1. The role of inositol 1,4,5-trisphosphate (InsP(3)) in the reduced vascular responsiveness to 5-hydroxytryptamine (5-HT) caused by chronic hypoxia was examined in uterine arteries obtained from normoxic (control) and chronically hypoxic pregnant sheep (similar to 140 days gestation) maintained at high altitude (3820 m; arterial P-O2, 60 mmHg) from 30 days gestation. 2. Chronic hypoxia significantly decreased uterine artery contractile sensitivity in that pD(2) (-logEC(50)) for the contractile response to 5-HT was 7.19 +/- 0.15 and 6.62 +/- 0.12 (P < 0.05) in uterine arteries from normoxic and chronically hypoxic sheep, respectively. The intrinsic efficacy of the agonist was reduced by 75%. Although 5-HT2A receptor density (B-max) in the uterine artery was not changed in chronically hypoxic sheep compared with normoxic sheep (32.0 +/- 9.8 vs. 31.9 +/- 5.9 fmol (mg protein)(-1), respectively) as assessed from the saturation binding of [H-3]ketanserin, the agonist binding affinity (pK(A), -log of dissociation constant) was decreased from 6.25 +/- 0.07 in normoxic sheep to 5.85 +/- 0.08 in chronically hypoxic sheep (P < 0.05). 3. Chronic hypoxia did not change the time course of 5-HT-induced InsP(3) synthesis but decreased its potency in inducing InsP(3) synthesis, with the pD(2) being 6.09 +/- 0.11 and 5.51 +/- 0.08 (P < 0.05) in uterine arteries from normoxic and chronically hypoxic sheep, respectively. The maximal response of 5-HT-induced InsP33, generation in the uterine artery was decreased from 251.3 +/- 24.2 pmol(mg protein)(-1) in normoxic sheep to 146.6 +/- 11.3 pmol (mg protein)(-1) in chronically hypoxic sheep (P < 0.05). Furthermore, the ability of the activated 5-HT receptors to couple InsP(3), synthesis was significantly decreased in chronically hypoxic compared with normoxic sheep (280 +/- 10 vs. 450 +/- 20 fmol InsP(3), (fmol receptor)(-1), P < 0.01). In addition, for a given amount of InsP(3) generated, the contractile force of the uterine artery was significantly less in chronically hypoxic sheep (0.82 +/- 0.08 g tension (pmol InsP(3))(-1)) than that in normoxic sheep (1.28 +/- 0.05 g tension (pmol InsP(3))(-1)) (P < 0.05). 4. These results suggest that chronic hypoxia suppresses pharmacomechanical coupling of the ovine uterine artery by inhibiting the efficiency of receptor-effector-contraction coupling. This suppression of the InsP(3), pathway may play an important role in the adjustment of vascular tone and uterine blood flow in response to the stress of chronic hypoxia in late pregnancy.
