Voltage-dependent Vmax blockade in Na+-dependent action potentials after beta 1- and H2-receptor stimulation in mammalian ventricular myocardium

In isolated papillary muscles of guinea pigs, the influence of isoproterenol, histamine, theophylline, and phenylephrine on the maximal rate of rise (Vmax) of Na+-dependent action potentials and on isometric contractile force was studied under rested state conditions. Isoproterenol (1 x 10(-7) mol/L), histamine (2 x 10(-5) mol/L), and theophylline (2 x 10(-3) mol/L) shifted the voltage dependence of Vmax into the hyperpolarizing direction and, consequently, led to a voltage-dependent Vmax blockade. The alpha-adrenoceptor agonist phenylephrine, on the other hand, proved to be ineffective in depressing Vmax. The beta-receptor blocker pindolol (4 x 10(-6) mol/L) or the H2-receptor blocker cimetidine (4 x 10(-5) mol/L) abolished the inhibitory effects of isoproterenol and histamine, respectively, and caused Vmax to return to the initial control value. A concentration-response relationship analysis at -65 mV revealed that isoproterenol exerted only a weak inhibitory effect on Vmax compared with its positive inotropic action. The IC50 value of the former effect amounted to approximately 5 x 10(-6) mol/L, but the EC50 value of the latter effect was 4 x 10(-8) mol/L. It is, therefore, concluded that, in physiologically relevant concentrations, beta-adrenergic agonists are unlikely to significantly modulate Na+-dependent excitability even in partially depolarized myocardium.     

Evidence against the role of alpha 1-adrenoceptor reserve in buffering the inhibitory effect of nifedipine on the contractility of canine vascular smooth muscle

The relationship between the postsynaptic alpha 1-adrenoceptor reserve and the sensitivity of vasoconstriction induced by alpha-adrenoceptor agonists to the dihydropyridine Ca2+ entry blocker nifedipine was investigated in isolated muscle strips of dog mesenteric artery (DMA) and saphenous vein (DSV). The amplitudes of the contractile responses of DMA induced by phenylephrine were the same as those in DSV in the presence and in the absence of extracellular Ca2+. The use of 3 x 10(-9) M phenoxybenzamine to irreversibly block the alpha 1-adrenoceptors revealed a marked difference in the size of the alpha 1-adrenoceptor reserve between DMA (40%) and DSV (7%). In spite of a larger receptor reserve, the contractile responses induced by phenylephrine in DMA were more sensitive to nifedipine compared with those in DSV. These results suggest that the postsynaptic alpha 1-adrenoceptor reserve in vascular smooth muscle, at least in DMA and DSV, does not play an important role in buffering the inhibitory effect of nifedipine on the contractile response to a full agonist of alpha 1-adrenoceptors. Other factors, such as the difference in the membrane depolarizing effect, the ability to utilize intracellular Ca2+ for contraction, and the possible existence of alpha 1-adrenoceptor subtypes, may contribute to the different inhibitory effects of nifedipine on these blood vessels.     

Role of the Na+-H+ exchanger (NHE1) in heart muscle function during transient acidosis. A study in papillary muscles from rat and guinea pig hearts

The sodium-hydrogen exchanger (NHE) helps the cell to recover from intracellular acidosis. In this study, we have investigated the effect of HOE 642 (a specific NHE1 blocker) on papillary muscles from rats and guinea pigs during transient acidosis and PKC activation by recording developed force (DF), action potential characteristics, and electrical conductance (stimulus-response interval). Two protocols were used, with or without HOE 642 (10(-5) mol/L): papillary muscle was exposed (i) for 15 min to a glucose-free, nonoxygenated HEPES buffer containing lactate (20 mmol/L) (pH 6.8) followed by 15 min recovery or (ii) to a PKC activator (phorbolmyristate acetate (PMA) (10(-9) mol/L)) for 30 min. The DF after acidification remained significantly decreased in the NHE-blocked papillary muscles. During recovery from acidosis, papillary muscles exposed to HOE 642 remained at a higher electrical resistance. The present study shows that post-acidotic continued depression of DF and change in tissue electrophysiological properties might occur as a result of blocking the NHE. During infarct development, the tissue-protecting effect of NHE blockade has been well documented. When acidosis or reduced contractile function is present, however, blocking NHE by HOE 642 might not improve the situation.     

