The receptor systems through which serotonin (5-HT), histamine, angiotensin II and endothelin increase the force of contraction were studied in isolated right atria from patients without apparent heart failure. All agonists increased the atrial force of contraction in a concentration-dependent manner; maximal effects, however, were significantly less than those evoked by isoprenaline or Ca2+. 5-HT and histamine, but not angiotensin II and endothelin, activated adenylate cyclase, whereas endothelin and angiotensin II stimulated inositol phosphate generation. Experiments with subtype-selective antagonists revealed that histamine effects were mediated by H2-receptors (sensitive to ranitidine), 5-HT-effects by 5-HT4-receptors (sensitive to SDZ 205-557) and angiotensin II effects by AT1-receptors (sensitive to losartan). We conclude that in human right atria the force of contraction can be increased by cyclic AMP-dependent (histamine, 5-HT) and -independent (angiotensin II, endothelin) pathways. Compared to beta-adrenoceptors, however, all other receptor systems increase the force of contraction only submaximally indicating that the beta-adrenoceptor pathway is the most important physiological mechanism to regulate force of contraction and/or heart rate in the human heart.
CPB with cardioplegic cardiac arrest decreases beta-adrenoceptor-mediated adenylate cyclase activation in a manner compatible with an uncoupling of beta-adrenoceptors from the Gs-protein-adenylate cyclase complex. Such a beta-adrenoceptor desensitization may be the reason why after CPB many patients need inotropic support but do not respond sufficiently to catecholamines.
In end-stage heart failure, cardiac beta-adrenoceptors are decreased and cardiac Gi protein is increased. We assessed beta-adrenoceptors, G proteins, and effects of several beta-adrenoceptor agonists, histamine, and 5-HT on adenylyl cyclase activity in right and left atria and left ventricles and on left ventricular contractility in six potential heart transplant donors (nonfailing hearts; NFHs) and in nine patients with end-stage dilated cardiomyopathy (DCM) and 11 patients with end-stage ischemic cardiomyopathy (ICM) to establish whether the functional responsiveness of all cardiac Gs-coupled receptors is reduced. Beta-adrenoceptors were reduced in all three tissues; in DCM, beta1-adrenoceptors were more markedly downregulated; in ICM, both beta1- and beta2-adrenoceptors were diminished. In all three tissues, isoprenaline-, terbutaline-, histamine- and 5-HT-induced adenylyl cyclase activation was reduced similarly in DCM and ICM. Moreover, in DCM and ICM, guanosine triphosphate (GTP)- (involving Gs and Gi) activated adenylyl cyclase was significantly diminished, whereas NaF-activated (involving only Gs) and Mn2+-activated (acting at the catalytic unit of the enzyme) adenylyl cyclase was unaltered. Left ventricular positive inotropic responses to beta1- (noradrenaline, dopamine, and dobutamine), beta2- (terbutaline), and beta1- and beta2-adrenoceptors (isoprenaline, adrenaline, and epinine), as well as H2-receptor (histamine) stimulation were significantly reduced. The extent of reduction was not different for each agonist in ICM and DCM. We conclude that in DCM and ICM, functional responsiveness of all cardiac Gs-coupled receptors is similarly reduced.
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