Different toxicological profiles for various beta-blocking agents on cardiac function in isolated rat hearts.
Propranolol, timolol and sotalol were compared regarding their cardiotoxic properties in isolated, perfused and catecholamine depleted rat hearts. Catecholamine depletion was performed in order to exclude interference of the drugs with beta-adrenergic receptors. The results demonstrate that both in spontaneously beating and atrial- stimulated hearts propranolol (3 - 30 micrograms/ml) and timolol (30 - 300 micrograms/ml) induced a dose dependent decrease in myocardial contractility, stimulus formation and stimulus conduction. Lacking local anesthetic properties as evidenced by effects on coronary flow and threshold voltage in the heart it can be deduced that the negative inotropic effect and an impaired stimulus conduction due to timolol can neither attributed to beta-adrenoceptor antagonism nor membrane stabilising activity. In addition, both propranolol (5 micrograms/ml) and timolol (200 micrograms/ml) reduced myocardial contractility to the same extent in ventricular-paced hearts. Therefore, a direct myocardial depressive effect rather than an indirect effect due to a reduced heart rate must be responsible for the negative inotropy. The hydrophilic beta-blocker sotalol demonstrated a slight cardiodepressant activity either in the spontaneously beating and atrial-stimulated hearts (30 - 300 micrograms/ml) or ventricular-paced hearts (300 micrograms/ml). It is concluded that the toxicological profile of various beta-blocking drugs might be determined by an yet unknown pharmacological property apart from beta-adrenoceptor blockade or membrane stabilising activity. Furthermore, the degree of lipophilicity of the drug might be an important determinant for the cardiotoxic profile of this class of drugs.
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003864:Depression, Chemical; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011433:Propranolol / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013015:Sotalol / Q000633:toxicity*; D013997:Time Factors; D013999:Timolol / Q000633:toxicity*
D013999:Timolol; D011433:Propranolol; D013015:Sotalol