Effects of 3,6-dimethamidodibenzopyriodonium citrate (I-65) on action potentials and contractions in guinea pig papillary muscles

Synchronous recordings of action potentials and contractile force in isolated guinea pig papillary muscles administered 3,6-dimethamidodibenzopyriodonium citrate (I-65) 30 mumol/L showed excitation-contraction uncoupling, ie, the contractile force was markedly depressed although the Vmax and amplitudes of the action potentials were unaffected. At the same concentration, I-65 shortened the duration of the action potentials at 50% and 90% repolarization. However, I-65 at lower concentrations (1-10 mumol/L) decreased Vmax and the amplitude of the slow action potentials which were elicited by isoprenaline in papillary muscles were rendered partially depolarized by KCl 25 mmol/L Tyrode solution. These effects were partially reversed by elevation of the concentration of Ca2+ from 2.7 to 5.4 mmol/L. I-65 also suppressed the abnormal automaticity elicited by BaCl2 and DAD and triggered activity induced by ouabain. The results suggest that I-65 may be a calcium channel blocker.     

Negative inotropic properties of isradipine, nifedipine, diltiazem, and verapamil in diseased human myocardial tissue.

We investigated the inotropic responses to Ca2+ antagonists using electrically driven human papillary muscle strips and human auricular trabeculae. Specimens were obtained during cardiac surgery for mitral valve replacement [New York Heart Association (NYHA) Class II-III] or heart transplantation (NYHA IV) and during aortocoronary bypass operations. The inotropic effects were studied with cumulative concentration-response curves. All Ca2+ antagonists tested significantly (p less than 0.05) depressed force of contraction at concentrations above 0.01 mumol/L, but their potencies were different. A 50% reduction of the initial force of contraction occurred at the following concentrations (NYHA II-III): nifedipine (mean IC50) 0.09 mumol/L isradipine 0.12 mumol/L, diltiazem 0.69 mumol/L, and verapamil 0.79 mumol/L. There were no significant differences in the negative inotropic effects of any tested Ca2+ antagonist between NYHA II-III and NYHA IV. When the initial force of contraction was reduced by 90%, addition of Ca2+ increased force of contraction significantly less after diltiazem (2.76 +/- 0.4 mN), isradipine (1.82 +/- 0.23 mN), and nifedipine (1.68 +/- 0.25 mN) compared to control (4.63 +/- 0.56 mN) (NYHA II-III). The negative inotropic potencies of nifedipine and verapamil were significantly greater in human auricular trabeculae compared to papillary muscle strips (p less than 0.05). However, on the relation between therapeutic vasoactive plasma concentrations and IC25 values, an entirely different rank order of potential negative inotropism could be observed: verapamil greater than nifedipine greater than diltiazem greater than isradipine.     

钙增敏剂MCI-154对内毒素血症大鼠心肌收缩系统钙敏感性的影响(英文)

目的:研究MCI-154对内毒素血症大鼠心肌收缩系统钙敏感性的影响.方法:利用皂素500 mg/L制备内毒素血症大鼠蜕膜右心室乳头状肌标本,用不同钙浓度的含或不含强心药物的激活液进行顺序激活,记录Ca~(2 )激活张力.结果:同正常对照组相比,内毒素血症大鼠蜕膜乳头状肌钙最大激活张力(T_(max))降低,pCa_(50)值下降.甲腈吡酮50μmol/L对上述异常无明显的改善作用.内毒素血症大鼠蜕膜乳头状肌经含MCI-154 10 μmol/L的激活液处理后,T_(max)和pCa_(50)值明显增加,与假休克组类似,明显高于内毒素血症组和内毒素血症 甲腈吡酮组值.MCI-154的上述作用还具有剂量依赖性.结论:大鼠内毒素血症后,心肌收缩系统对Ca~(2 )敏感性降低,MCI-154可明显增加内毒素血症大鼠心肌收缩蛋白对钙的敏感性,增加心肌钙最大激活张力.     

