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

In light of recent observations that receptor-ligand binding and coupling a re physiologically regulated, the present study examined the hypothesis tha t the direct effects of hypoxia on vascular contractility involve modulatio n of pharmacomechanical coupling via changes in agonist affinity and/or rec eptor density. Because the direct effects of hypoxia on vascular smooth mus cle contractility can vary with age, we carried out these experiments using both fetal and adult arteries. In common carotid arteries from near-term f etal and adult sheep, hypoxia (PO2 = 9-12 Torr for 30 min) reduced the maxi mum responses to potassium by 17.8 +/- 3.5% (fetus) and 20.5 +/- 2.2% (adul t), significantly reduced the pD(2) 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 significan tly 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) bu t only in the adult (from 83 +/- 15 to 25 +/- 7%, P < 0.05) arteries. Hypox ia significantly attenuated 5-HT binding affinity (pK(A), determined by par tial 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 compet itive 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. The se effects may contribute to hypoxic vasodilatation and help explain why th e effects of hypoxia on vascular contractility differ between fetuses and a dults.