Differential effects of trichothecenes on the canine cardiac action potential

We investigated the hypothesis that trichothecenes directly alter cardiac electrical activity. Action potentials were recorded from electrically stimulated canine false tendons before, during and after exposure to trichothecenes (1.0 mg/l). Action potentials recorded prior to and 60 min after exposure to trichothecenes were compared statistically. T-2 toxin decreased resting potentials in interventricular septum cells (7%), decreased action potential durations in papillary muscle cells (19%) and decreased both in false tendon cells (11% and 27%, respectively). Scirpentriol shortened durations of action potentials recorded in false tendon cells (24%), but had no other effects on any of the cell types tested. T-2 tetraol shortened the duration of interventricular septum cell action potentials (35%), but had no significant effects on other cardiac cells. Adenosine-5'-triphosphate (ATP) (final concentration 1100 mg/l) reversed all the effects of the trichothecenes on canine cardiac action potentials. These action potential changes may reflect a deficit of high energy phosphate and directly contribute to trichothecene-induced arrhythmias.     

Effects of nicorandil and its interaction with isoproterenol on force of contraction and cyclic nucleotide levels of canine atrial muscle: comparison with carbachol

Experiments were carried out on isolated canine right atria to investigate the effects of N-(2-hydroxyethyl)nicotinamide nitrate (nicorandil, SG-75) and its interaction with beta-adrenoceptor stimulation on the cyclic nucleotide levels accompanying inotropic changes. The results were compared with those during muscarinic receptor stimulation. The effects of nicorandil were similar to those of carbachol insofar as its negative inotropic effect was accompanied by a significant elevation of cyclic GMP levels in the absence of beta-adrenoceptor stimulation. However, the effects of nicorandil differed strikingly from those of carbachol in that the negative inotropic action of nicorandil was readily counteracted by isoproterenol, while that of carbachol was not. This difference may be ascribed to differences in cyclic AMP metabolism caused by these agents: carbachol but not nicorandil decreased the isoproterenol-induced elevation of cyclic AMP levels. The negative inotropic effects of muscarinic receptor stimulation on canine atria are associated with two different sorts of changes in cyclic nucleotide metabolism, i.e., cyclic GMP elevation and cyclic AMP reduction; nicorandil mimics the former but not the latter process.     

Differential effects of the antianginal drug nicorandil on canine arteries and veins.

Nicorandil, a potent coronary vasorelaxant used in the treatment of angina, has differential effects on arteries and veins in vivo. To explain this phenomenon, experiments were designed to characterize the relaxant and inhibitory actions of this compound on canine isolated arteries and veins. Paired rings of canine coronary, femoral, and saphenous arteries and saphenous veins were suspended at optimal length for isometric tension recording in organ chambers containing physiologic salt solution at 37 degrees C and gassed with 95% O2-5% CO2. In certain experiments, one ring of each pair was denuded of the endothelium. Removal of the endothelium did not affect nicorandil-induced relaxations of contracted blood vessels. Nicorandil exerted a differential relaxant effect on arteries and veins contracted with KCl (order of potency: saphenous vein greater than coronary artery greater than femoral artery). No difference in sensitivity to nicorandil was observed in arteries and veins contracted with prostaglandin F2 alpha. Contractions of saphenous arteries and veins to norepinephrine (NE) were equally sensitive to the inhibitory action of nicorandil. However, contractions of saphenous veins induced by sympathetic nerve stimulation were more sensitive to nicorandil than were contractions of saphenous arteries. Furthermore, nicorandil did not affect contractions to phenylephrine in saphenous veins, although contractions to B-HT 920 were virtually abolished by the compound. Saphenous veins contracted with St 587 were more sensitive to the relaxant action of nicorandil than when contracted with phenylephrine. These results suggest that nicorandil inhibits preferentially contractions of canine arteries and veins mediated by alpha 2- rather than alpha 1-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential antagonism by glibenclamide of the relaxant effects of cromakalim,pinacidil and nicorandil on canine large coronary arteries

