Positive Inotropic Action Of Isoprenaline Research Articles

THYROTROPIN RELEASING HORMONE SENSITIZING MYOCARDIAL ADRENOCEPTROS DURING HEMORRHAGIC SHOCK IN RATS AND ITS MECHANISMS

The present experiment is aimed to elucidate the relationship between the antishock property of thyrotropin-releasing hormone(TRH) and adrenoceptors. Based on this purpose, the effects of TRH on the positive inotropic actions of adrenergic agonists and on the myocardial adrenoceptors were observed during hemorrhagic shock in rats, meanwhile effects of TRH alone and combined with adrenergic agonists on calcium current(Ica) in single cardiac cells were also investigated. The results indicated that TRH potentiated the positive inotropic actions of isoprenaline(ISO) and dopamine(DA) on isolated left atria of rats subjected to hemorrhagic shock, but it did not potentiate the effect of phenylephrine(Phe).TRH(5mg.kg-1) up-regulated the number of myocardial β-adrenoceptors and DA receptors during hemorrhagic shock, and increased the affinity of β-receptors. TRH prolonged the open duration of calcium channel (Dca) and augmented the calcium ionic inward induced by ISO and DA. It was suggested that TRH could promote the cadiac adrenoceptors sensitivity of shocked animals, TRH up-regulation of myocardial adrenoceptors of shoched animal, prolongation of Dca, and increase of the calcium ionic inward of ISO and DA might be the mechanisms by which TRH sensitizes β and DA receptors.

β1- and β2-adrenoceptors in sheep cardiac ventricular muscle

The presence of β 2-adrenoceptors in the sheep ventricular myocardium was assessed by the radioligand binding technique and functional studies. In membrane preparations, the competition curve between [ 3H]-dihydroalprenolol and the selective β 1-antagonist CGP 20712A (0.1 n m–1 m m) was clearly biphasic, and revealed the presence of two different binding sites showing an affinity (p K D) for CGP 20712A of 9.5 ± 0.9 and 4.5 ± 0.4, respectively. The relative proportion of β 1: β 2 adrenoceptors was about 70:30 in both the right and left ventricle. In ventricular trabeculae driven at 1Hz, isoprenaline (1–300 n m) caused a dose-dependent increase in the force of contraction, the maximum effect being 298 ± 26 mg, associated with reduction of time to peak tension ( t 1, clinotropic effect) and relaxation time ( t 2, lusitropic effect). The inotropic dose-response curve for isoprenaline was significantly shifted to the right by pretreatment of the preparations with 0.1 μ m CGP 20712A or with the selective β 2-antagonist ICI 118 551 (50 n m). In the presence of CGP 20712A (0.1 μ m), isoprenaline, up to a concentration of 10 μ m, did not affect either t 1 or t 2; on the other hand, pretreatment of the preparations with ICI 118 551 (50 n m) fully antagonized the clinotropic but not the lusitropic effect of isoprenaline. In the presence of CGP 20712A procaterol (0.01–10 μ m), a β 2-adrenoceptor agonist, induced a positive intropic effect which was not associated with any significant modifications in t 1 or t 2. This effect was completely abolished by ICI 118 551 (50 n m). The positive inotropic action of isoprenaline (1 μ m) was associated with a significant decrease in action potential duration measured at −60 mV (220 ± 8 and 193 ± 10 ms in the absence and presence of isoprenaline, respectively; P<0.05). In the presence of CGP 20712A (0.1 μ m) alone, isoprenaline (1μ m) still induced a significant increase in contractility but the action potential profile was only slightly affected. The effects of isoprenaline were fully antagonized by the simultaneous presence of CGP 20712A and ICI 118 551 (10 n m). It is concluded that both β 1- and β 2-adrenoceptors appear to coexist in sheep ventricular myocardium where their stimulation mediates a positive inotropic effect. However, their functional role on the relaxation phase of the twitch may be different.

The effects of the stereoisomers of propafenone and diprafenone in guinea-pig heart.

