EFFECTS OF A NEW BRADYCARDIAC AGENT ON TH E ISOLATED RABBIT HEART

Beside wall tension and contractility, heart rate is a major determina nt of myocardial oxygen consumption. Therefore, a decrease in heart ra te could prevent ischemia or reduce its consequences. We examined the effect of a new bradycardic agent of the benzazepinone-type (DK-AH 269 ) on eight isolated, saline-perfused rabbit hearts; bradycardia result ed from a specific blockade of i(f)-channels in sinus node cells. Afte r control measurements (C), the substance was added in three increasin g concentrations (D-1: 10(-8) M, D-2: 10(-7) M, D-3: 10(-6) M). We obs erved a dose-dependent reduction in heart rate (C: 206 +/- 25, D-1: 19 5 +/- 30, D-2: 77 +/- 41, D-3: 154 +/- 48/min). In the highest dosage, the duration of diastole was increased by 100%. To characterize systo lic function, we measured stroke volume (SV), peak left ventricular pr essure (LVP(max)) and its first derivative (dP/dt(max)). Aortic flow w as slightly decreased whereas SV increased to 108 % of control after i nitial reduction at the two lower dosages. LVP(max) remained unchanged , and dP/dt(max) was dose-dependently reduced to 91, 81, and 70 % of c ontrol (C: 1885 +/- 376, D-1: 1712 +/- 525, D-2: 1526 +/- 504, D-3: 13 27 +/- 337 mm Hg/s); dP/dt(min) as a measure of early relaxation was a lso reduced. The coronary flow per beat did not change compared with c ontrol in the presence of the two lower doses of DK-AH 269, but was si gnificantly increased with the highest dose (C: 0.29 +/- 0.06, D-1: 0. 28 +/- 0.07, D-2: 0.29 +/- 0.09, D-3: 0.34 +/- O.11 ml). The myocardia l oxygen demand was dose-dependently decreased (C: 10.4 +/- 2.5, D-1: 9.6 +/- 2.5, D-2: 8.8 +/- 2.6, D-3: 7.9 +/- 2.4 ml/min/100 g). The rel ation between subendocardial and subepicardial flow, assessed with col ored microspheres, exhibited no changes in the presence of the highest dose of DK-AH 269 (C: 1.28 +/- 0.09, D-3: 1.27 +/- 0.08). DK-AH 269 r educed heart rate in isolated rabbit hearts and increased the duration of diastole. Whereas systolic function was primarily left unchanged, coronary flow per beat and oxygen consumption were decreased. Accordin g to our results, this new bradycardic agent could be useful in treati ng coronary heart disease.