Summary The relaxant mechanisms of action of cromakalim, pinacidil and nicorandil, potassium channel openers, on large epicardial coronary arteries were investigated in isolated canine left circumflex arteries contracted by 10^–7 mol/l U46619, a thromboxane A₂ analogue, or addition of 25 mmol/l KCl in comparison with nitroglycerin.Cromakalim (3 × 10^–8–3 × 10^–5 mol/l), pinacidil (10^–6–10^–4 mol/l), nicorandil (3 × 10^–6–10^–3 mol/l) and nitroglycerin (3 × 10^–8–10^–5 mol/l) all produced a concentration-dependent relaxation in both U46619- or KCl-contracted arteries. At their maximum effects pinacidil, nicorandil and nitroglycerin produced full relaxation in arteries contracted by either means. In contrast, cromakalim produced about a 73% relaxation in KCl-contracted arteries, although it caused full relaxation in U46619-contracted ones. In the presence of glibenclamide the concentration-relaxation curves for cromakalim in U46619- or KCl-contracted arteries underwent rightward parallel shifts. Schild regression had a slope of 1.00 and yielded a pA₂ of 7.47 for glibenclamide in U46619-contracted arteries, and corresponding values obtained in KCl-contracted arteries were 0.86 (not significantly different from unity) and 7.28. The concentration-relaxation curves for pinacidil in U46619-contracted arteries also underwent rightward parallel shifts in the presence of glibenclamide, however, Schild regression had a slope of 0.60. The concentration-relaxation curves for pinacidil in KCl-contracted arteries underwent rightward parallel shifts only to a limited extent in the presence of glibenclamide. The concentration-relaxation curves for nicorandil and nitroglycerin in U46619- or KCl-contracted arteries were not affected by glibenclamide in concentrations which antagonized cromakalim. The concentration-relaxation curves for nicorandil or nitroglycerin in U46619-contracted arteries were shifted by methylene blue (10^–5 mol/l) to the right without suppression of the their maximum effects. Similar curves for cromakalim were not affected at all by this concentration of methylene blue. The concentration-relaxation curves for nicorandil in U46619-contracted arteries determined in the presence of methylene blue (10^–5 mol/l) and glibenclamide (3 × 10^–7, 10^–6 and 3 × 10^–6 mol/l) were not significantly different from those in the presence of methylene blue alone.These results indicate the following: In canine large epicardial coronary arteries (1) cromakalim produced relaxation by the mechanism antagonized by glibenclamide, probably opening ATP-sensitive potassium channels, (2) pinacidil did so by the mechanism shared with cromakalim and by one not antagonized by glibenclamide as well, and (3) nicorandil did so exclusively by the mechanism of action as a nitrate. Send offprint requests to N. Taira at the above address     

Dissimilarity in the mechanisms of action of KRN2391, nicorandil and cromakalim in canine renal artery

Abstract— In the present study, we examined the mode of action of KRN2391 (N-cyano-N′-(2-nitroxyethyl)-3-pyridinecarboximida-mide monomethanesulphonate) in isolated canine renal artery compared with those of nicorandil and cromakalim. KRN2391 (10^?8-3 × 10^?5 m ), nicorandil (10^?7-3 × 10^?4 m ) and cromakalim (10^?8-3 × 10^?5 m ) relaxed renal arteries contracted by 25 Mm KCl in a concentration-dependent manner. KRN2391-induced relaxation was inhibited by methylene blue (10^?5 m ) and glibenclamide (10^?6 m ). Nicorandil-induced relaxation was inhibited by methylene blue, but not by glibenclamide. The concentration-relaxation curve for cromakalim displayed a rightward parallel shift in the presence of glibenclamide. In the control observation, KRN2391 and nicorandil also produced full relaxation, but cromakalim did not. The present results suggest that KRN2391 acts as both a nitrate and a potassium channel opener, and nicorandil acts only as a nitrate and only in canine renal artery.     

Differential effects of quinidine on transmembrane action potentials of normal and infarcted canine Purkinje fibers.

