Vasodilating β-adrenoceptor blocking drugs do not redistribute myocardial flow during acute coronary ligation in dogs

Berdeaux, Alain; Bonhenry, C; Jf, Giudicelli

doi:10.1016/0014-2999(85)90784-8

Cited by 3 publications

(1 citation statement)

References 20 publications

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“…Amosulalol also reduced myocardial ischemic injury, as reflected by a decrease in ST segment elevation in ischemic areas. Under the same experimental conditions, labetalol and bucindolol have been reported not to have any favorable effects on myocardial blood flow in nonischemic or ischemic myocardium (5).…”

Section: Hemodynamic and Coronary Effects In Anesthetized Animalsmentioning

confidence: 80%

Amosulalol

Takenaka¹

1987

Cardiovascular Drug Reviews

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The most important hemodynamic disturbance in patients with hypertension is an increase in peripheral vascular resistance due to arteriolar constriction (8). Accordingly, the most desirable way to lower blood pressure is to decrease peripheral vascular resistance without adversely affecting cardiac function.Both aand P-adrenoceptor antagonists are effective drugs for the treatment of hypertension. Although or-adrenoceptor antagonists decrease the peripheral resistance through attenuation of the sympathetic vasoconstriction, especially at the arterioles, most of these drugs have limited use because of unacceptable reflexly mediated cardiovascular side effects. On the other hand, P-adrenoceptor antagonists are less effective as hypotensives and have a slower onset of action than cx-antagonists. They may even cause an initial increase in peripheral vascular resistance. A combination of an a-antagonist with a @-antagonist is theoretically beneficial because a-blockade eliminates peripheral vasoconstriction and P-blockade overcomes reflex cardiac acceleration and renin release. In fact, such a cbmbination has resulted in some clinical studies in good control of high blood pressure with few side effects (12,26).Based on the above considerations, the concept of combining the activities of aand P-adrenoceptor blockade in a single molecular entity is logical and should lead to an effective treatment of hypertension. Takenaka et al. (46) and Fujikara et al. (9) found that a series of arylethanolamines derived from benzenesulfonamide possessed both a-and /3-adrenoceptor blocking activities in different ratios. Amosulalol was selected from these derivatives, as it blocked or,-and p,-adrenoceptors almost to the same extent and showed beneficial antihypertensive activity in animals (46). CHEMISTRY Amosulalol hydrochloride (YM-09538) is (*)-5-[ I -hydroxy-2-[[2-(o-methoxyphenoxy)ethyl]amino]ethyl]-2-methylbenzenesulfonamide hydrochloride (Fig. 1). It was synthesized and patented by Imai and co-workers at Central Research Laboratories of Yamanouchi Pharmaceutical Co. Ltd. (19). Synthesis pathways of amosu-AMOS ULA LOL SO2 NH2 CH~-&H-CHZ -NH-CH2 -CHz -0 *HCI OCH3 OH FIG. 1. Structure of amosulalol hydrochloride (YM-09538).lalol and 14C-amosulalol and resolution of its optical isomers were reported (2,lO). Amosulalol is a white, odorless crystalline powder with a bitter taste. It has a molecular weight of 416.93 (C18H24N20SS.HC1) and a melting point of 158-162°C. The substance is soluble in methanol, sparingly soluble in water (1.5 g/ 100 ml) and in absolute ethanol, very slightly soluble in acetone, and practically insoluble in ether, chloroform, and benzene. The pKal for the secondary amine and pKa2 for amosulalol are 7.72 and 10.04, respectively. Its n-octanol-water partition coefficient at pH 7.0 is 2.70, which is lower than the values reported for propranolol or labetalol (54). ANIMAL PHARMACOLOGY Zn Vitr5 a-and P-Adrenoceptor Blocking ERectsThe activity of amosulalol as an antagonist of two subtypes of aor P-adrenoceptors wa...

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Section: Hemodynamic and Coronary Effects In Anesthetized Animalsmentioning

confidence: 80%

Amosulalol

Takenaka¹

1987

Cardiovascular Drug Reviews

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Effects of Four Angiotensin I Converting Enzyme Inhibitors on Regional Myocardial Blood Flow and Ischemic Injury During Coronary Artery Occlusion in Dogs

Berdeaux¹,

Bonhenry²,

Giudicelli³

1987

Fundamemntal Clinical Pharma

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The effects of 4 angiotensin I converting enzyme inhibitors (ACEI), captopril, enalapril, ramipril, and trandolapril, were investigated on regional myocardial blood flow (RMBF, radioactive microspheres) distribution in ischemic and nonischemic zones and on ST-segment elevation in ischemic zones during intermittent coronary artery occlusion in anesthetized dogs. The 4 ACEI inhibited plasma ACE activity to an almost similar extent. All similarly reduced systemic blood pressure, an effect related to a decrease in systemic vascular resistance. Heart rate and myocardial contractility were not affected, but myocardial oxygen consumption presumably decreased because of the reduction in afterload. RMBF and their distribution (between epicardial and endocardial layers and between nonischemic and ischemic zones) were not modified by ACEI. Coronary vascular resistance was slightly decreased in nonischemic zones. ACEI had no effect on ST-segment elevation in ischemic zones. Thus, in this experimental model, all ACEI exhibited the same profile, including no change in RMBF and affording no protection against ischemic injury.

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Comparative Effects of Arotinolol, Labetalol and Propranolol on Regional Myocardial Dysfunction Induced by Flow-Limiting Coronary Stenosis in Anesthetized Dogs

Noguchi¹,

Kato²,

Kinjo

et al. 1990

Japanese Journal of Pharmacology

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Abstract-Effects of arotinolol, a combined alpha-and beta-adrenoceptor blocking agent, on regional myocardial dysfunction produced by severe coronary stenosis in anesthetized dogs were examined and compared with those of labetalol and propranolol. Doses of these three antagonists were selected to produce a com parable degree of the negative chrono-and inotropic effect but a different potency of alpha-adrenoceptor blockade (labetalol>arotinolol). Regional myocardial function measured as segment shortening (%SS) was decreased to around 2-3% by constriction of the left circumflex coronary artery (LCX), and then drug or saline was administered i.v. The stenosis of LCX was released 30 min after the adminis tration. No significant alteration in hemodynamic and contractility parameters was seen as compared to the predrug value up to at least 30 min after saline i.v. Arotinolol and propranolol both reduced heart rate and peak positive left ventricular dP/dt (LVdP/dt) without a significant change in LCX flow. Concomitantly, %SS distal to a coronary stenosis was significantly improved by arotinolol and pro pranolol. On the other hand, labetalol significantly reduced LCX flow probably due to systemic hypotension and failed to improve %SS in the ischemic area, although the agent markedly decreased heart rate and LVdP/dt. These results indicate that arotinolol improves impaired regional myocardial function distal to a coronary stenosis in a similar manner with propranolol.

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Vasodilating β-adrenoceptor blocking drugs do not redistribute myocardial flow during acute coronary ligation in dogs

Cited by 3 publications

References 20 publications

Amosulalol

Amosulalol

Effects of Four Angiotensin I Converting Enzyme Inhibitors on Regional Myocardial Blood Flow and Ischemic Injury During Coronary Artery Occlusion in Dogs

Comparative Effects of Arotinolol, Labetalol and Propranolol on Regional Myocardial Dysfunction Induced by Flow-Limiting Coronary Stenosis in Anesthetized Dogs

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