Ma. Salas et al., Positive inotropic and negative lusitropic effect of angiotensin II: Intracellular mechanisms and second messengers, J MOL CEL C, 33(11), 2001, pp. 1957-1971
In the cat ventricle angiotensin H exerts a positive inotropic effect produ
ced by an increase in intracellular calcium associated with a prolongation
of relaxation. The signaling cascades involved in these effects as well as
the subcellular mechanisms of the negative lusitropic effect are still not
clearly defined. The present study was directed to investigate these issues
in cat papillary muscles and isolated myocytes. The functional suppression
of the sarcoplasmic reticulum (SR) with either 0.5 muM ryanodine or 0.5 mu
M ryanodine plus I um thapsigargin or the preincubation of the myocytes wit
h the specific inhibitor of the inositol 1,4,5-triphosphate (IP3) receptors
[diplienylborinic acid, ethanolamine ester (2-APB), 5-50 muM] did not prev
ent the positive inotropic effect and the increment in Ca2+ transient produ
ced by 1 muM angiotensin II. In contrast, protein kinase C (PKC) inhibitors
, chelerythrine (20 muM) and calphostin C (1 muM) completely inhibited both
, the angiotensin II-induced increase in L-type calcium current and positiv
e inotropic effect. The prolongation of half relaxation time produced by 0.
5 muM angiotensin II [207 +/- 15.4 msec (control) to 235 +/- 19.98 msec (an
giotensin H), P <0.05] was completely blunted by PKC inhibition. This antir
elaxant effect, which was independent of intracellular pH changes, was asso
ciated with a prolongation of the action potential duration and was preserv
ed after either the inhibition of the SR and the SR Ca(2+)ATPase (ryanodine
plus thapsigargin) or of the reverse mode of the Na+/Ca2+ exchanger (KB-R7
943, 5 muM). We conclude that in feline myocardium. the positive inotropic
and negative lusitropic effects of angiotensin H are both entirely mediated
by PKC without any significant participation of the IP3 limb of the phosph
atidyltnositol/phospholipase C cascade. The results suggest that the antire
laxant effect of angiotensin H might be determined by the decrease in Ca2efflux through the Na+/Ca2+ exchanger produced by the angiotensin H-induced
prolongation of the action potential duration. (C) 2001 Academic Press.