Subcellular mechanisms of the positive inotropic effect of angiotensin II in cat myocardium.
1. Cat ventricular myocytes loaded with [Ca2+]i- and pHi-sensitive probes were used to examine the subcellular mechanism(s) of the Ang II-induced positive inotropic effect. Ang II (1 microM) produced parallel increases in contraction and Ca2+ transient amplitudes and a slowly developing intracellular alkalisation. Maximal increases in contraction amplitude and Ca2+ transient amplitude were 163 +/- 22 and 43 +/- 8 %, respectively, and occurred between 5 and 7 min after Ang II administration, whereas pHi 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 presence 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 extracellular [Ca2+] or by Ang II application produced similar increases in peak systolic Ca2+ indicating that an increase in myofilament responsiveness to Ca2+ does not participate in the Ang II-induced positive inotropic effect. 3. Ang II significantly increased the L-type Ca2+ current, as assessed by using 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 min 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 ryanodine 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 intracellular Ca2+ transient, an enhancement of the L-type Ca2+ current being the dominant mechanism underlying this increase.
Petroff
M G
MG
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Medicas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
Aiello
E A
EA
Palomeque
J
J
Salas
M A
MA
Mattiazzi
A
A
D000200:Action Potentials / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D004594:Electrophysiology; D005456:Fluorescent Dyes; D006321:Heart / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007211:Indoles; D008564:Membrane Potentials / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects*
D015220:Calcium Channels; D002316:Cardiotonic Agents; D005456:Fluorescent Dyes; D007211:Indoles; D019831:Sodium-Calcium Exchanger; D000804:Angiotensin II; C048960:indo-1