赛庚啶对豚鼠乳头状肌的收缩性与动作电位的影响

Cyp对豚鼠孔头状肌有浓度依赖性负性肌力作用,提高浴液钙浓度此作用减弱,对高K~+除极后ISO恢复的收缩抑制作用更强。较高浓度的Cyp使频率依赖性正阶梯现象取消和翻转。对乳头状肌AP,Cyp浓度依赖性地使APD_(20),APD_(50),APD_(90)和ERP缩短。灌流液中Ca~(2+)降低或升高分别使该作用增强或减弱,K~+的改变对其作用影响较小。提示Cyp对豚鼠乳头状肌收缩性和AP的作用可能主要是抑制心肌跨膜Ca~(2+)内流所致。     

国产烟浪丁对豚鼠乳头状肌生理特性的影响

烟浪丁(NICO)对豚鼠乳头状肌的收缩力,有剂量依赖性抑制作用;降低乳头状肌的自律性,对其兴奋性和功能不应期(FRP)无明显影响。普萘洛尔和1.90mmol/L NICO,均使ISO量-效曲线平行右移,且心肌收缩力仍可达到给药前的最高水平,符合竞争性拮抗的特点。维拉帕米使CaCl_2量—效曲线非平行右移,最大收缩幅度明显降低;大剂量(3.80mmol/L)的NICO,亦使最大收缩幅度明显下降。     

Effects of lisinopril on electromechanical properties and membrane currents in guinea-pig cardiac preparations.

1. The effects of the angiotensin-converting enzyme inhibitor, lisinopril, were studied in guinea-pig atria and papillary muscles and in single isolated ventricular cells. 2. In isolated right atria, lisinopril (0.001-10 microM) decreased the amplitude and rate of the spontaneous contractions. In electrically driven left atria this negative inotropic effect was accompanied by a shortening of the time to peak tension and time for total contraction. 3. Lisinopril did not modify the electrophysiological characteristics of the ventricular action potentials recorded in papillary muscles perfused with normal Tyrode solution or elicited by isoprenaline in papillary muscles perfused with 27 mM K Tyrode solution. 4. In single ventricular cells, lisinopril (10 microM) had no effect on the inward L-type Ca2+ (ICa,L), the inward rectifier (IK1) or the delayed rectifier K+ currents (IK). However, it abolished the stimulation-dependent facilitation of the L-type Ca2+ current. 6. These results indicate that the negative inotropic effect of lisinopril cannot be explained by a decrease in Ca2+ entry through L-type channels and suggest that lisinopril may possibly act at an intracellular site to reduce contractile force.     

Muscarinic receptors mediate negative and positive inotropic effects in mammalian ventricular myocardium: differentiation by agonists.

