In end-stage heart failure, no significant change of I(f) could be found, although there was a trend toward increased I(f). Together with an elevated plasma norepinephrine concentration and a previously reported reduction in I(K1) in human heart failure, I(f) might favor diastolic depolarization in individual myopathic cells.

The increased expression of the Na(+)-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na(+)-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.

1 Clinical studies have shown di erent e ects of b-blockers on the b-adrenergic system, tolerability and outcome in patients with heart failure. 2 The study examines b-adrenoceptor-G-protein coupling and intrinsic activity of bucindolol, carvedilol and metoprolol in human ventricular myocardium. 3 Radioligand binding studies ([ 125 I]-Iodocyanopindolol) were performed in membrane preparations of human failing and nonfailing myocardium. Functional experiments were carried out in isolated muscle preparations of human left ventricular myocardium from failing hearts. 4 Bucindolol and carvedilol bound non-selectively to b 1 -and b 2 -adrenoceptors and exerted guanine nucleotide modulatable binding. Metoprolol was 35-fold b 1 -selective and lacked guanine nucleotide modulatable binding. 5 All b-blockers antagonized isoprenaline-induced enhancement of contractility. 6 In preparations in which the coupling of the stimulatory G-protein to adenylate cyclase was facilitated by forskolin, bucindolol increased force of contraction in three and decreased it in ®ve experiments. Carvedilol increased force in one and decreased it in six experiments. Metoprolol decreased force in all experiments by 89.4+2.2% (P50.01 metoprolol vs carvedilol and bucindolol). The negative inotropic e ect of metoprolol was antagonized by bucindolol. 7 It is concluded that di erences in intrinsic activity can be detected in human myocardium and have an impact on cardiac contractility. In human ventricular myocardium, bucindolol displays substantially higher intrinsic activity than metoprolol and carvedilol. Bucindolol can behave as partial agonist or partial inverse agonist depending on the examined tissue. 8 Di erences in intrinsic activity may contribute to di erences in b-adrenoceptor regulation and possibly to di erences in tolerability and outcomes of patients with heart failure.

Background-The pacemaker current I f is present in atrial and ventricular myocytes. However, it remains controversial whether I f overexpression in diseased states might play a role for arrhythmogenesis, because first I f activation in whole-cell recordings hardly overlapped the diastolic voltage of working myocardium.

OH. radicals induce an impairment of contraction and relaxation and an attenuation of the force-frequency relationship in human myocardium accompanied by an inhibition of SERCA. Carvedilol and BM-910228 partly prevented OH.-induced contractile dysfunction. These observations could explain the improvement of ejection fraction in heart failure trials with carvedilol without a restoration of beta-adrenergic receptor density.