The contractile state of the human heart is modulated by numerous G-protein coupled receptors including β-adrenoceptors and endothelin receptors. Both β1- and β2-adrenoceptors are localized throughout the heart including the sinus node, atrium, atrioventricular conducting system and ventricle. In failing hearts with idiopathic dilated cardiomyopathy or ischemic heart disease, the density of β1- and β2-adrenoceptors in the interatrial and ventricular septa and the atrioventricular conducting system was assessed. Sections (10 μm) were cut on a cryostat and labeled with (-)-[125I]cyanopindolol in the absence and presence of 70 nM ICI 118,551 to block β2-adrenoceptors or 100 nM CGP 20712A to block β1-adrenoceptors or 1 μM (-)-propranolol to block both β1- and β2-adrenoceptors. These studies revealed a lower density of β1-adrenoceptors in the bundle of His than in the atrioventricular node or interatrial and ventricular septa. On the otherhand there was a uniform distribution of β2-adrenoceptors throughout these regions. The sympathetic nervous system may have a greater modulatory effect on conduction in the atrioventricular node compared to the bundle of His due to different β1-adrenoceptor densities. In atrium and ventricle from failing and non-failing human hearts, activation of β1- or β2-adrenoceptors causes increases in contractile force, hastening of relaxation and cyclic AMP dependent protein kinase phosphorylation of proteins implicated in hastening of relaxation, phospholamban, troponin I and C-protein. These observations are consistent with coupling of both β1- and β2-adrenoceptors to stimulatory Gsα-protein. Human β1-adrenoceptors exist in multiple forms including ‘affinity states’ and polymorphisms. Activation by noradrenaline elicits powerful increases in contractile force and hastening of relaxation. These effects are blocked with high affinity by β-blockers including propranolol, (-)-pindolol, (-)-CGP12177 and carvedilol. Some β-blockers, typified by (-)-pindolol and (-)-CGP12177, not only block the receptor, but also activate it, but at much higher concentrations (~2 log-units) than those required to block the receptor. Abrogation of cardiostimulant effects of (-)-CGP12177 in β1-/β2-adrenoceptor double knockout mice but not β2-adrenoceptor knockout mice revealed an obligatory role of the β1-adrenoceptor. On the basis of these results, the β1-adrenoceptor is thought to exist in two ‘affinity states’, β1H- and β1L-adrenoceptor, where β1H-adrenoceptor is activated by noradrenaline and blocked with high affinity by β-blockers, and β1L-adrenoceptor is activated by drugs such as (-)-CGP12177 and blocked with low affinity by β-blockers such as (-)-propranolol. In human heart (-)-CGP12177 and (-)-pindolol cause increases in contractile force and hastening of relaxation. There are two common polymorphic locations of the β1-adrenoceptor, at amino acids 49 (Ser/Gly) and 389 (Gly/Arg). In the non-failing heart the cardiostimulant effects of noradrenaline at β1H-adrenoceptors and (-)-CGP12177 at β1L-adrenoceptors are conserved across β1-adrenoceptor polymorphisms. On the other hand, the effect of β-blockers in human heart failure may be determined by β1-adrenoceptor polymorphisms. Idiopathic cardiomyopathy patients receiving a maximal dose of carvedilol >1 year exhibit greater increases in left ventricular ejection fraction if they have Arg389 compared to patients carrying Gly389, P<0.05. In failing hearts, the density of ETA and ETB receptors in the interatrial and ventricular septa and the atrioventricular conducting system was assessed. Sections were cut on a cryostat and labeled with [125I]ET-1 in the absence and presence of 100 nM BQ123 to block ETA receptors or 200 nM BQ3020 to block ETB receptors or 1 μM ET-1 to block both ETA and ETB receptors. Both ETA and ETB receptors are located in the interatrial and interventricular septum, the atrioventricular node and the penetrating and branching bundles of His. There was a higher proportion of ETB receptors in the atrioventricular conducting system compared with surrounding atrial and ventricular myocardium. While these studies might predict a greater role or ETB receptors in the atrioventricular conducting system compared to surrounding atrial and ventricular myocardium, the role of ETA and ETB receptors in the human atrioventricular conducting system has however not been clarified, particularly in heart failure which is associated with elevated levels of the endogenous agonist, ET-1. On the otherhand it has been shown that ET-1 causes increases in contractile force in human atrium and ventricle.