Fourteen days after proximal ligation of the left anterior descending coronary artery (LAD) of mongrel dogs, the effects of quinidine on action potentials of normal and infarcted Purkinje fibers were evaluated. The concentration-dependent (10(-7)-3 x 10(-5) M) and frequency-dependent (1 and 3 Hz) actions of quinidine were evaluated by the following parameters: maximum upstroke velocity (Vmax), action potential duration at 50 and 95% repolarization (APD50, APD95), effective refractory period (ERP), resting membrane potential (RMP), and action potential amplitude (APA). Quinidine reduced Vmax in normal and abnormal Purkinje fibers in a concentration- and frequency-dependent manner; these effects were more pronounced in infarcted tissue. The APD50 was shortened significantly at 1 Hz in noninfarcted Purkinje fibers, whereas in infarcted Purkinje fibers quinidine had no effect on APD50. The APD95 was not significantly altered by quinidine in normal Purkinje fibers; in infarcted areas APD95 was significantly prolonged at 1 and 3 Hz. The effective refractory period (ERP) was prolonged in normal and infarcted Purkinje fibers, these effects were more marked in ischemically damaged fibers. No effects were observed on resting membrane potential (RMP). APA was reduced significantly after quinidine at 1 and 3 Hz; there was no difference between normal and infarcted tissue. These data indicate a differential effect of quinidine in normal and infarcted Purkinje fibers which may be an important mechanism of action of quinidine in infarcted tissue.     

Spasmolytic action of nicorandil in canine conductive coronary arteries in vivo is not modified by glibenclamide.

The spasmolytic effects of nicorandil, cromakalim, and nitroglycerin on coronary arteries were investigated by angiographic technique in anesthetized dogs. With intracoronary arterial (i.a.) U 46619, a thromboxane A2 mimetic, the diameter of coronary arteries decreased in a sustained manner by 36.1 +/- 1.6% from control levels (coronary spasm). With a successive i.a. injection of nicorandil (300 micrograms), cromakalim (30 micrograms), or nitroglycerin (3 micrograms), the diameter recovered control levels (102.9 +/- 3.9, 96.8 +/- 5.6, and 100.1 +/- 4.3%, respectively). In dogs treated intravenously (i.v.) with glibenclamide, a pharmacologic antagonist of K-channel openers, the spasmolytic effect of cromakalim was significantly reduced, whereas the activity of nicorandil or nitroglycerin remained unaffected. We also investigated a possible modification by glibenclamide of the increase in coronary blood flow (CBF) induced by i.a. nicorandil and cromakalim in anesthetized dogs. The dose-dependent blood flow responses to cromakalim and nicorandil were significantly attenuated by glibenclamide, whereas the response to nitroglycerin remained unaffected. These results suggest that the spasmolytic effect of nicorandil on canine conductive coronary vessels is not mediated by K-channel opening but by a nitroglycerin-like action and that the dilatation of resistive coronary vessels induced by nicorandil may be largely due to its action as a K-channel opener.     

Lack of effects of carbachol on the Na-Ca exchange mechanism in frog atrial muscle treated with goniopora toxin

Carbachol (CCh) at a concentration of 10(-7) M completely inhibited the twitch contraction of frog atrial muscle. However, when the preparation was treated with goniopora toxin (GPT), a selective inhibitor of Na channel inactivation, and the twitch contraction was augmented through the activation of Na-Ca exchange by this toxin, the reduction in contractile amplitude by CCh was only about 30% even at higher concentrations. The maximum rate of rise of the twitch contraction was not affected by CCh in GPT-treated preparations. The time course of configuration change of the twitch contraction after application of CCh in GPT-treated muscle indicated that the attenuation of amplitude preceded the shortening of duration. The residual contraction under the combined treatments with GPT and CCh was abolished by removal of external Ca++ or addition of TTX. CCh only moderately shortened the action potential which was prolonged by GPT, and further addition of TTX abolished the action potential. From these results, we suggest that CCh does not influence the twitch contraction which is augmented via the activation of the Na-Ca exchange mechanism in frog atrial muscle.     

