Time course of a new ultrashort-acting beta-adrenoceptor-blocking drug, ONO-1101: comparison with those of esmolol and propranolol by using the canine isolated, blood-perfused heart preparations

Abstract

Time courses of beta-adrenoceptor-blocking actions of ONO-1101, a new cardioselective beta-blocker, were compared with those of esmolol and propranolol by using the isolated, blood-perfused sinoatrial node (SAN) and papillary muscle (PM) preparations of dogs. ONO-1101 per se given intraarterially (i.a.) in each nutrient artery did not affect basal sinoatrial rates (SARs; 99 +/- 2 beats/min, n = 7) in the SAN and developed tension (DT; 3.2 +/- 0.7 g, n = 7) of the PM preparations. Norepinephrine (NE) injected i.a. into the each artery induced increases in SAR (42 +/- 6 beats/min at 0.051 +/- 0.014 microg) and PMDT (2.9 +/- 0.4 g at 0.048 +/- 0.011 microg). The i.a. injections of NE were repeated every 3 min after i.v. bolus injections of ONO- 1101 into the support dog. NE-induced increases in SAR and PMDT were maximally inhibited 3 to 6 min after the i.v. injections of ONO-1101. Maximal percentage inhibitions by ONO-1101 of NE-induced increases in SAR were 54 +/- 6, 78 +/- 3, and 96 +/- 2% at 0.01, 0.1, and 1 mg/kg of the drug, respectively. Similarly, maximal percentage inhibitions by ONO-1101 of NE-induced increases in PMDT were 50 +/- 12, 93 +/- 2, and 100% +/- 0, respectively. The inhibition was quickly recovered; times required for 50% recovery (RT1/2) were 12 +/- 3. 17 +/- 3, and 32 +/- 10 min in the SAN preparation, and 13 +/- 3, 16 +/- 2, and 39 +/- 11 min in the PM preparations, after i.v. injections of 0.01, 0.1, and 1 mg/kg of ONO-1101, respectively. In comparison, maximal percentage inhibitions by esmolol of NE-induced increases in SAR were 45 +/- 5, 79 +/- 6, and 96 +/- 2%, and those in PMDT were 34 +/- 4, 75 +/- 5, and 97 +/- 1%, whereas the RT1/2 values were 11 +/- 2, 15 +/- 4, and 40 +/- 12 min in the SAN preparation, and 10 +/- 2, 16 +/- 7, and 27 +/- 6 min in the PM preparations, after i.v. injections of 0.01, 0.1, and 1 mg/kg of esmolol, respectively. In contrast, the maximal percentage inhibitions by an i.v. bolus injection of 0.1 mg/kg of propranolol of NE-induced increases in SAR and PMDT were 77 +/- 18% and 87 +/- 13% (n = 4). respectively. The maximal inhibitions were obtained 6-15 min after injections of propranolol and then slowly recovered only by 21% in the SAN and 8% in the PM preparations, even after 60 min. These results clearly demonstrate that ONO-1101 is an ultrashort-acting beta-blocker, but the recovery time is dose dependent, and that the beta-blocking action of ONO-1101 is almost similar to or slightly more potent (or both) than esmolol.