The concentration-dependence of the negative and positive inotropic effect of choline esters and of oxotremorine was studied in isometrically contracting papillary muscles of the guinea-pig. The preparations were obtained from reserpine-pretreated animals and were electrically driven at a frequency of 0.2 Hz. In the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl xanthine (IBMX, 100 mumol l-1), choline esters and oxotremorine produced concentration-dependent negative inotropic effects. Oxotremorine exhibited the highest negative inotropic potency (with a half-maximal effective concentration, EC50, of 20 nmol l-1) followed by carbachol (139 nmol l-1), methacholine (490 nmol l-1), acetylcholine in the presence of 10 mumol l-1 physostigmine (1.36 mumol l-1) and bethanechol (10 mumol l-1). Atropine was a competitive antagonist of the negative inotropic effects. Carbachol and oxotremorine decreased Vmax, overshoot and duration of slow Ca2+-dependent action potentials which had been elicited in the presence of 100 mumol l-1 IBMX. Choline esters produced a concentration-dependent positive inotropic effect. With an EC50 of 32 mumol l-1, carbachol was the most potent compound, followed by methacholine (35 mumol l-1), acetylcholine in the presence of 10 mumol l-1 physostigmine (46 mumol l-1) and bethanechol (142 mumol l-1). Compared to carbachol and methacholine which increased force by 100% of control, the increase induced by acetylcholine and bethanechol was only 64 and 58%, respectively. Atropine shifted the concentration-effect curves of all choline esters to higher concentrations. Choline esters caused intracellular Na+ activity to increase in the quiescent papillary muscle. This effect was reversed by atropine. Oxotremorine produced a small concentration-dependent positive inotropic effect (about 30% of the maximal effect of carbachol) which was resistant to atropine. Oxotremorine was a potent inhibitor of the positive inotropic effect of choline esters, and did not cause an increase in intracellular Na+ activity in the quiescent papillary muscle. The results show that muscarinic receptors of the ventricular myocardium mediate two inotropic effects, which are opposite in direction and differ in their concentration-dependence by a factor of 100. Although agonists differentiate between both inotropic effects, it is unknown whether the receptors involved represent receptor states or separate receptor subpopulations. The negative inotropic effect of choline esters and of oxotremorine can be best explained by adenylate cyclase inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of eugenol, an essential oil, on the mechanical and electrical activities of cardiac muscle

Eugenol (EUG) acts as a calcium antagonist but effects on the contractile proteins could also occur. We investigated inotropic effects of EUG in rat left ventricular papillary muscles, measuring isometric force, time variables, and post rest potentiation and EUG actions on the effects of Ca2+ (0.62 to 2.5 mM) and isoproterenol (5 ng/ml), on myosin ATPase activity and on the calcium currents in single ventricular myocytes. EUG reduced tension and time variables without altering the sarcoplasmic reticulum activity increasing post-pause relative potentiation. Isoproterenol and Ca2+ counteract these negative inotropic effects. Tetanic tension diminished, but not the myosin ATPase activity suggesting an isolated sarcolemmal effect. EUG 0.1 mM decreased the Ca2+ current amplitude in the entire potential range tested and 0.5 mM almost completely blocked this inward current. Results suggested that EUG depresses force without affecting the contractile machinery and its action is the only dependent blockade of the calcium inward current.     

Enhancement of amrinone-induced positive inotropy in rabbit papillary muscles with depressed contractile function: effects on cyclic nucleotide levels and phosphodiesterase isoenzymes.

The inotropic activity of amrinone and its effects on cyclic nucleotide levels in rabbit papillary muscles with normal and depressed contractile function have been compared. The effects of amrinone on the cyclic (c) AMP hydrolytic activity of cyclic nucleotide phosphodiesterase (PDE) isoenzymes were also examined. Amrinone (2.4 x 10(-4) - 1.2 x 10(-3) M) produced a relatively weak (maximal increase 11%) positive inotropic effect in papillary muscles stimulated at the near optimal stimulation frequency of 1 Hz. In contrast, large positive inotropic responses (maximal 138-200%) were obtained with amrinone in papillary muscles in which contractile force had been depressed by: (a) lowering stimulation frequency to 0.4 Hz, (b) reducing extracellular Ca2+ concentration from 2.5 x 10(-3) M to 6.3 x 10(-4) M, (c) prior addition of sodium pentobarbitone (6.5 x 10(-4) M). The EC50 values for amrinone under conditions (a), (b), and (c) were 3.0 x 10(-3), 2.6 x 10(-3), and 2.8 x 10(-3) M, respectively. Force-frequency curves in rabbit papillary muscles were compared at normal (2.5 x 10(-3) M) and low (6.3 x 10(-4) M) extracellular Ca2+ concentration. Contractions at low frequencies of stimulation (less than 0.4 Hz) were less sensitive to removal of extracellular Ca2+ than higher stimulation rates indicating that in the former situation, recycling of intracellular Ca2+ is more important for maintaining contractile force.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of tiamulin on contractile and electrical responses in isolated thoracic aorta and cardiac muscle of guinea-pigs.

