Effects of maturation and acute hypoxia on receptor-IP3 coupling in ovine common carotid arteries

Abstract

Whereas previous studies have established that many mechanisms mediating pharmacomechanical coupling are subject to regulation, evidence of physiological regulation of the coupling efficiency between receptor activation and second-messenger production is scarce. The present studies address the hypothesis that acute hypoxia and maturation can influence the mass of second-messenger production for each activated agonist-bound receptor (“receptor gain”). For this assessment, receptor density and agonist affinity values were used to calculate 5-hydroxytryptamine (5-HT) concentrations that would produce standardized numbers of bound receptors (8.5 fmol/mg protein) in each experimental group and thus minimize effects of age or hypoxia on receptor density or agonist affinity. After 3 min of exposure to these 5-HT concentrations, normoxic magnitudes of contraction were similar (as %potassium maxima) in fetal (50 ± 14%) and adult (40 ± 9%) arteries, but hypoxia (Po 2 ≈ 9–12 Torr for 30 min) depressed contractile tensions with a significantly different time course and magnitude in fetal (30 ± 10%) and adult (17 ± 11%) arteries ( P < 0.05). Basal inositol 1,4,5-trisphosphate (IP3) values (in pmol/mg protein) were significantly greater in fetal (94 ± 16) than in adult (44 ± 6) arteries, and integrated areas above baseline for the IP3 time courses (in nmol-s/mg protein) were significantly greater in fetal than in adult arteries both in normoxic (14.3 ± 1.8 vs. 9.1 ± 1.6) and hypoxic (15.0 ± 2.1 vs. 8.6 ± 1.2) conditions ( P < 0.05). Hypoxia altered the IP3 time courses both in the fetus and the adult but had no significant effect on IP3 mobilization or receptor gain. These data demonstrate that for the 5-HT2areceptor predominant in this preparation, receptor gain can be experimentally determined, is not influenced by acute hypoxia, but is greater in fetal than in adult ovine carotid arteries.