Αlpha1B-adrenoceptor-mediated positive inotropic and positive chronotropic actions in the mouse atrium.

Modulation of cardiac contractility by α-adrenoceptor is well known in several mammals. Mice are useful experimental animals, but α-adrenoceptor-mediated responses have been examined only in the ventricles. To determine function of α-adrenoceptors in the atrium, effects of α-adrenoceptor agonists on spontaneous contraction and electrical-field stimulation (EFS)-induced contraction were examined. In addition, expression of α1A, α1B, α1D and ß1-adrenoceptor mRNAs were examined. In the right atrium, noradrenaline and phenylephrine caused positive inotropic and positive chronotropic actions. However, methoxamine, clonidine and xylazine caused positive inotropic actions, but contractile frequency was decreased at high concentrations. Phenylephrine-induced positive inotropic and chronotropic actions were partially decreased by propranolol, and both actions remained in the presence of propranolol were inhibited by phentolamine or prazosin. A low concentration of silodosin (<100 nM) did not but a high concentration (1 µM) decreased the phenylephrine-induced chronotropic actions. Negative chronotropic actions of clonidine and xylazine were insensitive to propranolol and phentolamine. The EFS-induced contraction of the left atrium was potentiated by noradrenaline, phenylephrine and methoxamine but was not changed by clonidine or xylazine. Propranolol partially decreased the actions of phenylephrine, and prazosin caused additional inhibition. Expression of ß1-, α1A-, α1B- and α1D-adrenoceptor mRNAs was found in the atrium, and the expression level of ß1-adrenoceptor was the highest. Of α1-adrenoceptors, the expression level of α1B was higher than that of α1A and α1D. In conclusion, α1B-adrenoceptors are expressed in the mouse atrium and mediate both positive chronotropic and inotropic actions. In contrast, the α2-adrenoceptor is not functional in the isolated atrium.

Cardiotonic actions of quercetin and its metabolite tamarixetin through a digitalis-like enhancement of Ca2+ transients.

The plant-derived flavonoid, quercetin (QCT), has many biological actions, including cardioprotective actions, resulting from its antioxidant and anti-inflammatory effects. In this study, effects of QCT and its metabolites on the contraction and Ca2+ transients (CaT) of mouse single cardiomyocytes were simultaneously measured and compared with those of isoproterenol and digoxin. Furthermore, cardiac function and plasma concentrations were analyzed after bolus intravenous administration of QCT in mice. QCT and its metabolite, tamarixetin, as well as isoproterenol and digoxin, enhanced the contraction and CaT of cardiomyocytes. The inotropic action of isoproterenol was accompanied by an increase in the velocities of sarcomere shortening and relengthening and CaT decay through activation of cAMP-dependent protein kinase; however, no such lusitropic effects accompanied the inotropic action of QCT, tamarixetin or digoxin. Intravenous administration of QCT to mice resulted in a sustained increase in cardiac systolic function; QCT was rapidly metabolized to tamarixetin and its plasma concentration was maintained at high levels over a similar time frame as the enhancement of cardiac systolic function. These results suggest that QCT exerts a cardiotonic action in vivo at least, in part, through digitalis-like enhancement of CaT by itself and its metabolite tamarixetin.

Neuropeptide Y (NPY) inhibits spontaneous contraction of the mouse atrium by possible activation of the NPY1 receptor.

Neuropeptide Y (NPY) causes various central and peripheral actions through activation of G-protein-coupled NPY receptors. Although a species-dependent difference in cardiac actions of NPY has been reported, the responses to NPY have not been examined in mice, widely used experimental animals. This study aimed to clarify the responses to NPY and the receptor subtype involved in the responses in mouse atrium. Neuropeptide Y caused negative inotropic and negative chronotropic actions in spontaneous beating right atria. Negative inotropic actions were more marked than negative chronotropic actions. Therefore, negative inotropic actions were studied in detail for evaluation of the NPY-induced cardiac actions in mouse atrium. Neuropeptide Y-induced negative inotropic actions were not affected by atropine but were abolished in the atria from pertussis toxin-treated mice. In isolated atrial preparations from reserpine-treated mice, NPY-induced negative inotropic actions were significantly attenuated. [Leu31, Pro34]-NPY, but not peptide YY, was effective in decreasing spontaneous contraction in atrial preparations. Although Y1 , Y2 , Y4 and Y5 receptor mRNAs were expressed almost equally in the brain, NPY1 receptor mRNA was dominantly expressed in the atrium. In conclusion, NPY caused negative inotropic and chronotropic actions through activation of the Y1 receptor in the mouse atrium. A high expression level of Y1 mRNA in the atrium suggests a functional role of NPY in the regulation of mouse cardiac contraction.

Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs.

An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to qualitatively and quantitatively clarify the effects of rapidly activating delayed rectifier K+ current (IKr)-selective blockade by E-4031 on the electro-mechanical relationship in vivo. We adopted the halothane-anesthetized canine model (n=4). E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same. Since these observed changes were solely caused by the repolarization delay, the inversion of electro-mechanical coupling may have a similar extent of sensitivity to QT-interval prolongation as a surrogate marker in predicting the onset of IKr inhibitor-induced arrhythmias.