1. Optically pure enantiomers of propafenone and diprafenone were prepared from their racemic mixtures and tested for their ability to block beta-adrenoceptors and to prolong functional refractory period in the guinea-pig heart. beta-Adrenoceptor affinity of the enantiomers was determined by the radioligand binding technique and in functional experiments. 2. Propafenone and diprafenone inhibited specific binding of the beta-adrenoceptor antagonist (-)-[3H]-CGP-12177 to guinea-pig myocardial membranes. beta-Adrenoceptor affinities of diprafenone enantiomers exceeded those of corresponding propafenone enantiomers by one order of magnitude. Displacement of (-)-[3H]-CGP-12177 by both antiarrhythmics was highly stereoselective, in that the (S)-enantiomers were 40-60 fold, i.e. 1.6-1.8 log units more potent than the (R)-enantiomers. 3. Propafenone and diprafenone antagonized the positive inotropic action of isoprenaline in isolated atria. beta-Adrenoceptor antagonist potencies of diprafenone enantiomers were about one order of magnitude higher than those of corresponding propafenone enantiomers. For both drugs the (S)-enantiomer was found to be considerably more potent (14-40 fold) than the (R)-enantiomer. 4. Propafenone and diprafenone prolonged functional refractory period of isolated auricles with equal potency and no difference in the antiarrhythmic activity of purified enantiomers was found. 5. It is concluded that the enantiomers of propafenone and diprafenone exert comparable antiarrhythmic activity, whereas only (S)-enantiomers block cardiac beta-adrenoceptors with high affinity, which explains the beta-adrenoceptor antagonist effects of the racemic drugs.

The role of cyclic AMP in the positive inotropic effect mediated by beta 1- and beta 2-adrenoceptors in isolated human right atrium.

The time course of the effects of isoprenaline (3 X 10(-7) mol/l) on contractile force and on the cyclic AMP level was studied in the electrically driven isolated muscle strip of the human right atrium. Isoprenaline produced a rise in cyclic AMP content (maximum increase after 60 s) preceding the increase in contractile force. The effects of isoprenaline on contractile force and on the intracellular level of cyclic AMP were enhanced in the presence of the phosphodiesterase inhibitor papaverine (10(-5) mol/l). On the other hand, the beta-adrenoceptor antagonist propranolol (10(-7) mol/l) suppressed isoprenaline-induced cyclic AMP increases, but reduced the increase in force of contraction by only 35%. In addition, both the beta 1-selective antagonist bisoprolol (3 X 10(-9)-3 X 10(-8) mol/l) and the beta 2-selective antagonist ICI 118,551 (3 X 10(-9)-3 X 10(-8) mol/l) inhibited the isoprenaline-induced cyclic AMP increase concentration-dependently; ICI 118,551 produced more pronounced inhibition than bisoprolol. It is concluded that cyclic AMP is involved in the positive inotropic action of isoprenaline evoked by beta 1- and beta 2-adrenoceptor stimulation in isolated human right atrium; however, an additional cyclic AMP independent mechanism cannot be ruled out.

Inhibition by purines of the inotropic action of isoprenaline in rat atria.

The effects of a series of adenosine derivatives were examined on the catecholamine-stimulated electrically-driven rat left atrium in vitro. All the purines tested reduced the positive inotropic action of isoprenaline, 0.1 microM, with the potency order: L-N6-phenlylisopropyladenosine (L-PIA) greater than 5'-N-ethylcarboxamide adenosine (NECA) greater than D-PIA greater than 2-chloroadenosine greater than adenosine. Dipyridamole did not change the IC50 of adenosine. The adenosine deaminase inhibitor, 2'deoxycoformycin, produced a small but nonsignificant shift to the left of the adenosine concentration-response curve. The cardiac depressant effects of these purines were reversed by theophylline and the IC50 values were unchanged in the presence of atropine or in atria taken from reserpine-treated rats. It is concluded that the purine receptor mediating these effects should not be classified on the A1/A2 system. The relationship between functionally characterized purine receptors and those originally defined as modulating adenylate cyclase is discussed.

