We tested a hypothesis that metabolism-contraction coupling in vascular smooth muscle is controlled by the rate of delivery of energy to
ATP-dependent reactions in the
inositol phospholipid transduction system that generate second messengers exerting control on smooth muscle force. Rabbit aorta was contracted by
norepinephrine (NOR) under conditions of normoxia and
hypoxia (bath PO2 less than 40 mmHg), and changes in
inositol phospholipid pool sizes and metabolic flux rates (JF) were determined. JF was determined by labeling free cytosolic myo-
inositol by incubation of unstimulated muscle with myo-[3H]
inositol and then measuring rates of incorporation of this
isotope into
inositol phospholipids and
inositol phosphates when the muscle was activated by NOR. JF measured during maintenance of NOR-induced force was markedly inhibited during
hypoxia to 40-50% of that determined during normoxia; rates of increases in
inositol phosphate radioactivities were similarly depressed during NOR activation under
hypoxia. The
hypoxia-induced decrease in JF was associated with four- to fivefold increase in
phosphatidylinositol 4-phosphate (PIP) total pool size, suggesting PIP
kinase was inhibited and rate limiting. Total pool sizes of
phosphatidylinositol,
phosphatidylinositol bisphosphate, and
phosphatidic acid were unchanged from values seen during activation under normoxia. These data suggest that activation of
inositol phospholipid metabolism, which generates
inositol 1,4,5-trisphosphate (IP3) and
diacylglycerol, is blunted under conditions where aerobic energy production is inhibited. Data are consistent with "rate-limiting" effects of decreased
ATP delivery, or decreased
phosphate potential, on PIP
kinase and reactions that control resynthesis of
phosphatidylinositol.