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

Abstract

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 μM) 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. 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. 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). 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. 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.

The increased angiotensin II (type 1) receptor density in myocardium of type 2 diabetic patients is prevented by blockade of the renin–angiotensin system

“…It is generally accepted that angiotensin II stimulation of the heart in vivo is largely dependent on high concentrations of angiotensin II produced by the local RAS. This may be one of the reasons why concentrations of angiotensin II used in the present and in previous studies for the stimulation of cardiac tissue in vitro [17][18][19] are significantly higher than the angiotensin II concentrations present in plasma.…”

“…Angiotensin II is known to be a strong positive inotropic agent in atrial and ventricular myocardium of different species [15][16][17]. The increase in FOC is mainly attributed to stimulation of the L-type Ca 2+ current secondary to activation of protein kinase C (PKC) [18,19]. Accordingly, upon stimulation with angiotensin II, we recorded a concentration-dependent increase in FOC in myocardium both from diabetic and from non-diabetic patients.…”

“…This prolonged relaxation was equally present in myocardium from diabetic and non-diabetic patients. The positive inotropic action of angiotensin II is mainly attributed to an enhancement of the L-type Ca 2+ current, secondary to the activation of PKC, and is probably independent of changes in pH i or changes in myofilament responsiveness to Ca 2+ [18,19]. The negative lusitropic action of angiotensin II has been well described in cat ventricular myocardium [19].…”

Hyperglycemia Inhibits Capacitative Calcium Entry and Hypertrophy in Neonatal Cardiomyocytes

“…Diabetes 51:3461-3467, 2002 A gonists such as angiotensin II (Ang II), endothelin 1, thrombin, and ␣-adrenergic agents influence cardiac physiology via signal transduction pathways involving activation of the G q heterotrimeric G protein complex and phosphoinositolspecific phospholipase C (PLC) (1). In addition to eliciting acute positive inotropic effects (2), this pathway is important over longer time periods to the development of compensatory cardiac hypertrophy (3), as well as to apoptosis and lethal cardiomyopathy (4).…”

Contractile recovery from acidosis in toad ventricle is independent of intracellular pH and relies upon Ca2+ influx

“…After 10·min, the myocytes were gently centrifuged for 2·min, diluted in Hepes buffer and stored at room temperature until use. pH i and cell length were monitored on the stage of a modified inverted microscope (Nikon Diaphot 200, Tokyo, Japan), as previously described (Vila-Petroff et al, 2000). After excitation at 530±5·nm, the ratio of SNARF-1/AM emission at 590±5·nm to that of 640±5·nm, was used as a measure of pH i , according to an in vivo calibration.…”