Dissociation of cyclic AMP and contractile responses to isoprenaline: effects of a dihydropyridine derivative, nicardipine (YC-93), on canine ventricular muscle

Nicardipine (YC-93), a 1,4-dihydropyridine derivative, inhibited the cyclic AMP phosphodiesterase (PDE) activity of purified PDE in a cell-free preparation. Its inhibitory action on the purified PDE was about seven times that of papaverine. On the other hand, YC-93 did not affect the intracellular cyclic AMP level and the accumulation of cyclic AMP caused by isoprenaline in the isolated canine right ventricular myocardium. YC-93 caused a prominent negative inotropic action which developed gradually to reach a steady level 1 h after its administration. The potency of YC-93 to depress the force of contraction was one tenth that of D600. The dose-response curve for isoprenaline was shifted to the right and downward in the presence of YC-93 in a concentration-dependent manner, and the positive inotropic action of calcium was also inhibited markedly by YC-93. The depressant action of YC-93 on the positive inotropic actions of isoprenaline and calcium was more prominent than that of D600. Although YC-93 is a potent PDE inhibitor in the cell-free preparation, the PDE in the intact cell system may be not accessible to the drug. Thus, it is considered that YC-93 acted as a calcium antagonistic drug on the isolated canine ventricular myocardium, and thereby inhibited the positive inotropic action of isoprenaline without affecting the intracellular accumulation of cyclic AMP caused by isoprenaline.

Inhibition of cyclic AMP phosphodiesterase activity and myocardial contractility: Effects of cilostamide, a novel PDE inhibitor, and methylisobutylxanthine on rabbit and canine ventricular muscle

The effects of cilostamide (N-cyclohexyl-N-methyl-4-[6-carbostyriloxy]butyramide; OPC-3689), a novel cyclic AMP phosphodiesterase (PDE) inhibitor were compared with those of 1-methyl-3-isobutylxanthine (IBMX) on the rabbit and canine heart preparations. Cilostamide was about three times less potent than IBMX in inhibiting the crude PDE activity of rabbit and canine heart in the cell-free system, while it was 10 times more potent than IBMX in enhancing the positive inotropic action of isoprenaline in the rabbit and canine ventricular myocardium: 10 −6 M cilostamide shifted the concentration-response curve for isoprenaline to the left in a parellel manner to the same extent as did 10 −5 M IBMX. Thus, cilostamide enhanced β-adrenoceptor stimulation more potently than did IBMX and the substances examined previously. Accumulation of intracellular cyclic AMP caused by 10 −6 M isoprenaline in the isolated canine ventricular myocardium was significantly enhanced by 10 −6 M cilostamide and 10 −5 M IBMX; isoprenaline (10 −6 M) induced cyclic AMP accumulation was greater with IBMX (10 −5 M) than with cilostamide (10 −6 M). The threshold concentration for cilostamide itself to induce positive chronotropic and inotropic actions in the rabbit heart was lower than that for IBMX, while the intrinsic activity of IBMX was greater than that of cilostamide. In the canine ventricular myocardium, the positive inotropic actions of cilostamide were comparable to those of IBMX; the action of cilostamide in concentrations of 10 −5 M and higher was partly inhibited by a β-adrenoceptor blocking agent, pindolol (3 × 10 −8 M). During the washout period of the drugs after the maximal response to the drugs had been reached, the positive inotropic action of cilostamide disappeared more rapidly than that of IBMX. The present results suggest that cilostamide is able to permeate the myocardial cell membrane more easily than IBMX and reach the PDE in the functionally important cyclic AMP compartment. The difference in turnover rate of cyclic AMP even in the same tissue in the physiological condition may also affect the direct action of the PDE inhibitors thereon.

Adenosine antagonizes the positive inotropic action mediated via β-, but not α-adrenoceptors in the rabbit papillary muscle

In the isolated rabbit papillary muscle, adenosine (1–300 μM) alone scarcely affected the basal tension developed. The positive inotropic action of isoprenaline, mediated via β-adrenoceptors, was inhibited by adenosine in a concentration-dependent manner. Atropine (0.3 μM) abolished the inhibitory action of carbachol on the isoprenaline-induced positive inotropic action but did not affect the inhibitory action of adenosine. Adenosine failed to inhibit the positive inotropic action exerted by phenylephrine via stimulation of α-adrenoceptors in the presence of pindolol (30 nM). The present results indicate that the positive inotropic action was mediated via α-adrenoceptors whose subcellular mechanism was not susceptible to the inhibitory action of adenosine as are β-adrenoceptors.

The time course of changes in cyclic nucleotide levels during cholinergic inhibition of positive inotropic actions of isoprenaline and theophylline in the isolated canine ventricular myocardium.