SUN 1165: a new antiarrhythmic Na current blocker in ventricular myocytes of guinea-pig

1. We compared the effect of a new antiarrhythmic compound, SUN 1165, on Na and Ca channels in papillary muscles and enzymatically dispersed single ventricular cells of guinea-pig. Action potential and contractile force in papillary muscle were measured by the conventional microelectrode technique and a strain gauge. The membrane currents were measured in internally perfused and voltage clamped cells by a single suction pipette technique. 2. In papillary muscles, SUN 1165 depressed the maximum rate of rise of action potential (Vmax) in a concentration dependent manner (IC30 = 1.7 X 10(-5) M) more markedly (about six times) than the contractile force. 3. In single ventricular cells, the Na current (INa) was reduced by the drug in a concentration dependent manner (IC30 = 9.1 X 10(-6) M). 4. It showed frequency-dependent block and the steady-state inactivation curve was shifted to more negative potentials. 5. The recovery of INa from inactivation was prolonged by SUN 1165. 6. The Ca current (ICa) was also blocked by the drug in a concentration dependent manner but much less than INa (IC30 = 5.5 X 10(-5) M). 7. These results suggested that SUN 1165 causes a selective inhibition of Na channels in guinea-pig ventricular cells at the antiarrhythmic concentrations.     

The electrophysiological and mechanical effects of atrial natriuretic peptide and acetylcholine on guinea pig ventricular papillary muscle

The direct effects of atrial natriuretic factor (ANF) and acetylcholine (ACh) on isolated guinea pig ventricular papillary muscle were studied. ANF (3 x 10(-9) - 3 x 10(-7) M), a cardiogenic hormone, had no significant electrical or mechanical effects on guinea pig papillary muscle driven at a frequency of 60 beats/min in normal (4 mM) and high [K]0 (27 mM) Tyrode solutions. On the other hand, ACh (3 x 10(-8) - 3 x 10(-7) M) caused a significant shortening of action potential duration and the contractile force showed no change or a slight decrease. At high concentration (5 microM), ACh reduced action potential durations at 50% and 90% repolarization (APD50 and APD90) by 10.5 +/- 2.1% and 12.4 +/- 1.8%, respectively, but the contractile force was slightly increased by 9.8 +/- 1.2%. In eleven of twenty-six preparations, spontaneous activity occurred and intermingled with driven activity. The ectopic rhythms were suppressed by ACh (1-5 microM). The changes in electrical but not mechanic activity induced by ACh were suppressed in the presence of five micromolar atropine. These results reveal that, in guinea pig papillary muscle, ANF had no direct chronotropic or inotropic effect. ACh may reduce APD and spontaneous discharges through an activation of muscarinic receptors but enhance twitch tension through other mechanisms.     

α2-肾上腺素受体对大鼠肠系膜动脉床降钙素基因相关肽释放的调节作用

降钙素基因相关肽（CGRP）从感觉神经末梢的释放受多种机制的调节。本文在离体灌流的大鼠肠系膜动脉床组织上,利用药理学工具药,研究了α2-肾上腺素受体对CGRP的基础和内毒素刺激后释放的作用。结果发现,α2-受体激动剂UK14304（3×10－6mol／L）可以显著抑制CGRP的基础释放和内毒素（1～5μg／ml）刺激后的释放,抑制幅度为22％～42％;用α2-受体拮抗剂Yohimbine（10－5mol／L）可以完全阻断UK14304的作用。结果表明突触前α2-受体对CGRP从外周阻力血管组织的释放,尤其是内毒素刺激后的释放具有抑制作用,在内毒素休克晚期,α2-受体功能减低可能介导了外周组织CGRP的过量释放。     

白藜芦醇甙对大鼠心室乳头状肌动作电位的影响及其离子机制(英文)

有研究表明白藜芦醇甙(polydatin)具有抗缺血性心律失常作用,但其电生理学机制尚未明了。本研究旨在应用细胞内记录和全细胞膜片钳方法,探讨白藜芦醇甙对大鼠心室乳头状肌动作电位的影响及其离子机制。结果显示:(1)白藜芦醇甙(50和100μmol/L)可剂量依赖性地缩短正常乳头状肌动作电位复极化50%时间(APD50)和90%时间(APD90)(P<0.01)。白藜芦醇甙对正常乳头状肌静息电位(resting potential,RP)、动作电位幅值(amplitude of action potential,APA)、超射值(overshoot,OS)和0期最大上升速度(Vmax)无影响(P>0.05)。(2)对部分去极化的乳头状肌,白藜芦醇甙(50μmol/L)不但缩短APD50和APD90,而且还降低动作电位OS、APA和Vmax(P<0.05)。(3)ATP敏感钾通道阻断剂格列本脲(10μmol/L)可部分阻断白藜芦醇甙(50μmol/L)的电生理效应。(4)一氧化氮合酶抑制剂L-NAME(1 mmol/L)对白藜芦醇甙的上述效应无影响。(5)白藜芦醇甙(25、50、75、100μmol/L)可浓度依...     

