Subcellular mechanisms of the positive inotropic effect of angiotensin II in cat myocardium

1. Cat ventricular myocytes loaded with [Ca2+](i)- and pH(i)-sensitive prob es were used to examine the subcellular mechanism(s) of the Ang II-induced positive inotropic effect. Ang II (1 muM) produced parallel increases in co ntraction and Ca2+ transient amplitudes and a slowly developing intracellul ar alkalisation. Maximal increases in contraction amplitude and Ca2+ transi ent amplitude were 163 +/- 22 and 43 +/- 8%, respectively, and occurred bet ween 5 and 7 min after Ang II administration, whereas pH(i) increase (0.06 +/- 0.03 pH units) became significant only 15 min after the addition of Ang II. Furthermore, the inotropic effect of Ang II was preserved in the prese nce of Na+-H+ exchanger blockade. These results indicate that the positive inotropic effect of Ang II is independent of changes in pHi. 2. Similar increases in contractility produced by either elevating extracel lular [Ca2+] or by Ang II application produced similar increases in peak sy stolic Ca2+ indicating; that an increase in myofilament responsiveness to C a2+ does not participate in the Ang II induced positive inotropic effect. 3. Ang II significantly increased the L-type Ca2+ current, as assessed by u sing the perforated patch-clamp technique (peak current recorded at 0 mV: - 1.88 +/- 0.16 pA pF(-1) in control vs. -3.03 +/- 0.20 pA pF(-1) after 6-8 m in of administration of Ang II to the bath solution). 4. The positive inotropic effect of Ang II was not modified in the presence of either KB-R7943, a specific blocker of the Na+-Ca2+ exchanger, or ryano dine plus thapsigargin, used to block the sarcoplasmic reticulum function. 5. The above results allow us to conclude that in the cat ventricle the Ang II-induced positive inotropic effect is due to an increase in the intracel lular Ca2+ transient, an enhancement of the L-type Ca2+ current being the d ominant mechanism underlying this increase.