Increase In Cardiac Contractile Force Research Articles

Cardiac RKIP induces a beneficial β-adrenoceptor-dependent positive inotropy.

In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β1-adrenoceptor (β1AR). This result is unexpected, as β1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.

Effects of dihydroergotamine and etilefrine on experimentally-induced postural hypotension in dogs.

The effects of dihydroergotamine and etilefrine on experimentally-induced postural hypotension were examined. Although dihydroergotamine at 3 and 10 micrograms/kg (i.v.) increased blood pressure (BP), it did not affect cardiac output (CO). However, dihydroergotamine at 10 micrograms/kg reduced the decrease in CO induced by the tilt. Therefore, it is suggested that the increase in BP is induced by the contraction of resistance vessels, and that the inhibition of the decrease in CO due to tilt is induced by the contraction of capacitance vessels. Etilefrine at 0.1 mg/kg (i.v.) increased BP and heart rate (HR), however, it did not attenuate the decrease in BP induced by the tilt. Although it tended to increase CO, it did not attenuate the decrease in CO. It is suggested that the increase in BP is due to the contraction of resistance vessels, and to the increase in cardiac contractile force and HR. In this study, dihydroergotamine and etilefrine did not attenuate the decrease in BP due to tilt, though dihydroergotamine inhibited the decrease in CO due to tilt. As an explanation, it is suggested that dihydroergotamine induces contraction of resistance vessels as well as capacitance vessels, however the effects of the drug on resistance vessels is weak, and that etilefrine has little or no effect on capacitance vessels. In our previous study, midodrine, an alpha-1 agonist, attenuated the decreases in BP and CO due to tilt, and it has been suggested that the inhibition was induced by the contraction of capacitance vessels. Therefore, dihydroergotamine, etilefrine and midodrine show different pahrmacological profiles in experimentally-induced postural hypotension.

Cardiovascular and renal hemodynamic effects of intravenous infusions of the selective DA1 agonist, fenoldopam, used alone or in combination with dopamine and dobutamine.

Fenoldopam (0.1 and 0.2 microgram/kg/min i.v.) was administered to pentobarbital-anesthetized dogs alone and combined with dopamine (DA) and dobutamine. Renal blood flow, heart rate, and mean arterial pressure were measured. Both dosages of fenoldopam increased renal blood flow without altering blood pressure, similar to the effects of DA (1 and 2 micrograms/kg/min). Administration of fenoldopam with only DA (1 microgram/kg/min) produced further increase in renal blood flow. After administration of phenoxybenzamine (15 mg/kg i.v.), DA produced significant increments in renal blood flow and reductions in renal vascular resistance when compared with experiments without phenoxybenzamine, suggesting even low dosages of DA exert alpha-adrenoceptor agonist activity. Dobutamine (2 and 4 micrograms/kg/min) increased renal blood flow about 37% of that produced by DA. Fenoldopam added to dobutamine produced similar increments in renal blood flow as DA. Fenoldopam did not affect the increase in cardiac contractile force produced by DA and dobutamine. Thus, fenoldopam alone or in combination with DA had no advantage over 2 and 4 micrograms/kg/min DA to further increase renal blood flow. In contrast, fenoldopam with dobutamine produced greater increments in cardiac contractile force than DA and equivalent increases in renal blood flow as DA.

Cardiovascular Properties of a New Cardiotonic Agent, MDL 19205

The cardiovascular properties of a new cardiotonic agent, MDL 19205, were investigated in anesthetized and conscious dogs and in a dog heart-lung preparation. MDL 19205 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced a dose-related increase in cardiac contractile force lasting up to 1 h. It also produced a relatively minor increase in heart rate and a brief decrease in blood pressure. These effects did not involve beta-adrenergic receptor stimulation, as they were observed in dogs after a myocardial-depressant dose of propranolol. Given orally to conscious dogs, MDL 19205 (1 and 3 mg/kg) produced a dose-related increase in dP/dt without producing a significant alteration in heart rate or blood pressure. When administered to anesthetized dogs by constant intravenous infusion, MDL 19205 (0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and decreases in blood pressure and left atrial pressure, but did not produce a significant change in cardiac output or stroke volume, indicating an enhancement of cardiac pump function. Intravenous MDL 19205 reversed the hemodynamic characteristics of heart failure produced by propranolol in anesthetized dogs. In addition, it reversed the depressant effect of pentobarbital on cardiac function in a dog heart-lung preparation. These studies show that MDL 19205 is a potent, direct-acting cardiotonic agent in animals.

