The potency of neuropeptide Y (NPY) to cause negative and positive contractile responses in rat ventricular cardiomyocytes was investigated. In these cells, NPY was found to activate the transient outward K+ current (Ito) and the slow inward Ca2+ current (Isi). As reported before (H. M. Piper, B. C. Millar, and J. R. McDermott, Naunyn Schmiedeberg's Arch. Pharmacol. 340: 333-337, 1989), NPY attenuated the increase in the contractile response induced by isoprenaline (10(-7) M). This effect of NPY could be abolished by 1) the presence of the inhibitor of Ito, 4-aminopyridine (4-AP, 0.5 mM); 2) pretreatment of the cells with pertussis toxin (1 microgram/ml for 6 h); and 3) the presence of the 19-amino acid COOH-terminal fragment of NPY, NPY-(18-36) (10(-6) M). In the absence of isoprenaline, but in the presence of 4-AP, NPY exerted a stimulatory effect on the cardiomyocytes. This effect could be abolished 1) by using the inhibitor of the Isi, verapamil (10(-8) M), but not 2) by pretreatment with pertussis toxin, nor 3) by coincubation with NPY-(18-36). The results indicate that in the rat the antiadrenergic negative contractile effect of NPY results from its action on the Ito. Blockade of this current by 4-AP unmasks a positive contractile effect of NPY that is related to activation of the Isi.

This study describes electrophysiological effects of estrogens in isolated male rat ventricular myocytes. According to the literature these cells do not express the nuclear estrogen receptor. Action potentials or membrane currents were recorded in the whole-cell configuration with standard techniques. Action potential durations (APD) measured at a level of 0 mV (APD 0) and -70 mV (APD -70) were prolonged by 17beta-estradiol (0.5 Hz stimulation frequency, 24-26 degrees C). Threshold concentration was 1 micromol/l. At the highest concentration used (30 micromol/l) no saturation of the response was reached and APD 0 was 162% and APD -70 was 230% of the respective control. The resting potential remained unaffected in most cells. The prolongation induced by 17beta-estradiol developed fast and reached a steady state 10 min after start of hormone superfusion. Effects of estrogen were completely reversible during 10-15 min wash-out with hormone-free solution. The extent of prolongation (10 micromol/l 17beta-estradiol) was frequency dependent. Expressed as percentage of the respective control APD 0 (or APD -70) was 115% (188%) at 0.05 Hz, 118% (163%) at 0.5 Hz and 99% (129%) at 5 Hz stimulation frequency. The response was stereoselective, because 30 micromol/l 17alpha-estradiol did not prolong action potentials (APD 0: 101%, APD -70: 104% of the respective control, 0.5 Hz stimulation frequency). The endogenous estrogens estrone and estriol were less effective than 17beta-estradiol. With 30 micromol/l estrone (0.5 Hz stimulation frequency) APD 0 was 103% and ADP-70 148% of control and with 30 micromol/l estriol APD 0 was 135% and APD -70 137% of control. The prolongation of action potentials can be explained by inhibition of transient outward current which, in rat ventricle, is composed of fast (i[to,f]) and slowly (i[to,s]) inactivating components. At 30 micromol/l 17beta-estradiol i(to,f) was reduced to 50% and i(to,s) to 43% of their maximal amplitudes. The voltage sensor of i(to,f) or i(to,s) was hardly affected. Additionally, 17beta-estradiol decreased the calcium current (i[Ca,L]) to 76% (10 micromol/l) and 38% at 30 micromol/l. The inwardly rectifying potassium current (i[K1]) was reduced partly with 30 micromol/l 17beta-estradiol and its amplitude was 72% of control at -90 mV (inward current flow) and 65% at -40 mV (outward current flow). These results show that 17beta-estradiol is active in cardiac cells which do not express the nuclear estrogen receptor. The hormone exerts class III activity and reduces calcium inward current. These effects, however, occur in vitro with concentrations above the physiological level and therefore may be without significance in vivo.

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(1) Effects of bepridil (0.3-100 mumol/l) on transmembrane currents which are active during the repolarization of the cardiac action potential were studied in sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique. Transmembrane currents were activated at a frequency of 0.03 Hz. (2) The initial inwardly rectifying current (iK1) was reduced by 1.8 mumol/l bepridil to 70% of the reference iK1-current in the absence of the drug. (3) An initial outward current, which is activated at positive membrane potentials (iinst) was depressed to 70% of reference by 14 mumol/l bepridil. (4) The time-dependent outward current (iK) was decreased by 1.8 mumol/l bepridil to 70% of its amplitude in the absence of bepridil. The biexponential time course of iK-current activation changed to be monoexponential with 100 mumol/l bepridil. The effect of bepridil on iK-current resulted in a shift of the activation curve of iK-current to more positive membrane potentials (10 mumol/l bepridil) and an additional decrease of driving force and/or conductance of the iK-channels with higher bepridil concentrations (100 mumol/l). (5) The transient outward current (ito) was completely blocked by 30 mumol/l bepridil. Inhibition to 70% of reference occurred with 1 mumol/l bepridil. The voltage-dependent inactivation of ito-current was affected by bepridil: the amplitude of the steady-state inactivation curve was reduced and ito-current was inactivated faster after application of bepridil. Bepridil caused no pronounced shift of the steady-state inactivation curve along the voltage axis.(ABSTRACT TRUNCATED AT 250 WORDS)