Differential effects of furnidipine and its active metabolites in rat isolated working heart

1,4,-dihydropyridines, belonging to the class of "privileged structures", are known to protect the heart from stunning, ischemia and ventricular arrhythmias and mainly used in hypertension. The aim of this study was to compare the continuous infusion of parent drug, furnidipine, with its two active metabolites (M-2; M-3) in rat isolated working heart model, where the following parameters were measured and calculated: heart rate, preload pressure, aortic systolic and diastolic pressures (AoD), as well as +/-dP/dt, aortic (AF) and coronary flow (CF), oxygen and carbon dioxide partial pressures and pH values in pulmonary effluent, myocardial oxygen consumption. At first, the optimal vasodilatatory dose of M-2 was estimated and afterwards it was compared with equivalent doses of both remaining substances. The strongest vasodilatatory effects were observed after the lowest dose of M-2 was used (10(-7) M), at the same time being without marked influence on pressure parameters. The pro-drug evoked significantly weaker influence on both flows. Furthermore, furnidipine significantly reduced AoD and AF in comparison to control as well as +dP/dt in comparison to the initial values, while M-2 did not. Both metabolites caused a significant CF increase, but M-3 additionally the AoS and AoD decrease in comparison to the control. Regarding clear differences in the measured parameters between the pro-drug and its metabolites found, the obtained results allow to claim that the metabolites vs. furnidipine possess a beneficial influence. The distinct flow shift from aorta into the coronaries was observed only after M-2 and to a lesser extent--M-3. The cardio-depressant potency of both metabolites is overcome by advantageous vasodilatatory effect. M-2, being a final product, easier to control and at the same time a precursor of the new chemical class of therapeutics, is promising as a cardio-protective agent.