苦参碱对心房颤动犬心房肌I_(KM3)电流的作用

目的探讨正常和持续性心房颤动时犬心房肌M3受体介导IKM3电流的变化及苦参碱对IKM3的作用,为筛选抗心律失常药物作用靶点提供理论和实验依据。方法建立快速心房起搏致心房颤动犬模型,通过膜片钳技术比较犬心房肌正常和模型组电流变化及药物作用的不同。结果持续性心房颤动犬心房肌IKM3电流密度明显增高(实验电压+50mV时,232±81pAvs198±80pA,n=4,P<0.05),苦参碱对IKM3电流有抑制作用,且对正常组抑制作用明显高于模型组。结论M3受体及其介导的IKM3电流可能是治疗房颤的新靶点。     

Failure of dibutyryl and 8-bromo-cyclic GMP to mimic the antagonistic action of carbachol on the positive inotropic effects of sympathomimetic amines in the canine isolated ventricular myocardium.

Effects of carbachol, dbcGMP and 8-bromo-cyclic GMP on the positive inotropic actions of sympathomimetic amines and dbcAMP were studied on the canine isolated right ventricular myocardium. Carbachol alone did not substantially change the developed tension of the muscle, but did markedly shift the dose response curve for isoprenaline on the developed tension to the right and depressed the maximal response to the drug in a concentration dependent manner. The positive inotropic action of phenylephrine was affected by carbachol in the same manner as that of isoprenaline. DbcGMP in concentrations of 10(-3) M and higher produced a significant increase in the developed tension. The positive inotropic action of dbcGMP was partly inhibited by a beta-adrenoceptor blocking agent, pindolol. In the presence of dbcGMP, isoprenaline produced an action similar to that seen in the control experiment, but this action was not maintained on such a steady state level as in the control. This rapid decline of the effect of isoprenaline in the presence of dbcGMP was prevented by adding ascorbic acid to the organ bath. The positive inotropic actions of phenylephrine and of dbcAMP were not substantially affected by dbcGMP. 8-Bromo-cyclic GMP in a concentration of 10(-4) M did not change either the basal developed tension or the positive inotropic actions of noradrenaline and of isoprenaline. The present results indicate that these cyclic GMP derivatives are not able to mimic the antagonistic action of cholinergic stimulation on the positive inotropic action of adrenergic stimulation on the positive inotropic action of adrenergic stimulation on the canine ventricular myocardium.     

Differential responses to carbachol, sodium nitroprusside and 8-bromo-guanosine 3′,5′-monophosphate of canine atrial and ventricular muscle

1 The relation between force of contraction and cyclic nucleotide levels during muscarinic receptor stimulation, and after administration of sodium nitroprusside was assessed in canine isolated atrial and ventricular muscle.

2 The pD₂ value (negative logarithm of ED₅₀) for carbachol to decrease force of atrial contraction was similar to that required to inhibit adenosine 3′,5′-monophosphate (cyclic AMP)-mediated positive inotropic responses in ventricular muscle.

3 The cyclic AMP level of atrial muscle did not significantly change during carbachol-induced negative inotropic action, whilst the guanosine 3′,5′-monophosphate (cyclic GMP) level was elevated immediately after administration.

4 Sodium nitroprusside elevated cyclic GMP levels (without changing cyclic AMP levels) both in atrial and ventricular muscle. The force of atrial contraction was significantly reduced by the drug, whilst ventricular contractile force was unaffected.

5 8-Bromo-cyclic GMP markedly decreased contractile force in atrial muscle. In contrast, similar concentrations of 8-bromo-cyclic GMP had no effect on ventricular contractile force.

6 The positive inotropic action of phenylephrine on canine cardiac muscle, which is mediated through β-adrenoceptors, was unaffected either by sodium nitroprusside or by 8-bromo-cyclic GMP.

7 The present results suggest that the effect of muscarinic receptor stimulation in canine atrial and ventricular muscle is related to different changes in intracellular cyclic nucleotide metabolism. The direct myocardial depressant action on atrial muscle seems to be related to an elevation of cyclic GMP level, whilst a reduction of cyclic AMP may be responsible for the indirect action (`accentuated antagonism') in both atrial and ventricular muscle.