The time course of changes in cyclic AMP and cyclic GMP levels during the cholinergic inhibition of the positive inotropic actions of isoprenaline and theophylline was assessed in the isolated canine right ventricular myocardium. 1. Carbachol (3×10−6 mol/l) caused biphasic changes in force of contraction and cyclic AMP levels when administered during the positive inotropic response to isoprenaline (10−6 mol/l): a positive inotropic action superimposed on the slowly developing negative inotropic action which was preceded by a reduction of cyclic AMP levels. The positive and negative inotropic actions of, and the reduction of cyclic AMP levels induced by carbachol in the presence of isoprenaline were inhibited by atropine (3×10−7 mol/l). The cyclic GMP levels were increased after the administration of carbachol in the presence of isoprenaline in a monophasic manner and reached a maximal level 120 s after the administration; the elevation was also abolished by atropine. The half-time (T1/2) for cyclic GMP elevation after the administration of carbachol was about 50 s. 2. Carbachol (3×10−6 mol/l) administered during the positive inotropic response to theophylline (2×10−3 mol/l) abolished the inotropic action of theophylline in a monophasic manner:T1/2, 40 s; a reduction of cyclic AMP levels (T1/2, 10 s) and an elevation of cyclic GMP levels (T1/2, 20 s) preceded the changes in force of contraction caused by carbachol. 3. The present results indicate that the reduction of cyclic AMP levels occurred immediately after the administration of carbachol during cholinergic inhibition of the positive inotropic actions of isoprenaline and theophylline; the elevation of cyclic GMP levels and reduction of force of contraction occurred following the changes in cyclic AMP levels. Considering the mediator role of cyclic AMP in cardiac contraction, it appears that the reduction of cyclic AMP levels is responsible for the cholinergic inhibition of the actions of isoprenaline and theophylline in the canine ventricular myocardium.

Effects of papaverine and its interaction with isoprenaline and carbachol on the contractile force and cyclic nucleotide levels of the canine ventricular myocardium

In the isolated ventricular myocardium of the dog the effects of papaverine on the contractile force and on the cyclic nucleotide levels were studied. Furthermore the interaction between papaverine and the adrenergic β-or cholinergic stimulation was investigated. 1. Papaverine (3×10−5 M) induced a positive inotropic action and increased the cyclic AMP level in the majority of preparations. Ventricular muscles isolated from certain dogs showed only a negative inotropic response to papaverine. As a whole, a significant correlation was found between the tension developed and the cyclic AMP level after the administration of papaverine. The cyclic GMP level was not changed or decreased by papaverine. 2. The positive inotropic action of papaverine and elevation of the cyclic AMP level in response to papaverine were not inhibited by a β-adrenoceptor blocking drug, pindolol (3×10−8 M), indicating that these effects are not caused by catecholamine release. 3. In muscles, in which papaverine failed to cause the positive inotropic action, contractile as well as cyclic AMP responses to isoprenaline were significantly enhanced by papaverine. 4. Carbachol (3×10−6M) diminished the positive inotropic actions of isoprenaline and papaverine, abolished the accumulation of cyclic AMP produced by these agents, and increased significantly the cyclic GMP level. The elevation of cyclic GMP level by carbachol in the presence of papaverine was especially marked and amounted to 4-fold the corresponding control value. These results indicate that papaverine inhibits the break down of the intracellular cyclic AMP and GMP in the intact myocardial cells and may thereby interact functionally with the autonomic nervous system.

The effects on cardiac muscle and nerve of a fluorinated decahydroquinoline derivative, L7810, rapidly absorbed after oral administration.

1. L7810 (4-carbamoyloxy-1-(4-(4-fluorophenyl)-4-oxobutyl) decahydroquinoline, has a local anaesthetic action on frog nerve 1.75 times that of procaine.2. L7810 protected anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation and increased the lethal dose of ouabain.3. L7810 reduced the rate of rise of intracellularly recorded action potentials in rabbit isolated atria; the resting potential was not affected, but the duration of the action potential was prolonged.4. Unlike most drugs with local anaesthetic properties L7810 did not depress contractions in isolated atria but increased them.5. L7810 reduced the spontaneous frequency, maximum follow frequency and conduction velocity of rabbit isolated atria.6. L7810 had no blocking action on the chronotropic or positive inotropic actions of isoprenaline on isolated atrial muscle.7. In anaesthetized dogs L7810 caused a small dose-related bradycardia, and a large dose-related decrease in peripheral vascular resistance. There was no blockade of the effects of isoprenaline on heart rate or peripheral blood flow.