Effects of low-flow ischemia on the positive inotropic action of angiotensin II in isolated rabbit and rat hearts.
OBJECTIVE
Angiotensin II (ANG II) has recently been reported to increase inotropy in adult rabbit myocytes by a mechanism of alkalinization and consequent increased myofilament sensitivity to calcium. Accordingly, we tested the hypothesis that ANG II would have a greater inotropic effect during ischemic conditions than it would during normoxia, since ischemia-induced intracellular acidosis contributes to ischemic contractile depression by decreasing myofilament calcium sensitivity.


METHODS
We studied the effects of ANG II in isolated, red-blood-cell-perfused, isovolumic rat and rabbit hearts during normoxic perfusion conditions and at graded reductions in coronary perfusion pressure (CPP). At each level of perfusion, ANG II was infused at progressively increasing concentrations ranging from 10(-11) to 10(-5) M. The maximal effective ANG II concentration was 10(-7) M.


RESULTS
Our studies show that ANG II caused comparable absolute increases in isovolumic LV developed pressure in normoperfused and hypoperfused rabbit hearts. However, since contractile function was markedly depressed in ischemic hearts prior to ANG II administration, the relative inotropic response to ANG II was significantly greater during ischemia than normoxia. Similarly, ANG II had no positive inotropic effect in the rat during normoxia, but increased contractility during ischemia. To assess specifically the potential of ANG II to reverse the negative inotropy of acidosis, normoxic non-ischemic rat hearts were perfused with a hypercarbic acidotic perfusate (pH = 7.1). During the hypercarbic perfusion when contraction was depressed by acidosis, ANG II [10(-7)]M increased LV developed pressure by 19% and +dP/dt by 27% (P < 0.05), in contrast to its lack of intropic effect at a normal pH. The positive inotropic effect observed in rat hearts with ANG II during ischemia was significantly attenuated (P < 0.001) by concomitant infusion with amiloride, 5-(N-ethyl-N-isopropyl) (EIPA), a Na+/H+ exchange inhibitor.


CONCLUSIONS
We conclude that during normoxia, ANG II has a different inotropic potency in rabbits from that in rats. In both species, the relative inotropic responsiveness of ANG II is potentiated during low-flow ischemia. These results are consistent with a relative intracellular alkalinization that occurs secondary to ANG II's action to stimulate Na+/H+ exchange.
Libonati
J R
JR
Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, MA 02118, USA.
Eberli
F R
FR
Sesselberg
H W
HW
Apstein
C S
CS
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006321:Heart / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000503:physiopathology*; D010477:Perfusion; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013268:Stimulation, Chemical; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D017725:Ventricular Pressure / Q000187:drug effects
D014662:Vasoconstrictor Agents; D000804:Angiotensin II