The inhibitory effect of tiamulin, an antibiotic produced by Pleurotus mutilis, on contractile and electrical responses in isolated thoracic aorta and cardiac muscle of guinea-pigs was studied. In the thoracic aorta, tiamulin with an IC50 of 9.7 x 10(-6) M inhibited sustained contractions induced by isosmotically added 60 mM KCl. The inhibitory effect of tiamulin on a Ca(2+)-induced contraction in a depolarized muscle was competitively antagonized by raising external Ca2+ concentration. Bay K 8644 (10(-7) M) antagonized tiamulin's inhibition of the Ca(2+)-induced contraction. Tiamulin (2 x 10(-5) M) decreased the elevated cytoplasmic Ca2+ level measured by the fura 2 AM method in the depolarized muscle. In high K(+)-isoprenaline-treated left atria, tiamulin (2 x 10(-5)-2 x 10(-4) M) produced negative inotropic effects. On the other hand in the membrane action potential of papillary muscles, tiamulin (2 x 10(-6)-2 x 10(-4) M) produced decreases in action potential and durations and 2 x 10(-4) M tiamulin depressed the slow response action potential in depolarized muscles. Tiamulin produced prolongations of the PR interval in ECG, negative chrono- and inotropic effects, and an increase in perfusion flow in guinea-pig isolated and perfused hearts. These effects of tiamulin on the aorta or cardiac muscle were similar to those of verapamil and nifedipine. These results suggest that both the inhibitory action of tiamulin on the high K(+)-induced contraction in the aorta and the negative inotropic effect of tiamulin on the cardiac muscle are due to an inhibition of Ca2+ entry through the voltage-dependent Ca2+ channels of cells of both these muscles.     

Adenosine inhibits the positive inotropic effect of 3-isobutyl-1-methylxanthine in papillary muscles without effect on cyclic AMP or cyclic GMP.

1 Adenosine and the adenosine receptor agonist (-)-N6-phenylisopropyladenosine (PIA) produced a small positive and negative inotropic effect, respectively, in isolated electrically driven papillary muscles of guinea-pigs. 2 Adenosine (100 mumol l-1) had no effect on cyclic AMP or cyclic GMP content. PIA (100 mumol l-1) slightly increased cyclic AMP. 3 In the presence of 3-isobutyl-1-methylxanthine (IBMX; 60 mumol l-1), which increased force of contraction 2 fold, adenosine and PIA exerted strong negative inotropic effects. PIA was more potent than adenosine (mean IC25 2.1 and 168 mumol -1, respectively). 4 In contrast, the nucleosides did not affect the increase in force of contraction produced by elevating extracellular Ca2+ concentration. 5 The IBMX-antagonistic effects of adenosine and PIA were not accompanied by modification of the IBMX-induced increase in cyclic AMP and cyclic GMP. 6 The effects of adenosine and PIA on force of contraction were accompanied by a partial reversal of the IBMX-induced increase in the maximal rate of depolarization of slow action potentials. 7 It is concluded that adenosine and PIA are able to attenuate the positive inotropic effect of a phosphodiesterase inhibitor. This effect is unlikely to be due to a reduction of the IBMX-induced increase in cyclic AMP content. It is conceivably due to an inhibition of the stimulant action of cyclic AMP on slow Ca2+ channels leading to the reduction of the slow inward current which in turn reduces force of contraction.     

