M Schramm, R Towart, S Kazda, G Thomas, G Franckowiak
{"title":"Calcium agonism, a new mechanism for positive inotropy. Hemodynamic effects and mode of action of BAY K 8644.","authors":"M Schramm, R Towart, S Kazda, G Thomas, G Franckowiak","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>BAY K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl -phenyl)-pyridine-5-carboxylate] is a nifedipine-like 1,4-dihydropyridine (DHP). In contrast to the well-known calcium antagonistic DHPs, it has vasoconstricting and positive inotropic properties. In the pentobarbital-anesthetized dog, it increases blood pressure, peripheral resistance, and left ventricular (dP/dt)max dose-dependently from 3 to 100 micrograms/kg i.v. If the vagus is blocked, heart rate is unchanged. In the isolated isovolumic perfused guinea pig heart, BAY K 8644 has positive inotropic and coronary constricting actions from 10(-9) mole/liter. At 10 times higher concentrations, this compound also increases the heart rate up to 20%. BAY K 8644 has no effect on rabbit aortic strip at physiological K+ concentrations, but potentiates the K+ -induced contraction of the strip. In the partially depolarized aortic strip (18 mM K+), BAY K 8644 induces concentration-dependent contractions, which are competitively inhibited by the calcium-antagonistic DHP nifedipine. Chemically different calcium antagonists such as verapamil or diltiazem inhibit the BAY-K-8644-induced contractions noncompetitively. These results indicate that a specific DHP receptor exists, which binds nifedipine and BAY K 8644. In contrast to the calcium-antagonistic DHPs like nifedipine, BAY K 8644 increases the calcium influx into the cell.</p>","PeriodicalId":77831,"journal":{"name":"Advances in myocardiology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"1985-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advances in myocardiology","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
BAY K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl -phenyl)-pyridine-5-carboxylate] is a nifedipine-like 1,4-dihydropyridine (DHP). In contrast to the well-known calcium antagonistic DHPs, it has vasoconstricting and positive inotropic properties. In the pentobarbital-anesthetized dog, it increases blood pressure, peripheral resistance, and left ventricular (dP/dt)max dose-dependently from 3 to 100 micrograms/kg i.v. If the vagus is blocked, heart rate is unchanged. In the isolated isovolumic perfused guinea pig heart, BAY K 8644 has positive inotropic and coronary constricting actions from 10(-9) mole/liter. At 10 times higher concentrations, this compound also increases the heart rate up to 20%. BAY K 8644 has no effect on rabbit aortic strip at physiological K+ concentrations, but potentiates the K+ -induced contraction of the strip. In the partially depolarized aortic strip (18 mM K+), BAY K 8644 induces concentration-dependent contractions, which are competitively inhibited by the calcium-antagonistic DHP nifedipine. Chemically different calcium antagonists such as verapamil or diltiazem inhibit the BAY-K-8644-induced contractions noncompetitively. These results indicate that a specific DHP receptor exists, which binds nifedipine and BAY K 8644. In contrast to the calcium-antagonistic DHPs like nifedipine, BAY K 8644 increases the calcium influx into the cell.
BAY K 8644[甲基1,4-二氢-2,6-二甲基-3-硝基-4-(2-三氟甲基苯基)-吡啶-5-羧酸盐]是一种类硝苯地平的1,4-二氢吡啶(DHP)。与众所周知的钙拮抗DHPs相反,它具有血管收缩和正性肌力特性。在戊巴比妥麻醉的狗,它增加血压,外周阻力和左心室(dP/dt)最大剂量依赖性从3到100微克/千克静脉注射。如果迷走神经被阻断,心率不变。在离体等容量灌注的豚鼠心脏中,BAY K 8644在10(-9)mol /l范围内具有正性肌力和冠状动脉收缩作用。在10倍的浓度下,这种化合物还能使心率增加20%。在生理K+浓度下,BAY k8644对兔主动脉条无影响,但能增强K+诱导的主动脉条收缩。在部分去极化主动脉带(18 mM K+)中,BAY K 8644诱导浓度依赖性收缩,这种收缩被钙拮抗DHP硝苯地平竞争性地抑制。化学上不同的钙拮抗剂如维拉帕米或地尔硫卓非竞争性地抑制bayk -8644诱导的收缩。这些结果表明存在一种特异性的DHP受体,它可以结合硝苯地平和BAY K 8644。与硝苯地平等钙拮抗dhp相反,BAY k8644增加钙流入细胞。