Moderate Negative Inotropic Effect Research Articles

Neutral/negative α1-AR antagonists and calcium channel blockers at comparison in functional tests on guinea-pig smooth muscle and myocardium

Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α1-adrenoceptors (α1-ARs). Inhibition of such an activity at α1-AR subtypes by antagonists with negative efficacy is difficult to be adequately tested. In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α1-AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α1A/α1B-α1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α1D-AR, that is the α1- AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist. We found that all the three benzodioxane-related α1-AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers. Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α1-AR antagonist is related neither to a particular profile of α1-AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α1-AR antagonists with L-type Ca2+ channels.

Beta-3 Adrenoceptors as New Therapeutic Targets for Cardiovascular Pathologies

Catecholamines play a key role in the regulation of cardiovascular function, classically through ß(1/2)-adrenoreceptors (AR) activation. After ß(3)-AR cloning in the late 1980s, convincing evidence for ß(3)-AR expression and function in cardiovascular tissues recently initiated a reexamination of their involvement in the pathophysiology of cardiovascular diseases. Their upregulation in diseased cardiovascular tissues and resistance to desensitization suggest they may be attractive therapeutic targets. They may substitute for inoperant ß(1/2)-AR to mediate vasodilation in diabetic or atherosclerotic vessels. In cardiac ventricle, their contractile effects are functionally antipathetic to those of ß(1/2)-AR; in normal heart, ß(3)-ARs may mediate a moderate negative inotropic effect, but in heart failure, it may protect against adverse effects of excessive catecholamine stimulation by action on excitation-contraction coupling, electrophysiology, or remodelling. Thus, prospective studies in animals and patients at different stages of heart failure should lead to identify the best therapeutic window to use ß(3)-AR agonists and/or antagonists.

Kinetic analysis of myocardial uptake and negative inotropic effect of amiodarone in rat heart

The distribution kinetics of the highly lipophilic antiarrhythmic agent amiodarone is not well understood. The purpose of the present investigation was to develop a pharmacokinetic–pharmacodynamic (PK/PD) model to describe cardiac uptake and the negative inotropic effect of amiodarone in the isolated perfused rat heart. Amiodarone (10 μM) was infused for 15 min to 6 hearts. The time course of outflow concentration and left ventricular developed pressure were measured and analyzed by the model. The uptake of amiodarone by the heart was flow limited and characterized by an extremely high partition coefficient with a predicted tissue washout half-live of 17 h. Only 36.8% of input amount to heart recovered within 45 min after start of the 15 min infusion. The negative inotropic effect was delayed with a time constant of 11 min and the maximal decrease in left ventricular developed pressure was described by a sigmoid E max model with an E max of 37.7% and an EC 50 of 0.53 μM. Our results suggest a rapid tissue uptake and a moderate negative inotropic effect of amiodarone after intravenous injection.

Myocardial effects of desflurane in hamsters with hypertrophic cardiomyopathy.

The effects of desflurane on myocardial contraction and relaxation in diseased myocardium have not been completely understood. The effects of desflurane (1.8 to 9.4 vol%) in left ventricular papillary muscles of healthy hamsters and those with genetically induced cardiomyopathy (strain BIO 14.6) were investigated in vitro (29 degrees C, pH 7.40, Ca2+ 2.5 mM; stimulation frequency, 3/min) under low (isotony) and high (isometry) load. Data are mean percentages of baseline +/- SD. Desflurane induced no significant inotropic effect in healthy muscles (maximum unloaded shortening velocity and isometric active force at 9.4 vol%: 97 +/- 9% and 92 +/- 20%, respectively). In contrast, in cardiomyopathic muscles, desflurane induced a moderate negative inotropic effect (maximum unloaded shortening velocity and active force at 9.4 vol%: 84 +/- 19% and 75 +/- 25%, respectively). The negative inotropic effect was more pronounced than that in healthy muscles under low (P < 0.05) but not high load, and even when concentrations were corrected for minimum alveolar concentrations in each strain. Adrenoceptor blockade or pretreatment with reserpine did not modify the inotropic effect of desflurane, suggesting the absence of intramyocardial catecholamine release. However, tyramine also did not induce any significant catecholamine release in hamster myocardium. In both strains, desflurane induced no significant lusitropic effect under low or high load. Desflurane had no inotropic effect in healthy muscles and a moderate negative inotropic effect in cardiomyopathic muscles. The absence of desflurane-induced intramyocardial catecholamine release was related to hamster myocardium characteristics.

