Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Abstract

1 The cardiostimulant effects of CGP12177, mediated through a b 1 -adrenoceptor site with low affinity for (À)-propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4-selective inhibitor rolipram (1 mM) on the positive inotropic and cyclic AMPenhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat. 2 CGP12177 (under (À)-propranolol 200 nM) only increased contractile force in the presence of either cilostamide or rolipram with ÀlogEC 50 M 6.7 (E max ¼ 23% over basal) and 7.1 (E max ¼ 50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with ÀlogEC 50 M ¼ 7.7 and E max ¼ 178%. 3 The positive inotropic effects of noradrenaline (ÀlogEC 50 M ¼ 6.9) were potentiated by rolipram (ÀlogEC 50 M ¼ 7.4) but not by cilostamide (ÀlogEC 50 M ¼ 7.0). 4 In the presence of rolipram and (À)-propranolol, noradrenaline (2 mM) and CGP12177 (10 mM) produced matching inotropic effects but failed to increase cyclic AMP levels. 20 mM (À)-noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram. 5 Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low-affinity b 1 -adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (À)-noradrenaline interacts with the b 1 -adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.

Phosphodiesterase‐4 blunts inotropism and arrhythmias but not sinoatrial tachycardia of (−)‐adrenaline mediated through mouse cardiac β1‐adrenoceptors

“…(1995) in rat myocardium is also in agreement with work on murine hearts, because activation of β 2 ‐adrenoceptor, at low agonist concentrations that cause positive inotropic and lusitropic effects in neonatal cardiomyocytes, is lost in adult myocytes. In the adult rat, the ventricular inotropic responses to (−)‐noradrenaline, mediated through β 1 ‐adrenoceptors, are potentiated by rolipram but not by cilostamide ( Vargas et al , 2006 ), findings compatible with our present work using (−)‐adrenaline in adult murine right ventricle and left atrium.…”

“…Cumulative concentration–effect curves for (−)‐adrenaline were carried out in the absence and presence of the PDE3 inhibitor cilostamide (300 n M ) or PDE4 inhibitor rolipram (1 μ M ) ( Vargas et al , 2006 ), followed by the administration of a saturating concentration of (−)‐isoprenaline (200 μ M ). For inotropic studies, the experiments were terminated by elevating the CaCl 2 concentration to 9 m M as shown in representative experiments for left atrium (Figure 1) and right ventricular wall (Figure 2).…”

“…To elucidate whether the activity of PDE3 and/or PDE4 prevent the manifestation of cardiostimulation through murine β 2 ‐adrenoceptor, we investigated the effects of the PDE3 inhibitor cilostamide and PDE4 inhibitor rolipram ( Vargas et al , 2006 ) on the responses to (−)‐adrenaline under conditions of β 1 ‐adrenoceptor blockade in murine cardiac tissues. To investigate whether there are regional differences in the roles of PDE3 and PDE4, we first studied the effects of the PDE inhibitors on the responses to (−)‐adrenaline, mediated through β 1 ‐adrenoceptor in three cardiac regions: sinoatrial node, left atrium and right ventricle.…”

Differential regulation of β2‐adrenoceptor‐mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non‐failing rat cardiac ventricle

“…Thus, PDE3 and PDE4 play prominent roles in the functional limitation of the cardiac b2-adrenoceptor signals. In the present study, the b1-adrenoceptor-mediated PIR was also found to be regulated by both PDE3 and PDE4, which is different from the findings by others that only PDE4 played such a role in non-failing mouse and rat right ventricle (Vargas et al 2006;Galindo-Tovar and Kaumann, 2008) and left ventricle (Christ et al, 2009). Interestingly, another study reported an increase in the inotropic potency of isoprenaline in non-failing rat right ventricle during PDE4 inhibition but not during PDE3 inhibition by 10 mM milrinone (Katano and Endoh, 1992), a concentration which inhibits approximately 97% of PDE3 (Shakur et al, 2002).…”

Increased spontaneous activity and reduced inotropic response to catecholamines in ventricular myocytes from footshock-stressed rats

“…This speculation is based on the observation that the development of catecholamine-dependent automatism at both rest and pacing in FS myocytes was similar to that observed in control cells exposed to b 2 -AR blockers, and that b 2 -AR antagonism failed to further enhance automatic responses in the FS group. It has been shown that PDE4 strongly modulates the inotropic response to b 1 -AR activation in rodent ventricle, and that its inhibition potentiates catecholamine-induced contractile and spontaneous activity (Vargas et al 2006;Galindo-Tovar and Kaumann 2008). Moreover, we were able to reproduce in control cells the qualitative changes in the magnitude of the responses to ISO seen in FS group myocytes by either b 2 -AR blockade or PDE inhibition with caffeine.…”