HYPOXIC PH(I) AND FUNCTION MODULATION BY NA+ H+ EXCHANGE AND ALPHA-ADRENOCEPTOR INHIBITION IN HEART IN-VIVO/

Regulation of intracellular pH (pH(i)) may contribute to maintenance o f cardiac contractile function during graded hypoxia in vivo. To test this hypothesis, we disturbed pH(i) regulation in vivo using two appro aches: alpha-adrenoreceptor antagonism with phentolamine (1 mg/kg) (Ph en; n = 9); and Na+/H+ exchange inhibition with HOE-642 (2 mg/kg; n = 6) before graded hypoxia in open-chest sheep. Hemodynamic parameters i ncluding left ventricular maximal pressure development (dP/dt(max)) ca rdiac index (CI), and left ventricular power were monitored continuous ly and simultaneously with high-energy phosphate levels and pH(i), mea sured with P-31 nuclear magnetic resonance spectroscopy in Phen, HOE-6 42, and control (Con; n = 9). In subgroups (n = 6) in Con and Phen, co ronary flow, myocardial oxygen consumption (M(V) over dotO(2)), and la ctate uptake were also measured. During hypoxia, the functional parame ters left ventricular dP/dt(max), CI, and left ventricular power decre ased significantly compared with baseline and Con values. These decrea ses were preceded by a significant drop (P < 0.05) in pH(i) from 7.10 +/- 0.04 to 6.69 +/- 0.05 in Phen and corresponded temporally to a pH( i) drop from 7.10 +/- 0.02 to 6.77 +/- 0.03 in HOE-642. Decreases in p H(i) in Phen were not preceded by decreases in cardiac function or M(V ) over dotO(2). In contrast, cardiac function parameters increased sig nificantly in Con, whereas no significant pH(i) decrease occurred (7.0 7 +/- 0.03 to 6.98 +/- 0.04). We conclude that these data indicate tha t pH(i) regulation can be disrupted through alpha-adrenergic antagonis m or Na+/H+-exchange inhibition in vivo. These studies demonstrate tha t pH(i) regulation performs a role in the modulation of cardiac functi on during hypoxia in vivo.