山梨医科大学雑誌　第7巻4号　157-167(1992)

Lipophilic β-Adrenoceptor Blocking Drugs Have Strong Membrane
Stabilizing Actions on Atrioventricular Nodal
and Intraventricular Conduction: Comparison
with Their β-Adrenoceptor Antagonizing Actions

Shigeru MOTOMURA

Abstract: The membrane stabilizing actions (MSA) of eight β-blockers were compared with their β-adrenoceptor antagonizing action in relation to their lipophilicity. The MSA on atrioventricular (AV) nodal and intraventricular conduction were determined as the doses of ID25(AH) and ID50(HV), which produced 25% and 50% increases in atrio-His (AH) and His-ventricle (HV) intervals by their injection into the posterior or the anterior septal artery of the canine isolated, blood-perfused AV node preparations. The basal AH and HV intervals were 83±3 and 40±2 msec (n=52). ID25(AH), the doses producing a 21 msec prolongation of the AH interval, were 71 μg for propranolol (P), 108 μg for alprenolol (A), 129 μg for oxprenolol (O), 397 μg for pindolol (PIN), 385 μg for bunitrolol (B), 648 μg for timolol (T), 3.2 mg for atenolol (AT) and more than 10 mg for carteolol (C). ID50(HV), the doses producing a 20 msec prolongation of the HV interval, were 533(P), 428(A), 361(O), 471(PIN), 598(B), 1700(T), and > 10,000 μg (AT, C). The β-adrenoceptor antagonizing actions were estimated as the doses of ED20(NE), the minimum doses of β-blockers which completely suppress the 20 msec shortening of the AH interval by norepinephrine. ED20(NE) were 4.4(P), 3.0(A), 4.3(O), 0.40(PIN), 0.37(B), 1.9(T), 3.3(AT) and 0.29 μg(C). As a result, the ratio of ID25(AH)/ED20(NE) were 16(P), 36(A), 30(O), 990(PIN), 1040(B), 348(T), 970(AT) and >50000(C). Similarly, the ratio of ID50(HV)/ED20(NE) were 120(P), 142(A), 83(O), 1180(PIN), 1620(B), 930(T) and >30000(AT, C). These results indicate that 1) lipophilic β-blockers (P, A, O, PIN, B) directly suppress intraventricular conduction, but approximately 100 times larger doses than β-adrenoceptor antagonizing doses were required; 2) in addition, highly lipophilic β-blockers (P, A, O) preferentially suppress AV nodal conduction, but a hydrophilic β-blocker (AT) barely suppresses AV nodal and intraventricular conduction; and 3) the lipophilicity (or hydrophilicity) of β-blockers is not related to their β-adrenoceptor antagonizing potency. These results suggest that the MSA of highly lipophilic β-blockers are harmful as cardiodepressants, but might be therapeutic as antiarrhythmics.

Key words: Atrioventricular node, β-Adrenoceptor antagonizing action, Intraventricular conduction, Lipophilicity, Membrane stabilizing action




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