In Vitro and In Vivo Assessment of the Cardiovascular Effects of the Cardiotonic Drug MDL 19205

Various in vitro and in vivo techniques were used to evaluate the cardiovascular actions of MDL 19205, a new cardiotonic agent. In the anesthetized dog, intravenous administration of MDL 19205 (0.1-1 mg/kg) produced marked increases in cardiac contractile force which were accompanied by small increases in heart rate and minor decreases in blood pressure. These effects were not altered by alpha- or beta-adrenergic receptor blockade, reserpine pretreatment, or bilateral carotid sinus denervation. In isolated cat cardiac tissues, MDL 19205 (10(-5)-10(-3) M) produced a selective inotropic effect relative to isoproterenol and, unlike isoproterenol, was nonarrhythmogenic. Adrenergic beta-receptor or histamine H1-receptor blockade did not modify the inotropic effects of MDL 19205 in guinea pig atria. The vasodilatory effect of MDL 19205 in the canine isolated pump-perfused hindlimb preparation was not significantly attenuated by surgical sympathectomy, alpha- or beta-adrenergic receptor blockade, cholinergic or histaminergic receptor blockade, or indomethacin pretreatment, indicating that MDL 19205 produced direct relaxation of vascular smooth muscle. MDL 19205 was found to be safe and effective when administered acutely in combination with ouabain, hydralazine, nitroglycerin, or furosemide, agents commonly used in the treatment of congestive heart failure. The pharmacological profile revealed by these and other studies suggests that MDL 19205 should be useful in the clinical treatment of congestive heart failure.

Cardiac glycosides and sodium/potassium-ATPase.

The sodium/potassium-ATPase complex is, according to modern research, the binding site for cardiac glycosides on the outer surface of the cell membrane and their receptor. Inhibition of this enzyme by cardiac glycosides leads for instance in the heart to a decrease or a delay in membrane sodium/potassium-ion transport, and indirectly to an increase in the intracellular ionized calcium-concentration and an increase in cardiac contractile force. According to recent observations the activity of the sodium/potassium-ATPase or its concentration, and therefore the concentration of binding sites can increase in some tissues after long term treatment with cardiac glycosides. This might explain the occasionally observed tolerance to digitalis glycosides.

4-Aroyl-1,3-dihydro-2H-imidazol-2-ones, a new class of cardiotonic agents.

A series of 4-aroyl-1,3-dihydro-2H-imidazol-2-ones was synthesized and evaluated for pharmacological activity in the anesthetized dog. Most members of this series produced dose-related increases in cardiac contractile force as well as relatively minor increases in heart rate and decreases in systemic arterial blood pressure that were not blocked by propranolol. In general, 4-methoxy or 4-methylthiobenzoyl substitution afforded compounds of greatest inotropic potency. 1,3-Dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-one (6) was shown to produce a dose-related positive inotropic effect and reverse the depressant effect of pentobarbital on cardiac pump function in the dog heart-lung preparation. The cardiotonic activity of this series may have important utility in the treatment of congestive heart failure. 1,3-Dihydro-4-[4-(methylthio)benzoyl]-5-methyl-2H-imidazol-2-one (17) was chosen for human studies and is currently undergoing clinical trials.

Characterization of the cardiovascular activities of a new cardiotonic agent, MDL 17043 (1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazole-2-one).