Inotropic effects and mechanisms of matrine, a main alkaloid from Sophora flavescens AIT

It has been well documented that matrine, a tetracyclo-quinolizindine alkaloid, possessed a positive inotropic effect. However, the underlying mechanisms at the cellular and ion channel levels have not been completely clarified. Therefore, the present study was designed to identify the cellular target and the mechanisms of inotropic effect of matrine. Guinea pig papillary muscles were used to study the contractile force of the heart and ventricular myocytes were used to study L-type calcium channel (ICa-L) and intracellular calcium concentration ([Ca2+]i). In electrically driven papillary muscles, matrine enhanced the contractile force in a dose-dependent manner and the positive inotropic effect was not inhibited by alpha- and beta-adrenergic receptor antagonists. In ventricular myocytes, matrine also increased ICa-L in a dose-dependent manner and shifted the inactivation curve toward right. Matrine markedly enhanced the KCl-induced elevations of [Ca2+]i. In a conclusion, ICa-L might be a main target of matrine. Matrine enhanced [Ca2+]i by stimulating ICa-L and exerted positive inotropic effects on electrically driven guinea pig papillary muscles.     

Voltage-dependent effects of YC-170, a dihydropyridine calcium channel modulator,in cardiovascular tissues

Voltage-dependent effects of YC-170, a putative calcium channel activator, were examined and compared with those of Bay K 8644 in isolated guinea-pig cardiac tissues and rabbit aortae. In guinea-pig left atria superfused with a normal bathing solution (4 mmol/l K+), both YC-170 (10 mumol/l) and Bay K 8644 (1 mumol/l) produced a positive inotropic action accompanied by a prolongation of action potential durations (APDs). In normally-polarized guinea-pig papillary muscles Bay K 8644 increased force of contraction (fc) and APDs. However, YC-170 failed to increase fc in spite of a slight prolongation of APDs. In papillary muscles partially depolarized by 25 mmol/l K+ solution, Bay K 8644 enhanced the electrically-induced slow action potentials and contractile force. In contrast with Bay K 8644, YC-170 significantly depressed the slow action potentials and decreased fc. YC-170 also showed the depressant action on the slow action potentials induced by isoproterenol (0.1 mumol/l), histamine (3 mumol/l) and tetraethylammonium (10 mmol/l) plus high Ca2+ (4 mmol/l). In sinoatrial node cells of guinea-pig right atria Bay K 8644 produced a positive chronotropic action with increases in the maximum rate of rise (Vmax) and action potential amplitude (APA), whereas YC-170 produced a negative chronotropic action with decreases in Vmax and APA. In the rabbit aortic strips preincubated with bathing solution containing various concentrations of K+ (15, 20, 30 and 40 mmol/l), Bay K 8644 produced concentration-dependent contractions in a range of concentrations up to 0.3 mumol/l. However, when the concentration exceeded 1 mumol/l, Bay K 8644 caused a slight relaxation, irrespective of the K+ concentrations of bathing solution. YC-170 in concentrations of 10 and 30 mumol/l contracted the aortic strips placed in 5.9 or 15 mmol/l K+ bathing solution, but caused relaxation in 30 or 40 mmol/l K+ bathing solution. These results suggest that YC-170 is a dihydropyridine calcium channel modulator which behaves as a Ca2+ channel agonist in tissues of high membrane potentials, but as a Ca2+ channel antagonist in tissues of low membrane potentials.     

Cardiodepressant actions of the orally active male contraceptive, gossypol, in guinea-pig heart muscle

We have previously shown that gossypol has direct actions on isolated atrial muscle preparations. The possible mechanisms responsible for the transient positive and sustained negative inotropic effects of gossypol were examined under conditions that modify Ca2+ pools involved in contractile activation. In Langendorff preparations obtained from guinea-pig or rat heart, gossypol produced marked negative inotropic and arrhythmogenic effects but failed to produce a positive inotropic effect. Langendorff preparations were significantly more sensitive than atrial muscle preparations. In atrial muscle preparations, the negative inotropic effect of gossypol was not specific to utilization of superficial or intracellular Ca2+ pools; force-staircase phenomenon observed between 0.5 and 3 Hz, contractions elicited by slow action potentials in partially depolarized muscle, the inotropic effect of extracellular Ca2+ and potentiated post-rest contractions were all suppressed by gossypol to the similar extent. Low external Na+ concentrations abolished the positive inotropic effect of gossypol without affecting the negative inotropic effect. A low extracellular Ca2+ concentration enhanced the transient positive inotropic effect and delayed development of the negative inotropic effect. Simultaneous reduction of extracellular Na+ and Ca2+ concentrations abolished the positive inotropic effect and enhanced the negative inotropic effect. Gossypol inhibited ATP-dependent Ca2+ uptake by sarcolemmal vesicles obtained from dog heart. These results indicate that the actions of gossypol on cardiac muscle is not specific to utilization of either the superficial or intracellular Ca2+ pools involved in contractile activation.     

