On the Role of Cyclic Nucleotides in the Regulation of Cardiac Contractility and Glycolysis During Hypoxia *

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Abstract
A possible involvement of cyclic neucleotides (cAMP and cGMP) in the regulation of cardiac contractility and glycolysis during hypoxia was examined in spontaneously beating rat atria. A reduction of the high O2 saturation (HiOxSa) of the incubation medium from 95-100% to half produced a rapid decline of the amplitude. The deterioration of 50% was seen after 30 s of hypoxia. The decline was partly antagonized by noradrenaline [norepinephrine] (NA, 1 .times. 10-6 M) or hypercalcemia (5.7 .times. 10-3 M instead of 1.9 .times. 10-3 M). The cAMP level remained unchanged during the first 12 min of hypoxia, but the cGMP content increased gradually and reached a significantly increased level in 4-8 min. The production of lactate decreased after 30 s of hypoxia, but accelerated 2-4 min after the onset of hypoxia. The depletion of creatine phosphate and ATP stores was initiated after 2 min of hypoxia. The atrial content of the active forms of phosphofructokinase and lactate dehydrogenase gradually rose during hypoxia. Sodium nitroprusside (SNP, 1 .times. 10-4 M) and NA produced increases in cGMP and cAMP levels, respectively, in HiOxSa and hypoxia. SNP induced a slight and NA a marked increase in the amplitude in HiOxSa. Verapamil (1 .times. 10-6 M) decreased the contractility but did not affect the levels of cAMP or cGMP. SNP and verapamil decreased the lactate production, but they could not resist the NA-induced increase in the atrial lactate level. Hypercalcemia increased the amplitude but slightly reduced the lactate production in HiOxSa. 45Ca-uptake was reduced to .apprx. 35% of control as measured between 5-10 min of hypoxia. The lack of O2 could have direct and parallel effects on the sarcolemma and on the mitochondria. The former could result in the deterioration of contractility and the latter in the termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. At the low rate of anaerobic glycolysis, e.g. in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate the lactate production.