The cardiovascular actions of 1,3-dihydro-4-methyl-5[4-(methylthio)-benzoyl]-2H-imidazol-2-one (MDL 17043), a new noncatecholamine, nonglycoside cardiotonic agent, were examined in vivo in anesthetized dogs and in vitro in isolated cat atrial and papillary muscle preparations and guinea pig atria. In the anesthetized dog, intravenous administration of MDL 17043 (0.1--1 mg/kg) produced marked increases in cardiac contractile force which were accompanied by minor increases in heart rate and small decreases in blood pressure. These effects were not altered by alpha- or beta-adrenergic receptor blockade, catecholamine depletion produced by reserpine, bilateral vagotomy, or by bilateral carotid sinus denervation. MDL 17043 (10(-5)--10(-3) M) produced positive inotropic effects in isolated papillary muscle and left atrial strips of the cat that were much greater than the positive chronotropic effects seen in the spontaneously beating right atrium of the cat. The in vitro inotropic effects of MDL 17043 in guinea pig electrically driven left atrial strips were not modified by adrenergic beta-receptor or histamine H1-receptor blockade. The vasodilatory effect of MDL 17043 in the canine isolated pump-perfused hindlimb preparation was not attenuated by surgical sympathectomy, alpha- or beta-adrenergic receptor blockade, cholinergic or histaminergic receptor blockade, or by prostaglandin synthesis inhibition, indicating that MDL 17043 produces direct relaxation of vascular smooth muscle. MDL 17043 was found to be safe and effective when administered acutely in combination with ouabain, hydralazine, nitroglycerin, or furosemide, agents commonly used in the treatment of congestive heart failure.

Cardiovascular Properties of a New Cardiotonic Agent

The cardiovascular properties of a new noncatechol, nonglycoside cardiotonic agent, MDL 17,043, were investigated in anesthetized and conscious dogs and the dog heart-lung preparation. MDL 17,043 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced dose-related increases in cardiac contractile force lasting more than 1 h. It also produced relatively minor and shorter-lasting increases in heart rate, and brief decreases in blood pressure. These effects were not blocked by propranolol. Of these effects, the increase in cardiac contractile force was, by far, the most prominent. the cardiac effects were also observed in the dog heart-lung preparation. When administered to anesthetized dogs by constant intravenous infusion, MDL 17,043 (09.03 and 0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and a sustained decrease in blood pressure without altering heart rate, suggesting a wide separation between the inotropic instrumented dogs, MDL 17,043 (3-30 mg/kg) produced a sustained increase in dP/dt without altering heart rate or blood pressure. It reversed the depressant effect of pentobarbital on the ventricular function curve in the dog heart-lung. When the hemodynamic characteristics of compensated heart failure were produced by propranolol in anesthetized dogs, MDL 17,043 reversed these effects. These studies suggest that MDL 17,043 may have a beneficial effect in the treatment of heart failure.

Cardiotonic activity of amrinone--Win 40680 [5-amino-3,4'-bipyridine-6(1H)-one

The cardiotonic activity of a new, noncatechol, nonglycoside agent, amrinone, was investigated in vitro and in anesthestized and unanesthetized dogs. Amrinone (3-100 microgram/ml) caused a dose-dependent increase in papillary muscle developed tension and df/dt without significant changes in duration of the contractile cycle or time-to-peak tension. Amrinone induced slight increases in right atrial rate with no changes in electrophysiological properties of the cat papillary muscle or dog Purkinje fibers. In anesthetized dogs, intravenous bolus injections of amrinone at doses ranging from 1 to 10 mg/kg caused increases in cardiac contractile force and left ventricular dp/dt max with relatively small changes in heart rate and blood pressure. No significant changes in lead II ECG were observed. In unanesthetized dogs, intravenous infusion of amrinone (10-100 microgram/kg per min) caused increases in left ventricular dp/dt max and only small changes in heart rate and blood pressure. Amrinone, tested orally in this model at doses of 2-10 mg/kg, produced a positive inotropic effect with a rapid onset and long duration of action. The inotropic response to amrinone was not blocked by propranolol, dibenzyline, chlorisondamine, atropine, metiamide, or reserpine. Amrinone's inotropic response was not associated with significant alterations in cardiac norepinephrine, phosphodiesterase, cyclic AMP, or Na+, K+-activated ATPase.

