Angiotensin II increases spontaneous contractile frequency and stimulates calcium current in cultured neonatal rat heart myocytes: insights into the underlying biochemical mechanisms.

Abstract

The effect of angiotensin II on cultured neonatal rat heart myocytes was studied by measuring changes in cell length, the magnitude and kinetics of the calcium current, and changes in cyclic adenosine 3',5'-monophosphate (cAMP) and phosphoinositide metabolism. Spontaneous beating frequency of multicellular networks was increased by angiotensin II with a maximal increase of 100% above control values at concentrations of 5 nM or greater. The half-maximal response occurred at 0.6 nM angiotensin II. Shortening amplitude, shortening velocity, and relaxation velocity decreased concomitantly with the increasing contractile rate. In voltage-clamped single myocytes, both steady-state and transient components of the calcium current were increased by the addition of angiotensin II. Angiotensin II had no effect on either control or isoproterenol-stimulated adenylate cyclase activity in myocyte membranes. Neither the basal levels nor the isoproterenol-stimulated cAMP accumulation in intact cells was affected by addition of hormone. In myocytes labeled with [3H]inositol, angiotensin II stimulated the formation of [3H]inositol phosphates. One minute after addition of 5 nM angiotensin II, inositol monophosphate and inositol bisphosphate levels were increased to 73% and 99%, respectively, above control values and remained elevated at 10 minutes. Inositol trisphosphate levels were not significantly different from control values at either time point. Nifedipine (10 microM) had no effect on angiotensin II-induced increases in [3H]inositol phosphates. We conclude that the increases in both spontaneous beating rate and calcium current in angiotensin II-stimulated cultured neonatal heart cells are not dependent on cAMP or inositol trisphosphate levels but may involve sustained phosphoinositide hydrolysis.

Direct positive chronotropic effects of angiotensin II and angiotensin III in pithed rats and in rat isolated atria

“…It has also been found (Allen et al, 1988) that All increases the spontaneous contractile frequency in cultured heart myocytes from neonatal rats. The rat heart contains a high concentration of All-binding sites in the presynaptic neurones and in the conducting system, as substantiated by recent radioligand binding studies (Sechi et al, 1992;Saavedra et al, 1993).…”

Left ventricular insulin-like growth factor I increases in early renal hypertension.

“…The circulating levels of angiotensin II increase in early renal hypertension, and in addition, angiotensin II has been shown to increase cardiac contractility and contractile frequency in cultured myocytes. 38 Moreover, angiotensin II possesses hypertrophic properties in cultured neonatal chick heart cells, 3 but in myocytes from adult rats, no stimulatory effect on protein synthesis could be detected in response to angiotensin II. 36 This discrepancy may be attributed to the fact that angiotensin II receptors in adult rat hearts are mainly confined to the conduction system and are virtually absent in ventricular myocytes.…”

Effects of captopril on membrane current and contraction in single ventricular myocytes from guinea‐pig

“…We may rule out the possibility that inhibition of nearonal catecholamine release is involved since isolated myocytes are effectively denervated (Dow et al, 1981) and the effects of the drug on the activation variable are not those which would be expected from reversal of /-adrenoceptor stimulation (Cohen & Lederer, 1987). Angiotensin II increases the calcium current in neonatal rat ventricular myocytes (Allen et al, 1987). Could the drug be inhibiting endogenous angiotensin II synthesis, which has been demonstrated to occur in cardiac muscle (Nakashima et al, 1982)?…”