A comparison of the cardiotonic effects of AR-L115 and AR-L57: evidence for distinct inotropic mechanisms

AR-L57 and AR-L115 have been of interest as inotropic agents for management of heart failure. Although their physiological effects are well documented, their mechanism(s) of action are unclear. Both AR-L57 and AR-L115 increased contractile force of cat papillary muscles in concentration-dependent manners; these effects were independent of either alpha- or beta-adrenoceptor stimulation. To determine if these effects occurred via a cAMP-dependent mechanism, cardiotonic actions were studied in the presence of carbachol. Muscarinic stimulation of papillary muscles attenuated contractile responses to AR-L115 thus implying a cAMP-mediated response. By contrast, carbachol did not alter the dose-response profile to AR-L57. In addition, AR-L115 potentiated the inotropic actions of isoproterenol whereas AR-L57 was ineffective. Both AR-L57 and ouabain increased diastolic resting tension in papillary muscles--a phenomenon associated with a state of Ca2+ overload; AR-L115 was without effect. In anesthetized dogs, i.v. AR-L57 and AR-L115 increased contractility and heart rate while reducing mean arterial blood pressure. Both agents had similar rates of onset (10-15 s) and durations of action (40-60 min). Although in vitro studies clearly indicate that AR-L57 and AR-L115 enhance inotropic state by distinct mechanisms, their in vivo cardiovascular profiles are comparable.     

Inhibition by glibenclamide of negative chronotropic and inotropic responses to pinacidil, acetylcholine, and adenosine in the isolated dog heart.

The blocking effects of glibenclamide on the chronotropic and inotropic responses to K+ channel openers pinacidil (ATP-sensitive) and acetylcholine (ACh) or adenosine (receptor-operated) were investigated in the isolated, blood-perfused canine atrium or ventricle. Glibenclamide (0.1-3 mumol) induced no significant cardiac effects. Cumulative administration of pinacidil (0.03-3 mumol) dose-dependently decreased sinus rate much less than the contractile force of the atrial and ventricular muscles. Glibenclamide similarly inhibited the negative chronotropic and inotropic responses to pinacidil in a dose-related manner. A high dose of glibenclamide (3 mumol) slightly but significantly attenuated the negative chronotropic and inotropic responses to ACh and adenosine but not to verapamil. These results demonstrate that glibenclamide inhibits the negative chronotropic and inotropic responses to the ATP-sensitive K+ channel opener pinacidil and the receptor-operated K+ channel openers ACh and adenosine but more selectively antagonizes the responses to pinacidil in the dog heart and suggest that in contrast to ACh and adenosine, an ATP-sensitive K+ channel opener has a greater effect on the ventricle than on the sinoatrial node.     

Contractile proteins: possible targets for the cardiotonic action of MCI-154, a novel cardiotonic agent?

The effect on the contractile protein system of MCI-154, a novel and potent cardiotonic agent, was examined by using thin bundles of chemically skinned fibers from the guinea-pig papillary muscles. MCI-154 increased the Ca2+ sensitivity of the contractile protein system of the cardiac skinned fibers. Moreover, MCI-154 enhanced the maximum tension developed at pCa 4.4. These results suggest that an increase in responses of the contractile protein system to Ca2+ ion is, at least in part, responsible for the positive inotropic action of MCI-154.