Pharmacological and biochemical activities of some monomethylxanthine and methyluric acid derivatives of theophylline and caffeine

Some monomethylxanthine and methyluric acid derivatives of theophylline and caffeine have been studied to explore whether they possess pharmacological and biochemical activities similar to those of their parent compounds. Both 3-methylxanthine and 1-methylxanthine, but not 1,3-dimethyluric acid or 3-methyluric acid, produced the same maximal relaxation of guinea pig tracheal muscle as did theophylline. The EC 50 values for theophylline and 3-methylxanthine were not significantly different, whereas those for 1-methylxanthine, 1,3-dimethyluric acid and 3-methyluric acid were significantly higher than that if theophylline. In the Langendorff guinea pig heart, theophylline and 3-methylxanthine caused essentially identical increases in cardiac contractile force. Although less effective than theophylline, 1-methylxanthine and caffeine produced equivalent increases in cardiac contractility. At concentrations higher than those effective for the methylxanthines, 1,3-dimethyluric acid markedly increased contractile force. 3-Methylxanthine inhibited cyclic AMP phosphodiesterase to a lesser extent than did theophylline at both 1.4 and 400 μM cyclic nucleotide concentrations. However, at the higher substrate concentration, cyclic GMP phosphodiesterase activity was inhibited by 3-methylxanthine more than by theophylline. Thus, it appears that the monomethylxanthine and methyluric acid derivatives of theophylline and caffeine possess a spectrum of pharmacological activity similar to that of their parent compounds, a finding which raises important questions about various aspects of the current therapeutic use of methylxanthines.

Influence of midcollicular decerebration on the cardiovascular effects of ouabain

Ouabain (20 and 40, μg kg , i.v.) administered to debuffered anaesthetized cats with forebrain areas intact, produced increases in cardiac contractile force, heart rate, and arterial blood pressure. Removal of forebrain areas by midcollicular decerebration prevented the chronotropic effect, antagonized the positive inotropic effect, but did not alter the pressor effect of ouabain. These results suggest that sub-arrhythmic doses of ouabain increase heart rate and contractile force in the cat by activating forebrain structures.

Ifenprodilについての薬理学的研究

Pharmacological effects of ifenprodil (IP), 4-benzyl-alpha-(p-hydroxyphenyl)-beta-methyl-1-piperidineethanol-L-(+)-tartrate monohydrate (Funai Pharmaceutical), a potential vasodilator, were studied in the dog, rabbit, guinea-pig and mouse. 1) Intravenous administration of IP (0.1 approximately 1 mg/kg) exhibited a continuous fall in blood pressure, an increase in heart rate and an increase in cardiac contractile force in the dog. The depressor and chronotropic effects of IP appeared likewise in the pithed dog, and the depressor responses were slightly more evident in the rabbit. The cardiovascular responses to IP were not affected by pretreatment with atropine or diphenhydramine, however, the chronotropic and inotropic effects were completely removed and the depressor response was depressed to some extent by propranolol. On the contrary, a pressor response to adrenaline was reversed to a depressor one after IP in the dog. 2) In heart-lung preparation of dogs, IP brought about slight cardiac stimulating effects, such as an increase in contractile force and a rise in aortic pressure. 3) IP induced a transient slight excitation in in situ movements of the rabbit intestine, and a similar excitation followed with a inhibition in movements of isolated intestine (10(-6), 2.5 X 10(-5) g/ml. This slight excitation was not affected by pretreatment with atropine, whereas the inhibition was depressed to a certain degree by simultaneous pretreatment with phenoxybenzamine and propranolol. IP produced a slight tonic increase in the guinea-pig isolated intestine and inhibited markedly the excitatory effect of histamine in the intestine. 4) IP did not affect the bronchial muscle but inhibited prominently a contractile respose of the muscle to histamine in in situ experiments on guinea-pig. 5) Locomotor activity was reduced dose-dependently and thiopental hypnosis was potentiated similarly after subcutaneous administration of IP (5 approximately 40 mg/kg), while skeletal muscle relaxant effects were not observed. 6) Survival time under a condition of acute anoxia was not changed with a dose of 0.5 and 1 mg/kg, but shortened with a dose of 5 mg/kg. The results suggest that IP has a alpha-blocking, a beta-stimulating and a moderate antihistaminic effects, and shows some cardiovascular effects, such as continuous depressor and chronotropic effects, and a moderate central inhibition.

The role of the sympathetic nervous system in the cardiovascular responses to angiotensin in the pithed rat.