Positive inotropic action of dimethylamiloride in normal rat isolated hearts and papillary muscle and its primary mechanism / 中国药理学通报

Aim To study the inotropic action of DMA in normal rat isolated hearts and papillary muscle and search for its primary mechanism.Methods With Lansendorff-perfusion and isolated papillary muscle perfusion,cardiac performance and the systolic function of papillary muscle were measured to estimate the inotropic action of DMA;L-calcium channel blocker and sodium calcium exchanger(NCX)inhibitor were used to search for its primary mechanism.Results ①(1~20)?mol?L-1 DMA exerted a positive inotropic action in normal rat isolated hearts,that is in Langendorff-perfused hearts,DMA enhanced cardiac performance,i.e.LVSP-LVDP,+dp/dtmax,-dp/dtmax significantly(P

Effect of Tetrahydroisoquinoline Alkaloids on the alpha-adrenoceptors in Rat Aorta and Brain Homogenates

Tetrahydroisoquinoline(THI) alkaloids can be considered as cyclized derivatives of simple pthylamines and many of them, especially with 6,7-disubstitution, demonstrate relatively high affinity for catecholamines. In the present study, pharmacological action of limited series of THI has been examined using rat isolated atria and aorta. In addition, (H) prazosin displacement binding study with THI compounds using rat brain homogenates was performed to find out if these probes to have a-adrenoceptor affinity. In isolated rat atria, all THls and dobutamine increased heart rate and contractile force. In the presence of propranolol, the concentration response curves of YS 49 and YS 51 shifted to the right resulting in 8.07+0.84 and 7. 93+0.11 of pA values, respectively. The slope of each compound was not deviated from unity, indicating that these chemicals are highly competitive at the cardiac beta1-adrenoceptors. YS 49, YS 51 and higenamine showed alpha1- adrenoceptor affinity in rat brain in which the dissociation constant(K,) was 2.75, 2.81 and 1.02pM, respectively. It is concluded, therefore, that THI alkaloids have considerable affiniyt to alpha1-adrenoceptors in rat aorta and atria. while these probes show relatively high affinity for cardiac beta1-adrenoceptors. The authors speculate that it is worthy investigating whether these chemicals are useful in the management of vasospasm of aneurysmal subarachnoid hemorrhage.

Comparison of inodilator effect of higenamine, YS49, YS51, tetra-hydroisoquinoline analogs, and dobutamine in the rat

Tetrahydroisoquinoline (THI) alkaloids can be considered as cyclized derivatives of simple phenylethylamines. Many of them, especially with 6,7-disubstitution, demonstrate a relatively high affinity for catecholamines. Present study examines the pharmacological action of limited series of THI, using rats' isolated atria and aorta. In addition, a (3H) prazosin displacement binding study with THI compounds was performed, using rat brain homogenates to investigate whether these probes have a-adrenoceptor affinity. We also compared the vascular relaxation potency of these probes with dobutamine. YS 49, YS 51, higenamine and dobutamine, concentration-dependently, relaxed endothelium-denuded rat thoracic aorta precontracted with phenylephrine (PE, 0.1 micrometer) in which pEC50 were 5.56-0.32 and 5.55+/-0.21, 5.99+/- 1.16 and 5.57+/-0.34, respectively. These probes except higenamine also relaxed KCl (65.4 mM)-contracted aorta. In isolated rat atria, all THIs and dobutamine increased heart rate and contractile force. In the presence of propranolol, the concentration response curves of YS 49 and YS 51 shifted to the right and resulted in pA2 values of 8.07+/-0.84 and 7.93+/-0.11, respectively. The slope of each compound was not deviated from unity, indicating that these chemicals are highly competitive at the cardiac beta-adrenoceptors. YS 49 YS 51, and higenamine showed alpha-adrenoceptor affinity in rat brain, in which the dissociation constant (Ki) was 2.75, 2.81, and 1.02 micrometer, respectively. It is concluded, therefore, that THI alkaloids have weak affinity to alpha1-adrenoceptors in rat aorta and brain, respectively, while these probes show relatively high affinity for cardiac beta-adrenoceptors. Thus, these chemicals may be useful in the treatment of congestive heart failure.

CARDIOVASCULAR EFFECTS OF SOPHORAMINE / 中国药理学通报

Sophoramine ( Sa ) is an alkaloid from sophora alopecuroides. Linn., in anesthetize animals ( cat, rat and rabbit), intravenous adminstra-tion of Sa reduced rapidly and markly the arterial blood pressure. The mechanism of hypotension effect of Sa is mainly attributable to its sympathetic ganglionic blocking and direct vasodilatation. Experiment on the isolated hearts of guinea pig revealed that Sa produced negative chronotropic and positive inotropic action, and increased coronary flow simultaneously.In a study of experimental arrhythmia in animals,we observed that Sa could reduce the arrhythmia induced by aconitine in rats and decreased the incidence of ventricular fibrillation induced by chloroform in mice.

EFFECTS OF DEPHENETIN ON PERIPHERAL RESISTANCE AND CARDIOTONIC ACTION / 中国药理学通报

A study was made on the effects of Dephenetin on vascular resistance and cardiotonic action in anesthetized dogs. The results showed that Dephenetin reduced left coronary cifcumflexus, vertebral and femoral ateries resistance, it increased cardiac out put without significant heart rate changes.The results also showed that Dephenetin dilates peripheral vessels and produced positive inotropic action.