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Effects of S-596, a new beta-adrenoceptor blocking agent on the left ventricular performance of normal subjects
Abstract:
The effects of d1-2-(3'-t-butylamino-2'-hydroxypropylthio)-4-(5'-carbamoyl-2'-thi enyl) thiazole hydrochloride (S-596) were evaluated in 9 normal volunteers. Exercise echocardiography was performed in the semi-supine position before and 2, 4 and 24 hours after the oral administration of 15 mg of S-596. Two hours after administration, resting heart rate was unchanged, compared with control, but systolic blood pressure at rest was slightly decreased (114 +/- 6 vs 106 +/- 10 mmHg, p less than 0.05). Left ventricular dimensions were unchanged, but shortening fraction was increased in the resting state (30.3 +/- 4.6 vs 33.1 +/- 4.8%, p less than 0.05). During exercise on oral S-596, heart rate and systolic blood pressure responses were reduced (127 +/- 11 in control vs 108 +/- 6 beats/min on S-596, 198 +/- 25 vs 168 +/- 23 mmHg, p less than 0.001 and 0.05, respectively). Left ventricular end-diastolic dimension was not significantly altered by S-596 compared with the preceding control exercise test; however, end-systolic dimension was significantly larger after beta blockade with S-596 (2.6 +/- 0.4 vs 3.0 +/- 0.4 cm, p less than 0.05). Shortening fraction and cardiac output decreased significantly (43.7 +/- 3.7 vs 40.0 +/- 5.7%, 9.5 +/- 1.4 vs 8.4 +/- 1.3 L/min, p less than 0.05 and 0.01, respectively). These effects of S-596 were maximal at 2 hours after oral administration with reduced response of heart rate to exercise lasting for 24 hours. Compared with the effects of propranolol (30 mg, given orally) in the same subjects, beta-adrenergic blockade during exercise with S-596 was equivalent to or greater than that of propranolol. Thus, S-596 has little, if any, effect on resting left ventricular performance, but demonstrates potent negative chronotropic and inotropic effects during exercise in normal human subjects. Its beta-adrenergic blocking action also has long acting properties, especially its chronotropic effect.