1. Angiotensin (200-500 ng, intravenously) produced a biphasic pressor response accompanied by reflex bradycardia in rats anaesthetized with sodium pentobarbitone. In pithed rats and in anaesthetized animals treated with a ganglion blocking agent there was a similar pressor response but an increase in the heart rate which was coincident with the second phase of the pressor response. In pithed preparations an increase in cardiac contractile force accompanied the heart rate changes.2. Acute or chronic adrenalectomy did not alter the pressor responses and chronotropic effect of angiotensin in the pithed rat. Propranolol abolished the chronotropic and inotropic action of angiotensin, but left the biphasic pressor response unaltered. Bethanidine, or pretreatment with reserpine, altered the pressor response to a simple rise, and also abolished the chronotropic action of angiotensin. Phentolamine also abolished the second pressor component. Desmethylimipramine produced a marked potentiation of the cardiovascular effects of angiotensin at all dose levels tested (10-500 ng).3. It is concluded that in the rat only large doses of angiotensin are capable of indirectly stimulating the sympathetic nerves either at the site of their ganglionic cells or their post-ganglionic nerve ending.

THE EFFECT OF PHYSOSTIGMINE ON HEART PHOSPHORYLASE ACTIVITY IN THE SPINAL RAT

It was reported previously (1) that an increase in heart phosphorylase a following the intravenous administration of adrenaline in a dose of 10.0 μg/kg was less than that following 1.0 μg/kg, and that atropinization or vagotomy potentiated the phosphorylaseactivating action of adrenaline. In addition, a significant elevation of heart phosphorylase a was maintained for 2 hours after the injection of 1.0 μg/kg of adrenaline. From the results, it was suggested that the reflectively released endogenous acetylcholine inhibited the phosphorylase-activating action of adrenaline, and that the long-lasting elevation of heart phosphorylase a even after disappearance of the positive inotropic action of adrenaline was related to the uptake or storage mechanism of adrenaline in the heart tissue. Many investigators (2-6) demonstrated that the positive ino- and chrono-tropic responses to exogenous adrenaline of the heart were closely related to the activation of formation of cyclic 3', 5'-AMP with subsequent conversion of phosphorylase b to a. The finding (7) that injection of ganglionic stimulating agents such as DMPP and McNeil-A-343 produced an increase in heart phosphorylase a with concomitant hypertension and increase in cardiac contractile force may suggest a relationship between the level of circulating catecholamine endogenously liberated and the activity of phosphorylase in the heart. However, there are controversial reports regarding the effect of reserpine on heart phosphorylase activity: no significant change (4, 8), increase (6), and decrease (9). This is incompatible with the concept that there is a positive correlation between the amount of endogenous catecholamine and cardiac phosphorylase a activity. The inhibitory effects of injected acetylcholine and vagal stimulation on the activity of heart phosphorylase a in open-chest rats have been demonstrated by Hess et al. (7). In an attempt to study the effect of endogenous acetylcholine on heart phosphorylase a, anticholinesterase agents were injected to spinal rats. Unexpectedly, physostigmine increased the activity of the heart enzyme. Further, combined administration of adrenaline and physostigmine, both of which otherwise activated the heart enzyme, resulted in an inhibition of the enzyme activity.

Mechanism of the initial adrenergic effects of bretylium and guanethidine.

Treatment with phenoxybenzamine and dichloroisoprenaline prevented the rise of blood pressure, contraction of the nictitating membrane and increase in cardiac contractile force produced by intravenous injections of bretylium and guanethidine in anaesthetized or spinal cats. Treatment with cocaine, imipramine or reserpine reduced the sensitivity to bretylium and guanethidine of the spinal cat. In the spinal cat treated with reserpine, sensitivity to the drugs could be restored by an infusion of noradrenaline. Chlorpromazine also blocked the pressor and nictitating membrane responses to bretylium and guanethidine. The drug effects were unaltered 1 hr after bilateral adrenalectomy. During the intravenous infusion of noradrenaline into spinal cats the pressor responses to bretylium and guanethidine were increased, whilst those to adrenaline and to noradrenaline were decreased. Guanethidine (3 to 5 mg/kg) injected intravenously into the cat caused a sudden relaxation of the rat isolated stomach-strip bathed in blood. In seven similar experiments bretylium (3 to 5 mg/kg) relaxed the strip only once; in the other six experiments there was either no effect (four experiments) or an increase in the tone of the strip (two experiments). It is concluded that the initial adrenergic effects of bretylium and guanethidine are mediated, at least in part, through a release of catechol amines from stores in the effector organ.