     

Frequency-dependent effects of several class I antiarrhythmic drugs on Vmax of action potential upstroke in canine cardiac Purkinje fibers

Vmax of the action potential upstroke in canine cardiac Purkinje fibers was studied in the presence of seven class I antiarrhythmic drugs--lidocaine (4 micrograms/ml), mexiletine (4 micrograms/ml), propranolol (0.9 micrograms/ml), procainamide (30 micrograms/ml), quinidine (5 micrograms/ml), flecainide (4 micrograms/ml), and disopyramide (3.1 micrograms/ml)--at constant cycle lengths (CCL) and after abrupt changes in cycle length (ACCL). The time constant of Vmax recovery after ACCL at a basic cycle length of 500 ms was 0.09 +/- 0.01 s for lidocaine, 0.18 +/- 0.03 s for mexiletine, 1.35 +/- 0.20 s for propranolol, 4.4 +/- 0.8 s for procainamide, 8.3 +/- 1.2 s for quinidine, 11.0 +/- 0.9 s for flecainide, and 37.9 +/- 9.4 s for disopyramide. These values were similar to those reported by others in guinea pig papillary muscle, and, with the exception of flecainide, conformed to the scheme proposed by Courtney (J Mol Cell Cardiol 1980; 12:1273-86) based on the molecular weight and lipid solubility hypothesis. Each drug altered the Vmax differently at CCL from after ACCL at the same diastolic intervals. The magnitude of these differences and the range of diastolic intervals at which they were present varied among different drugs. These observations explain differences in the drug effects on the Vmax of the regularly and prematurely occurring depolarizations. In the presence of lidocaine and mexiletine, the recovery kinetics of Vmax were not altered by CCL within the 300-1,500-ms range, and the magnitude of Vmax depression was not influenced by action potential duration within the 200-270-ms range.     

Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone

Dronedarone, a noniodinated derivative of amiodarone, is under evaluation as a potentially less toxic anti-arrhythmic alternative to amiodarone. The acute and chronic electrophysiologic effects of dronedarone and amiodarone were compared in isolated rabbit atrial muscle by microelectrode techniques. Four-week PO treatment with dronedarone or amiodarone increased action potential duration (APD90) (58 +/- 4 ms control versus 69 +/- 2 ms dronedarone, p < 0.01; 68 +/- 3 ms amiodarone, p < 0.01 for a 100-mg/kg/d dose) and effective refractory period (49 +/- 6 ms control versus 68 +/- 4 ms dronedarone, p < 0.01; 63 +/- 3 ms amiodarone, p < 0.01). The APD90 prolonged reverse rate-dependency. In contrast, acute superfusion with 10 microM dronedarone or amiodarone decreased APD90 (61 +/- 6 ms control versus 53 +/- 4 ms dronedarone, p < 0.05; 52 +/- 6 ms amiodarone, p < 0.05), effective refractory period (50 +/- 5 ms control versus 44 +/- 4 ms dronedarone, p < 0.05; 43 +/- 6 ms amiodarone, p < 0.05), and the maximum upstroke slope of the action potential (Vmax) (188 +/- 9 V/s control versus 182 +/- 11 V/s dronedarone p < 0.05; 182 +/- 11 V/s amiodarone, p < 0.05). Thus, chronic and acute electrophysiologic effects of dronedarone on rabbit atrial muscle are similar to those of amiodarone, suggesting a similar potential against atrial arrhythmias.     

