The role of inositol 1,4,5-trisphosphate (InsP3) 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 (approximately 140 days gestation) maintained at high altitude (3820 m; arterial PO2, 60 mmHg) from 30 days gestation. 2. Chronic hypoxia significantly decreased uterine artery contractile sensitivity in that pD2 (-logEC50) 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 (Bmax) 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 [3H]ketanserin, the agonist binding affinity (pKA, -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 InsP3 synthesis but decreased its potency in inducing InsP3 synthesis, with the pD2 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 InsP3 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 InsP3 synthesis was significantly decreased in chronically hypoxic compared with normoxic sheep (280 +/- 10 vs. 450 +/- 20 fmol InsP3 (fmol receptor)-1, P < 0.01). In addition, for a given amount of InsP3 generated, the contractile force of the uterine artery was significantly less in chronically hypoxic sheep (0.82 +/- 0.08 g tension (pmol InsP3)-1) than that in normoxic sheep (1.28 +/- 0.05 g tension (pmol InsP3)-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 InsP3 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.
