The present study demonstrates that cardiovascular adaptations to training are intensity-dependent. A close correlation between VO2max, cardiomyocyte dimensions and contractile capacity suggests significantly higher benefit with high intensity, whereas endothelial function appears equivalent at moderate levels. Thus, exercise intensity emerges as an important variable in future preclinical and clinical investigations.

Functional ventricular 5-HT(4) receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT(4) receptors of human failing heart and may play a pathophysiological role in heart failure.

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An NPR-B-cGMP-PDE3 inhibitory pathway enhances beta(1)-AR-mediated responses and may in the long term be detrimental to the failing heart through mechanisms similar to those operating during treatment with PDE3 inhibitors or during chronic beta-adrenergic stimulation.

Abstract-Cardiac responsiveness to neurohumoral stimulation is altered in congestive heart failure (CHF). In chronic CHF, the left ventricle has become sensitive to serotonin because of appearance of G s -coupled 5-HT 4 receptors. Whether this also occurs in acute CHF is unknown. Serotonin responsiveness may develop gradually or represent an early response to the insult. Furthermore, serotonin receptor expression could vary with progression of the disease. Postinfarction CHF was induced in male Wistar rats by coronary artery ligation with nonligated sham-operated rats as control. Contractility was measured in left ventricular papillary muscles and mRNA quantified by real-time reverse-transcription PCR. Myosin light chain-2 phosphorylation was determined by charged gel electrophoresis and Western blotting. Ca 2ϩ transients in CHF were measured in field stimulated fluo-4-loaded cardiomyocytes. A novel 5-HT 2A receptor-mediated inotropic response was detected in acute failing ventricle, accompanied by increased 5-HT 2A mRNA levels. Functionally, this receptor dominated over 5-HT 4 receptors that were also induced. The 5-HT 2A receptor-mediated inotropic response displayed a triphasic pattern, shaped by temporally different activation of Ca 2ϩ -calmodulin-dependent myosin light chain kinase, Rho-associated kinase and inhibitory protein kinase C, and was accompanied by increased myosin light chain-2 phosphorylation. Ca 2ϩ transients were slightly decreased by 5-HT 2A stimulation. The acute failing rat ventricle is, thus, dually regulated by serotonin through G q -coupled 5-HT 2A Key Words: serotonin Ⅲ heart failure Ⅲ 5-HT 2A receptor Ⅲ Ca 2ϩ -calmodulin-dependent myosin light chain kinase Ⅲ Rho-associated kinase D irect cardioexcitation by the neurotransmitter and vasoactive mediator serotonin (5-hydroxytryptamine [5-HT]) was believed until recently to be restricted to atria because of the lack of positive inotropic effects in nondiseased ventricular tissues from different species. 1,2 In contrast to previous reports, we recently discovered functional 5-HT 4 receptors and increased 5-HT 4 mRNA levels in chronic failing human and rat ventricle, demonstrating altered cardiac serotonin responsiveness in chronic heart failure. 3,4 Recent studies also demonstrated involvement of 5-HT 2B receptors in cardiac hypertrophy and failure, emphasizing the pathophysiological relevance of serotonin in cardiac disease. 5 An extensive acute myocardial infarction (MI) causes a substantial loss of viable myocardium within a few hours and leads to progressive cardiac dysfunction. Consequently, a variety of compensatory mechanisms are initiated, such as increased neurohumoral drive, hypertrophy, and possibly reactivation of fetal genes, to rescue myocardial function. 6 Heart failure is a progressive disease and gene expression, as well as phenotype, will be different at various stages. It is not known whether serotonin receptor expression increases gradually or is even higher in the acute phase. It is possible that the pattern of expre...