Participation of noradrenergic neurotransmission in angiotensin III-induced dipsogenic behavior in the rat.

Conscious, adult, male Sprague-Dawley rats, instrumented with in-dwelling cannula for drug application into the lateral cerebral ventricle, were used to evaluate the participation of noradrenergic neurotransmission in angiotensin III (AIII)-induced dipsogenic behavior. Intracerebroventricular (i.c.v.) administration of AIII (20, 40 or 80 pmol) elicited a robust and dose-related drinking response. Chemical lesion produced by i.c.v. injection of the catecholaminergic neurotoxin, 6-hydroxydopamine (25 micrograms x 3), or the selective noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (250 micrograms), promoted significant antagonization of the dipsogenic behavior produced by AIII (40 or 80 pmol, i.c.v.). Under equimolar doses (3.25 or 6.50 nmol), the specific alpha 1-adrenoceptor blocker, prazosin, antagonized; the specific alpha 2-adrenoceptor antagonist, yohimbine, enhanced; and the nonselective alpha-adrenoceptor blocker, phentolamine, elicited minimal action, on AIII (40 pmol)-induced drinking response. These results suggest that central noradrenergic neurotransmission may participate actively in AIII-induced dipsogenesis, in a process that may involve both alpha 1- and alpha 2-adrenoceptors.     

Postsynaptic alpha adrenoceptors on vascular smooth muscle

A heterogeneous population of alpha adrenoceptors mediates vasoconstriction in the canine saphenous vein (CSV). Studies with isolated strips of venous smooth muscle incubated with selective alpha-adrenoceptor agonists and antagonists revealed that both alpha 1 and alpha 2 adrenoceptors exist independently in this tissue and both subtypes mediate a contractile response. Measurement of contractile responses in reduced or zero external calcium conditions indicates that stimulation of alpha 1 adrenoceptors induces contractions by influx of extracellular calcium and release of calcium from internal stores. In contrast, 45Ca uptake studies suggest that activation of the postsynaptic alpha 2 adrenoceptor produces vasoconstriction dependent only on influx of extracellular calcium. The influx of calcium produced by the selective alpha 2-adrenoceptor agonist BHT-920 is inhibited by calcium entry blockers. Measurements of transmembrane potentials from smooth muscle cells of the CSV suggest that alpha 1-adrenoceptor activation produces depolarization and contraction (electromechanical coupling) whereas alpha 2-adrenoceptor stimulation does not result in concentration-dependent depolarization of the smooth muscle cells (pharmacomechanical coupling).     

胍基丁胺在离体豚鼠乳头肌的电生理效应

应用细胞内微电极技术,观察了胍基丁胺（ａｇｍａｔｉｎｅ,ＡＧＭ）对豚鼠乳头肌细胞的电生理效应。结果表明：（１）ＡＧＭ浓度依赖地缩短正常乳头肌动作电位的时程;（２）对部分去极化的乳头肌,ＡＧＭ（１ｍｍｏｌ／Ｌ）除缩短动作电位时程外,还抑制动作电位零相最大上升速度,并降低其幅值和超射值;（３）预先应用一氧化氮合酶抑制剂ＬＮＡＭＥ（０５ｍｍｏｌ／Ｌ）,不能影响ＡＧＭ（１ｍｍｏｌ／Ｌ）的电生理效应;（４）预先应用咪唑啉受体（ｉｍｉｄａｚｏｌｉｎｅｒｅｃｅｐｔｏｒ,ＩＲ）和α２肾上腺素能受体（ａｌｐｈａ２ａｄｒｅｎｅｒｇｉｃｒｅｃｅｐｔｏｒ,α２ＡＲ）拮抗剂ｉｄａｚｏｘａｎ（０１ｍｍｏｌ／Ｌ）,则可完全阻断ＡＧＭ（１ｍｍｏｌ／Ｌ）的电生理效应。以上结果提示,ＡＧＭ对乳头肌的电生理效应似由α２ＡＲ和ＩＲ介导,并与胞浆内Ｃａ２＋减少有关。