In vitro effects of dantrolene on rat myocardium.

Dantrolene is the only known effective treatment for malignant hyperthermia. However, its effects on myocardial contraction and relaxation remain debatable. The effects of dantrolene (10(-5)-10(-3) M) on the contractility of rat left ventricular papillary muscles were investigated in vitro (Krebs-Henseleit solution, 29 degrees C, pH 7.40, 2.5 and 0.5 mM Ca2+, stimulation frequency 12 pulses/min). The authors studied contraction, relaxation, contraction-relaxation coupling under high and low load, energetics, and postrest potentiation. The effects of dantrolene after depletion of catecholamine stores with reserpine also were studied. Dantrolene induced a moderate concentration-dependent negative inotropic effect at a low calcium concentration (active force at 10(-4) M: 86 +/- 14% of control values, P < 0.05), but not at a high calcium concentration. Dantrolene did not significantly modify the curvature of the force-velocity relation, suggesting that it did not modify myocardial energetics. Dantrolene induced no significant lusitropic effect under low load, suggesting that it did not modify calcium uptake by the sarcoplasmic reticulum. Dantrolene did not significantly modify postrest potentiation and postrest potentiation recovery, suggesting that it did not modify maximum capacity of calcium release by the sarcoplasmic reticulum nor its postrest resetting capacity. Reserpine did not modify the myocardial effects of dantrolene. In rat myocardium, dantrolene did not modify any of the sarcoplasmic reticulum functions tested (uptake, release, postrest recovery). Dantrolene induced a moderate negative inotropic effect, probably mediated by a decrease in transarcolemmal calcium entry, and this negative inotropic effect was blunted by an increase in calcium concentration.

Hemodynamic Effects of the New Antiarrhythmic Agent Restacorin in Patients with Normal and Decreased Left Ventricular Function

Summary: The hemodynamic and pharmacokinetic effects of the novel class 1c antiarrhythmic drug restacorin were investigated in two groups of patients. Group I consisted of 5 patients with normal left ventricular (LV) function, and group II consisted of 10 patients with mild heart failure [New York Heart Association (NYHA) II; mean LV ejection fraction 33 ± 6%]. The study had an open label, baseline-controlled, single-dose design. Restacorin was infused in a total dosage of 1.2 mg/kg. In group I, the only significant change as compared with baseline findings was a 25% increase in right atrial pressure. In group II; cardiac output (CO), dP/dt, and stroke work index (SWI) decreased significantly (−18, −11, and −24%, respectively). In addition, a significant 32% increase was noted in pulmonary artery wedge pressure (PAWP), and a 27% increase occurred in systemic vascular resistance (SVR). No changes were observed in heart rate (HR) or mean arterial blood pressure (MAP). CO and SVR at baseline correlated with the average plasma concentrations (r = −0.65 and p = 0.009 and r = 0.56 and p = 0.028 respectively). Creatinine clearance was inversely correlated to the restacorin plasma concentration (r = −0.51, p = 0.05). The half-life (t½) elimination time of restacorin was 2.60 h for group I, and 4.06 h for group II. Clearance was 51.4 and 32.2 L • h−1, respectively. Restacorin appears to be well tolerated in patients with normal LV function. The drug is not recommended for use in patients with reduced LV function because of its moderate negative inotropic effect.

Hemodynamic Effects of the New Antiarrhythmic Agent Restacorin in Patients with Normal and Decreased Left Ventricular Function

The hemodynamic and pharmacokinetic effects of the novel class 1c antiarrhythmic drug restacorin were investigated in two groups of patients. Group I consisted of 5 patients with normal left ventricular (LV) function, and group II consisted of 10 patients with mild heart failure [New York Heart Association (NYHA) II; mean LV ejection fraction 33 +/- 6%]. The study had an open label, baseline-controlled, single-dose design. Restacorin was infused in a total dosage of 1.2 mg/kg. In group I, the only significant change as compared with baseline findings was a 25% increase in right atrial pressure. In group II; cardiac output (CO), dP/dt, and stroke work index (SWI) decreased significantly (-18, -11, and -24%, respectively). In addition, a significant 32% increase was noted in pulmonary artery wedge pressure (PAWP), and a 27% increase occurred in systemic vascular resistance (SVR). No changes were observed in heart rate (HR) or mean arterial blood pressure (MAP). CO and SVR at baseline correlated with the average plasma concentrations (r = -0.65 and p = 0.009 and r = 0.56 and p = 0.028 respectively). Creatinine clearance was inversely correlated to the restacorin plasma concentration (r = -0.51, p = 0.05). The half-life (t1/2) elimination time of restacorin was 2.60 h for group I, and 4.06 h for group II. Clearance was 51.4 and 32.2 L.h-1, respectively. Restacorin appears to be well tolerated in patients with normal LV function. The drug is not recommended for use in patients with reduced LV function because of its moderate negative inotropic effect.

