氟司喹南对正常雪貂与终末期心力衰竭患者心室肌的变力作用差异。

Differential inotropic effects of flosequinan in ventricular muscle from normal ferrets versus patients with end-stage heart failure.

作者信息

Perreault C L, Hague N L, Loh E, Hunneyball I M, Sim M F, Morgan J P

机构信息

Harvard-Thorndike Laboratory, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215.

出版信息

Br J Pharmacol. 1992 Jul;106(3):511-6. doi: 10.1111/j.1476-5381.1992.tb14367.x.

DOI:10.1111/j.1476-5381.1992.tb14367.x

PMID:1324072

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1907553/

Abstract

In right ventricular papillary muscles from control ferrets, flosequinan (10(-7)-10(-4) M) produced a concentration-dependent positive inotropic effect (10(-5) M = 153 +/- 24, 10(-4) M = 198 +/- 44% increase in isometric tension; control tension = 100%; n = 11) associated with a corresponding increase in amplitude of the intracellular Ca2+ ([Ca2+]i) transient recorded with aequorin (10(-5) M = 133 +/- 11, 10(-4) M = 187 +/- 36% increase in [Ca2+]i transient; n = 11). 2. The positive inotropic effect of flosequinan in control ferret ventricular muscle was neither blocked by propranolol (6 x 10(-7) M), nor associated with the abbreviation of the [Ca2+]i transient and contraction that is typical of catecholamines. 3. Neither flosequinan (n = 12) nor BTS 53 554, its sulphone metabolite (n = 6) produced a positive inotropic effect or altered the time course of contraction in myocardium from the hearts of patients with end-stage failure. 4. In contrast to milrinone, which produces a positive inotropic effect via phosphodiesterase inhibition, the unresponsiveness of myopathic human myocardium to flosequinan was not restored after intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were increased by prior treatment with forskolin (n = 13). 5. Taken together, these data indicate that flosequinan has a direct positive inotropic effect that is Ca(2+)-dependent, but independent of changes in intracellular cyclic AMP concentrations. 6. The positive inotropic effect may be species-dependent or altered by the presence of hypertrophy and/or heart failure. However, when used therapeutically in patients with severe heart failure, our data suggest that flosequinan should not adversely affect myocardial oxygen consumption through direct or catecholamine-mediated actions on the heart.

摘要

在对照雪貂的右心室乳头肌中，氟司喹南（10⁻⁷ - 10⁻⁴ M）产生浓度依赖性正性肌力作用（10⁻⁵ M时等长张力增加153±24%，10⁻⁴ M时增加198±44%；对照张力 = 100%；n = 11），同时用水母发光蛋白记录的细胞内Ca²⁺（[Ca²⁺]i）瞬变幅度相应增加（10⁻⁵ M时[Ca²⁺]i瞬变增加133±11%，10⁻⁴ M时增加187±36%；n = 11）。2. 氟司喹南在对照雪貂心室肌中的正性肌力作用既不被普萘洛尔（6×10⁻⁷ M）阻断，也与儿茶酚胺典型的[Ca²⁺]i瞬变和收缩的缩短无关。3. 氟司喹南（n = 12）及其砜代谢物BTS 53 554（n = 6）均未对终末期心力衰竭患者心脏的心肌产生正性肌力作用或改变收缩时程。4. 与通过抑制磷酸二酯酶产生正性肌力作用的米力农不同，在用福斯高林预先处理使细胞内3':5'-环磷酸腺苷（环磷酸腺苷）水平升高后，病变的人心肌对氟司喹南的无反应性并未恢复（n = 13）。5. 综上所述，这些数据表明氟司喹南具有直接的Ca²⁺依赖性正性肌力作用，但与细胞内环磷酸腺苷浓度的变化无关。6. 正性肌力作用可能因物种而异，或因肥大和/或心力衰竭的存在而改变。然而，当用于重度心力衰竭患者的治疗时，我们的数据表明氟司喹南不应通过对心脏的直接作用或儿茶酚胺介导作用对心肌耗氧量产生不利影响。