DISSOCIATION BETWEEN POSITIVE INOTROPIC AND ALKALINIZING EFFECTS OF ANGIOTENSIN-II IN FELINE MYOCARDIUM

The present study examines the intracellular pH (pH(i)) dependence of angiotensin (ANG) II-induced positive inotropic effect in cat papillar y muscles contracting isometrically (0.2 Hz, 30 degrees C). Muscles we re loaded with the fluorescent dye 2'-7'-bis(2-carboxyethyl)-5(6)-carb oxyfluorescein acetoxymethyl ester for simultaneous measurement of pH( i) and contractility. In N-2-hydroxyethylpiperazine-N'-2-ethanesulfoni c acid (HEPES) buffer (n = 4), there was a temporal dissociation betwe en the positive inotropic and the alkalinizing effects of ANG II (0.5 mu M) The positive inotropic effect of ANG II peaked at 9.7 +/- 0.8 mi n (240 +/- 57% above control) without significant changes in pH(i), Th e increase in pH(i) became significant (0.05 +/- 0.01 pH units) only a fter 16 min of exposure to the drug, when the positive inotropic effec t of ANG II was already fading. In HCO, buffer (n = 7), the ANG II-ind uced positive inotropic effect occurred without significant pH(i) chan ges. In the presence of 5 mu M ethyl isopropyl amiloride (EIPA, to spe cifically inhibit the Na+/H+ exchanger), the alkalinizing effect of AN G II was changed to a significant decrease in pH(i), despite which ANG II still increased contractility by 87 +/- 16% (n = 6). The results i ndicate that in HEPES buffer only a fraction of the ANG II-induced pos itive inotropic effect can be attributed to a pH(i) change, whereas in a physiological CO2-HCO3- medium the positive inotropic effect of ANG II is independent of pH(i) changes. Furthermore, an ANG II-induced in crease in myocardial contractility was observed even when ANG II admin istration elicited a decrease in pH(i), as occurred after Na+/H+ excha nger blockade. The results show that in feline myocardium, the increas e in contractility evoked by ANG II in a physiological CO2-HCO3- mediu m is not due to an increase in Ca2+ myofilament sensitivity secondary to an increase in myocardial pH(i).