Comparative effects of clarithromycin on action potential and ionic currents from rabbit isolated atrial and ventricular myocytes

Prolongation of QT interval by several antibacterial drugs is an unwanted side effect that may be associated with development of ventricular arrhythmias. The macrolide antibacterial agent clarithromycin has been shown to cause QT prolongation. To determine the electrophysiologic basis for this arrhythmogenic potential, we investigated clarithromycin effects on (i). action potentials recorded from rabbit Purkinje fibers and atrial and ventricular myocardium using conventional microelectrodes and (ii). potassium and calcium currents recorded from rabbit atrial and ventricular isolated myocytes using whole-cell patch clamp recordings. We found that (i). clarithromycin (3-100 microM) exerted concentration-dependent lengthening effects on action potential duration in all tissues, with higher efficacy and reverse frequency-dependence in Purkinje fibers. However, clarithromycin did not cause development of early afterdepolarizations, and the parameters other than action potential duration were almost unaffected; (ii). clarithromycin (10-100 microM) reduced the delayed rectifier current. Significant blockade (approximately 30%) was found at the concentration of 30 microM. At 100 microM, it decreased significantly the maximum peak of the calcium current amplitude but failed to alter the transient outward and inwardly rectifier currents. It was concluded that these effects might be an explanation for the QT prolongation observed in some patients treated with clarithromycin.     

Effects of nicorandil on electromechanical activity of frog atrial muscle

The effects of the antianginal drug nicorandil on electrical and mechanical activity of bullfrog atria were examined. The application of nicorandil at concentrations from 0.3 to 10 mM caused a negative inotropic effect without any appreciable change in the resting membrane potential. The amplitude of action potentials was attenuated. In the voltage clamp experiments, the slow inward current was slightly inhibited, but the background inward current and delayed outward current were not affected in the presence of nicorandil. The inward rectifying properties of time-independent outward current were slightly inhibited by 10 mM nicorandil. Nicorandil inhibited the caffeine-induced contractures elicited in the depolarized preparation, but had no effect on the contracture mediated through the Na-Ca exchange mechanism. These results suggest that the negative inotropic action of nicorandil is caused by inhibition of Ca influx and intracellular mobilization of Ca. Nicorandil had little effect on the potassium conductance in this preparation.     

Differential effects of prostaglandins on canine intrapulmonary arteries and veins

1 The sensitivity and contractility of isolated canine intrapulmonary arteries and veins to a variety of primary prostaglandin compounds was studied.

2 Intrapulmonary arteries produced no measurable contractile responses to prostaglandin A₁ (PGA₁), PGA₂, PGB₁, PGD₂, PGE₁, PGE₂ or to PGF_1α. However, high concentrations of both PGB₂ (> 10^-7 M) and PGF_2α (> 10^-6 M) elicited concentrated-related, but weak, contractile responses, measuring only 5-25% of KCl-induced maximum contractions.

3 Intrapulmonary arteries, partially contracted by 5-hydroxytryptamine (5-HT), exhibited concentration-related relaxations in response to PGE₁; PGE₂, PGA₁ or PGA₂ produced only weak superimposed contractions.

4 In contrast to intrapulmonary arteries, intrapulmonary veins contracted in a concentration-related fashion to all prostaglandins tested, where the contractile sensitivity was (based on EC₅₀ s and threshold concentrations): PGB₂ > PGB₁ > PGD₂ > PGF_2α > PGA₂ >> PGA₁ > PGF_1α > PGE₂ > PGE₁.

5 In terms of the ability to generate maximum contractile responses on intrapulmonary veins, the prostaglandins were also variable, with PGA₂ and PGB₂ being the most potent and PGD₂ the least potent.

6 Intrapulmonary veins, partially contracted by 5-HT, exhibited concentration-related relaxations to PGE₁ at low concentrations, followed by secondary contractile responses at higher concentrations.

7 Neither PGA₁ nor PGA₂ (3.4 × 10^-8 to 3.4 × 10^-5 M) inhibited or potentiated 5-HT responses of intrapulmonary arteries.

8 These data suggest that there are species, regional and major qualitative and quantitative, differences in the responsiveness of intrapulmonary arteries and veins to prostaglandin.