Assessment of the antiarrhythmic activity of nicorandil during myocardial ischemia and reperfusion

The potential pro- and antiarrhythmiceffects of nicorandil (1–100 μM) were assessed in isolated rat hearts subjected to coronary artery ligation and reperfusion under conditions of normal (5.9 mM) and lowered (3.2 mM) perfusate K +. Nicorandil dose dependently increased coronary flow, induced a moderate negative inotropic effect but had no chronotropic effects. During ligation (15 min), only high concentrations of nicorandil (50 and 100 μM) significantly reduced the incidence of ventricular premature beats and ventricular tachycardia in normal perfusate, but ventricular fibrillation was observed in 2 9 hearts. No antiarrhytmic effects were observed with hypokalemic conditions. During reperfusion, nicorandil was associated with a more rapid degeneration into ventricular fibrillation in normal perfusate while the incidence of ventricular fibrillation was only reduced by 100 μM nicorandil. No antiarrhythmic effects were observed during reperfusion with lowered K + and all drug-treated hearts demonstrated irreversible ventricular fibrillation. Nicorandil perfusion (50 μM; 5.9 mM K +) did not affect the depression of ATP or elevation of lactate within the ischemic tissue during coronary artery ligation. These data do not support an effect of nicorandil against ischemia- or reperfusion-induced arrhytmias in the intact heart in vitro and may suggest a proarrhythmic effect particularly at lowered K + concentrations.

The effects of m-AMSA on rat isolated heart.

m-AMSA (4'[9-acridinylamino]methansulphon-m-anisidide) is a new cytoxic agent now under clinical trial. We used the rat isolated perfused heart model in order to investigate the cardiac effects of m-AMSA. The results of the dose-response study indicate that m-AMSA has an acute moderate negative inotropic effect. The 90% effect (25% decrease in developed force compared to the control) was observed at drug concentration of 1.5 micrograms/ml. The refractory period (as measured by stimuli of twice diastolic threshold intensity) increased progressively as the drug concentration was increased (up to 2.5 micrograms/ml). Measurements of the strength-duration and strength-interval relationship showed that m-AMSA induced a significant reduction (P less than 0.005) in excitability and prolongation of refactoriness. We suggest that m-AMSA has a membranal cardiotoxic effect in addition to its known intracellular cytotoxic effect.

Inotropic and electrophysiological actions of verapamil and D 600 in mammalian myocardium

On isotonically contracting cat papillary muscles analysis, a comparison of the effects of the optical isomers of verapamil and D 600 and the racemic drugs was performed. 1. (-)-verapamil (0.2-3.0 mug/mo) and (-)-D-600 (0.1 mug/ml-3.0 mug/ml) leave the steady state contraction amplitudes nearly unchanged at 6/min, but produce a strong depression at 60/min. (-)-D 600 is about 8 times as effective as (-)-verapamil. The (+)-isomers exert only a moderate negative inotropic effect (particularly at low frequencies). 2. Increase of [Ca2+]O does not restitute the normal amplitude-frequency relationship during exposure to either the (-)-isomers or the (+)-isomers. 3. The (-)-isomers lead to typical biphasic staircases after step changes of frequency. A fast negative staircase occurs first followed by a rather slowly developing positive staircase. In contrast, the (+)-isomers have little influence on the usual staircase pattern. 4. The strength-interval relationship for single test contractions elicited after frequent conditioning stimulation indicated that the (-)-isomers probably slow the restitution of intracellular Ca-reavailability. The (+)-isomers have no such effects. 5. The effects produced by the (+/-)-compounds correspond qualitatively to those of the (-)-isomers. 6. The very different patterns of inotropic actions observed indicate that the (-)- and (+)-isomers of verapamil and D 600 probably interfere with cardiac excitation-contraction coupling at different sites.