clinicaltrials.gov Identifier: NCT00091637.

The different findings regarding the presence of apoptotic cells suggest a contribution of pathobiological pathways in the patients with DM to the underlying heart disease.

In isolated papillary muscles of cats the changes in Ca inward current and isometric contractile force following a decrease of extracellular pH from 7.4 to 5.5 were studied. The Ca current was analyzed (a) by measuring the upstroke velocity of Ca-mediated action potentials and (b) in voltage clamp experiments using the double sucrose gap technique. 1. At a pH of 5.5 the upstroke velocity of the Ca-mediated action potential decreased to 65% of the control, while overshoot and action potential duration remained almost unchanged. Furthermore, the relative refractory period was prolonged and in some cases, a "Wenckebach-like" phenomenon occurred. In voltage clamp experiments, the slow inward current was found to be diminished to 50-60% of the initial control value and over a broad voltage range the current voltage relationship curve was shifted to weaker currents. Acidosis did not influence the steady state inactivation but altered the kinetics of inactivation of the slow inward current and induced an increase of tauinactivation and taurecovery. This indicates that acidosis exerts a complex effect on the slow membrane channel. 2. The normal response of the Ca current towards variations of the extracellular Ca concentration (0.5-4 mM) or towards the addition of the beta-stimulating compound isoproterenol (2 mg/l) was not altered by the lowered extracellular pH. 3. In the acid medium, isometric contractile force declined to 40% of the control value within 25 min and, thus, reacted stronger than the Ca current. This indicates that those forms of acidosis used in the present experiments caused their negative inotropic effect not exclusively via a depression of the Ca current. Rather an additional intracellular effect has to be assumed which finally leads to a reduced activity of the contractile system. 4. At pH 5.5 excess Ca (4 mM) induced the same quantitative response of the contractile system as obtained at normal pH. In contrast, the positive-inotropic effect of 2 mg/l isoproterenol was more pronounced, whilst the sensitivity of the Ca inward current towards this beta-stimulating compound remained unchanged.

Cardiomyocytes are known to be androgen targets. Changing systemic steroid levels are thought to be linked to various cardiac ailments, including dilated cardiomyopathy (DCM). The mode of action of gonadal steroid hormones on the human heart is unknown to date. In the present study, we used high-resolution immunocytochemistry on semithin sections (1 microm thick), IN SITU hybridization, and mass spectrometry to investigate the expression of androgen-binding protein (ABP) in human myocardial biopsies taken from male patients with DCM. We observed distinct cytoplasmic ABP immunoreactivity in a fraction of the myocytes. IN SITU hybridization with synthetic oligonucleotide probes revealed specific hybridization signals in these cells. A portion of the ABP-positive cells contained immunostaining for androgen receptor. With SELDI TOF mass spectrometry of affinity purified tissue extracts of human myocardium, we confirmed the presence of a 50 kDa protein similar to ABP. Our observations provide evidence of an intrinsic expression of ABP in human heart. ABP may be secreted from myocytes in a paracrine manner perhaps to influence the bioavailabity of gonadal steroids in myocardium.

The slow upstroke velocity of the action potential of primary pacemaker cells of the sinoatrial node suggests the slow membrane channel to be involved in the excitation process of these cells. In order to prove this the effect of promotors and inhibitors of the slow membrane channel upon the excitation process of the isolated sinoatrial node of rabbits was studied. 1. The action potentials of primary pacemaker cells had an upstroke velocity of 1.7 +/- 1.1 V/sec and an overshoot of 8.1 +/- 4.6 mV with a threshold potential of -40.1 +/- 4.5 mV. A decrease of the extracellular Ca concentration from 2 mM to 0.2 mM led to reduction of upstroke velocity and overshoot whereas an increase from 2 mM to 4 mM augmented both parameters. But the inward current is not only carried by Ca ions but by Na ions as well, since Na withdrawal diminished upstroke velocity and overshoot. 2. The promotors of the slow inward current, isoproterenol and caffeine, produced a significant increase of upstroke velocity and overshoot. On the other hand, verapamil (1 mg/1) and D 600 (0.4 MG/1) completely blocked the excitation process within 20-25 min. The same effect could be produced by the bivalent cations Ni (1 mM), Co (1 mM), and Mn (1 mM). These organic and inorganic inhibitors exerted their blocking effect without significant changes of the maximal diastolic potential and the threshold potential. 3. In the continued presence of Ni, Co and Mn ions their inhibitory effect could be neutralized nearly completely by isoproterenol (2.5 mg/1). But excess Ca (6 mM) increased the upstroke velocity only to a small degree. In contrast to the findings in the ventricular myocardium the blocking effect of verapamil and D 600 could be overcome neither by isoproterenol nor by excess Ca. The excitation process in the sinotrial node is mediated solely by the slow membrane channel. It allows the influx of both Ca and Na ions which act as charge carrier of the slow inward current. The fact, that the inhibitory effect of verapamil and D 600 cannot be neutralized by catecholamines or excess Ca seems to indicate that some properties of the slow membrane channel are not exactly identical in sinotrial pacemaker cells and in the ventricular myocardium.