     

Effects of norfluoxetine on the action potential and transmembrane ion currents in canine ventricular cardiomyocytes

Norfluoxetine is the most important active metabolite of the widely used antidepressant compound fluoxetine. Although the cellular electrophysiological actions of fluoxetine are well characterized in cardiac cells, little is known about the effects of its metabolite. In this study, therefore, the effects of norfluoxetine on action potential (AP) configuration and transmembrane ion currents were studied in isolated canine cardiomyocytes using the whole cell configuration of patch clamp techniques. Micromolar concentrations of norfluoxetine (1–10 M) modified AP configuration: amplitude and duration of the AP and maximum velocity of depolarization were decreased in addition to depression of the plateau and elimination of the incisura of AP. Voltage clamp experiments revealed a concentration-dependent suppression of both L-type Ca²⁺ current, I_Ca (EC₅₀=1.13±0.08 M) and transient outward K⁺ current, I_to (EC₅₀=1.19±0.17 M) having Hill coefficients close to unity. The midpoint potential of the steady-state inactivation of I_Ca was shifted from –20.9±0.75 mV to –27.7±1.35 mV by 3 M norfluoxetine (P<0.05, n=7). No such shift in the steady-state inactivation curve was observed in the case of I_to. Similarly, norfluoxetine caused no change in the steady-state current–voltage relationship of the membrane or in the density of the inward rectifier K⁺ current, I_K1. All these effects of norfluoxetine developed rapidly and were fully reversible. Comparing present results with those obtained previously with fluoxetine, it can be concluded that norfluoxetine displays stronger suppression of cardiac ion channels than fluoxetine. Consequently, the majority of the cardiac side effects observed during fluoxetine treatment are likely to be attributed to its metabolite norfluoxetine.     

Differential relaxant effects of isoproterenol on methacholine- versus leukotriene D4-induced contraction in the guinea-pig trachea

The ability of isoproterenol to relax guinea-pig trachea was examined in tissues precontracted with three concentrations of methacholine or three corresponding equieffective concentrations of leukotriene D4. Although increasing the concentration of either contractile agent progressively shifted isoproterenol concentration-response curves to the right, the shifts produced by methacholine were greater than those produced by leukotriene D4. Thus, the sensitivity of tracheal smooth muscle to beta-agonists depends upon the initial contractile state of the tissue, and the type of agent used to induce tone.     

硝普钠与异丙肾上腺素松弛犬气管平滑肌的协同作用

目的：研究硝普钠（ＳＮＰ）与异丙肾上腺素（ＩＳＯ）对犬气管平滑肌松弛作用是否存在协同关系，并分析协同的机制。方法：采用放射免疫分析法测定犬气管平滑肌环核苷酸量，并用磷酸二酯酶（ＰＤＥ）同工酶抑制剂为工具分析ＳＮＰ与ＩＳＯ相互作用的机制。结果：ＳＮＰ（１～１００μｍｏｌ·Ｌ－１）增强ＩＳＯ（３０μｍｏｌ·Ｌ－１）对３μｍｏｌ·Ｌ－１乙酰甲胆碱预收缩的犬气管平滑肌的松弛作用。ＳＮＰ（１００μｍｏｌ·Ｌ－１）与ＩＳＯ（３０μｍｏｌ·Ｌ－１）对犬气管平滑肌松弛的协同作用伴有气管平滑肌中ｃＡＭＰ积聚比ＳＮＰ与ＩＳＯ单独时分别增加１．２倍与０．４倍。ＰＤＥⅤ抑制剂扎普司特（３μｍｏｌ·Ｌ－１）使ＳＮＰ的气管平滑肌ｃＧＭＰ积聚由２．４倍增加到４．６倍，可进一步增加气管松弛作用１．２倍。合并ＰＤＥⅢ抑制剂氰胍哒嗪（３０μｍｏｌ·Ｌ－１）和ＰＤＥⅣ抑制剂咯利普兰（３０μｍｏｌ·Ｌ－１）或合并ＳＮＰ（１００μｍｏｌ·Ｌ－１）和咯利普兰（３０μｍｏｌ·Ｌ－１）均能进一步增强ＩＳＯ的气管ｃＡＭＰ积聚与松弛作用。结论：ＳＮＰ是通过气管平滑肌ｃＧＭＰ含量增加而抑制ＰＤＥⅢ，导致ＳＮＰ与ＩＳＯ对气管松弛的协同作用。