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Inflammation is a significant player in the progression of heart failure and has detrimental effects on cardiac function. Prostaglandin (PG)E2, a major proinflammatory prostanoid in the cardiovascular system, is a potent stimulus in inducing intracellular CAMP but minimally affects cardiac contractile function. Here, we show that the PGE2 stimulation attenuates the adrenergic-induced cardiac coiitractile response in animal hearts. Stimulation with PGE2 leads to stimulatory G protein (Gs)-dependent production of CAMP. However, the induced CAMP is spatially restricted because of its degradation by phosphodiesterase (PDE)4 and cannot access the intracellular sarcoplasmic reticulum (SR) for increasing calcium signaling and myocyte contraction. Moreover, pretreatment with PGE2 significantly inhibits PKA activities at the SR induced by a β-adrenergic agonist, isoproterenol, and subsequently blocks isoproterenol-induced PKA phosphorylation of phospholamban and contractile responses in myocytes. Further analysis reveals that the PGE2-induced cAMP/PKA is sufficient to phosphorylate and activate PDE4D isoforms, which, in turn, spatially inhibits the diffusion of adrenergic-induced CAMP from the plasma membrane to the SR. Inhibition of PDE4 rescues the adrenergic-induced increase in cAMP/PKA activities at the SR. PKA phosphorylation of phospholamban, and contractile responses in PGE2-pretreated myocytes. Thus, this offers an example that one Gs-coupled receptor is able to inhibit the intracellular signaling transduction initiated by another Gs-coupled receptor via controlling the diffusion of CAMP, presenting a paradigm for G protein-coupled receptor (GPCR) signal transduction. It also provides a mechanism for the integration of signaling initiated by different neurohormonal stimuli, as well as long-term effects of chronically circulating proinflammatory factors in myocardium. [ABSTRACT FROM AUTHOR]

Cardiac remodeling during heart failure development induces a significant increase in the activity of the L-type Ca2+ channel (Cav 1.2). However, the effects of enhanced Cav 1.2 activity on myocyte excitation-contraction (E-C) coupling, cardiac contractility, and its regulation by the β-adrenergic system are not clear. To recapitulate the increased Cavl.2 activity, a double transgenic (DTG) mouse model overexpressing the Cavβ2a subunit in a cardiac-specific and inducible 'manner was established. We studied cardiac (in vivo) and myocyte (in vitro) contractility at baseline and upon β-adrenergic stimulation. E-C coupling efficiency was evaluated in isolated myocytes as well. The following results were found: 1) in DTG myocytes, L-type Ca2+ current (∫CA.L) density, myocyte fractional shortening (FS), peak Ca2+ transients, and sarcoplasmic reticulum (SR) Ca2+ content (caffeineinduced Ca2+ transient peak) were significantly increased (by 100.8%, 48.8%, 49.8%, and 46.8%, respectively); and 2) cardiac contractility evaluated with echocardiography [ejection fraction (EF) and (FS)] and invasive intra-left ventricular pressure (maximum dPldt and -dP/dt) measurements were significantly greater in DTG mice than in control mice. However, I) the cardiac contractility (EF, FS, dPldr, and -dP/dt)-enhancing effect of the β-adrenergic agonist isoproterenol (2 μg/g body wt ip) was significantly reduced in DTG mice, which could be attributed to the loss of β-adrenergic stimulation on contraction, Ca2+ transients, ∫Ca.L, and SR Ca2+ content in DTG myocytes; and 2) E-C couping efficiency was significantly lower in DTG myocytes. In conclusion, increasing Cay 1.2 activity by promoting its high-activity mode enhances cardiac contractility but decreases E-C coupling efficiency and the adrenergic reserve of the heart. [ABSTRACT FROM AUTHOR]