Effects of maturation and acute hypoxia on receptor-IP3coupling in ovine common carotid arteries

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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 (Po2≈ 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 IP3time 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 IP3time courses both in the fetus and the adult but had no significant effect on IP3mobilization 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.