth muscle contractility can vary with age, we carried out these experiments using both fetal and adult arteries. In common carotid arteries from near-term fetal and adult sheep, hypoxia (Po2 = 9-12 Torr for 30 min) reduced the maximum responses to potassium by 17.8 ± 3.5% (fetus) and 20.5 ± 2.2% (adult), significantly reduced the pD2 for 5-HT in the fetus (7.01 ± 0.1 to 6.3 ± 0.2) but not the adult (6.1 ± 0.1 to 6.0 ± 0.1), and significantly reduced 5-HT-induced maximum contractions (as % maximum response to 120 mM K+) not in the fetus (from 114 ± 7 to 70 ± 10%, not significant) but only in the adult (from 83 ± 15 to 25 ± 7%, P < 0.05) arteries. Hypoxia significantly attenuated 5-HT binding affinity (pK(A), determined by partial irreversible blockade with phenoxybenzamine) in both fetal (from 6.5 ± 0.2 to 6.0 ± 0.2) and adult arteries (from 6.2 ± 0.2 to 5.7 ± 0.1) and also decreased receptor density (fmol/mg protein, determined by competitive binding with ketanserin and mesulergine) in adult (from 18.3 ± 1.1 to 10.9 ± 1.0) but not in fetal (21.0 ± 1.0 to 23.2 ± 1.4) arteries. These results suggest that acute hypoxia modulates receptor-ligand binding via age-dependent modulation of agonist affinity and receptor density. These effects may contribute to hypoxic vasodilatation and help explain why the effects of hypoxia on vascular contractility differ between fetuses and adults.