Increase In Myocardial Contractile Force Research Articles

Failing Left Ventricles Gain Less Force by Tachycardia Despite Increase in Intrinsic Force Store

Background: Heart rate-dependent increase in myocardial contractile force, which is known as force-frequency relationship (FFR), is impaired in failing myocardium but clinical data on FFR are limited and underlying mechanisms of the impairment are still unclear. Materials and Methods: In 20 patients with dilated cardiomyopathy and 2 patients without LV dysfunction, the first derivative of left ventricular pressure (LV dP/dt) was recorded with a micromanometer-tipped pig tail catheter during incremental right atrial pacing. The heart rate at which LV dP/dt was maximal was defined as peak force rate (PFR-FFR), the maximal increase of dP/dt from basal dP/dt was defined as force gain (FG-FFR), and the ratio of FG-FFR to basal dP/dt was defined as %FG-FFR. Additionally, the first beat after stopping atrial pacing (first sinus beat :FSB) was examined at each pacing rate. The left ventricular ejection fraction was measured by left ventriculography. Results: FG-FFR was positively correlated with LVEF (p=0.005). dP/dt of FSB showed rate-dependent increase similar to FFR regardless of coupling interval, therefore PFR-FSB, FG-FSB, and %FG-FSB were defined in the same way as those of FFR. PFR-FSB was significantly higher than PFR-FFR (P<0.001). FG-FSB was not correlated with LVEF(p=0.87). %FG-FSB was inversely correlated with LVEF (p=0.01). Conclusion: In LV dysfunction, force development does not catch up with tachycardia despite rate-dependent increase in intrinsic force store.

CARDIOVASCULAR AND AUTONOMIC EFFECTS OF FENFLURAMINE HYDROCHLORIDE.

Abstract Fenfluramine hydrochloride (N-ethyl-α-methyl-3-trifluoromethylphenethylamine hydrochloride; AHR-965) administered orally or intravenously to anaesthetised or unanaesthetised dogs, caused a predominant rise in arterial blood pressure, tachycardia, an increase in myocardial contractile force and cardiac output, and an enhanced total peripheral resistance. Fenfluramine was qualitatively like dexamphetamine in its cardiovascular effects; however dexamphetamine was 10 to 20 times more potent as a pressor agent.

Positive inotropic action of angiotensin II in the pithed rat

The cardiovascular effects of angiotensin II were examined in aortic blood pressure-controlled and -uncontrolled pithed rats. Angiotensin II induced a dose-dependent increase in diastolic blood pressure, left ventricular pressure (LVP), dP/dt (the first derivative of LVP) and heart rate in pithed rats. The maximal responses for these parameters were similar to those to noradrenaline, except for the rise in diastolic blood pressure, where noradrenaline caused a greater increase than angiotensin II. After treatment with propranolol, the positive chronotropic effect of angiotensin II was abolished. Angiotensin II produced a dose-dependent increase in diastolic blood pressure, which was similar to that of vasopressin, and an increase in dP/dtmax, which proved much greater than that of vasopressin. When aortic blood pressure was controlled and the beta-receptors were blocked by propranolol, angiotensin II caused a dose-dependent increase in dP/dtmax without affecting the left ventricular enddiastolic pressure. The same results were obtained after both beta- and alpha-adrenoceptors were blocked by propranolol and phentolamine. Losartan but not PD123177 caused parallel rightward shifts of the dose-response curve of angiotensin II for dP/dtmax in the aortic blood pressure controlled pithed rat without altering the maximal response. It is concluded that in the pithed rat angiotensin II produced an increase in myocardial contractile force which is not mediated by beta- or alpha-adrenoceptors. The inotropic effect appears to be mediated by angiotensin receptors, of the AT1-subtype.

An analysis of positive inotropic effects of nitroglycerin in the canine hearts

1. 1. Nitroglycerin caused dose-dependent increases in regional myocardial contractile force (MCF) in open-chest dogs, along with dose-dependent decreases in left ventricular end-diastolic (LVEDP) and arterial pressures and an increase in plasma catecholamines level. 2. 2. The increase in MCF could not be completely prevented by propranolol along with a slight decrease in LVEDP and no increase in heart rate, although a nifedipine-produced increase in MCF without a significant decrease in LVEDP disappeared with propranolol despite the same decrease in arterial pressure.

Effects of atenolol and some other beta-adrenoceptor blocking agents on norepinephrine-induced responses in isolated and perfused rat hearts.

The effects of atenolol and another three beta-adrenoceptor blocking agents on norepinephrine (NE)-induced cardiac responses were examined in isolated and perfused rat hearts following a Langendorff method. Bolus injection of atenolol did not show significant inhibitory effects on NE-induced increases in myocardial contractile force (MCF) and heart rate. Bolus injections of metoprolol and timolol were also ineffective for inhibiting NE-responses. However, both bolus injection and infusion of propranolol or infusion of atenolol, metoprolol and timolol all significantly inhibited NE-responses. On sustained increase in MCF induced by infusion of NE, the inhibitory effect of atenolol was transient, while that of propranolol was continuous. From these results, it is concluded that atenolol displays a different time course of action on NE-induced cardiac responses by bolus injection or infusion because of its pharmacological properties, which may be due to its low lipophilicity.

Effects of Atenolol and Some Other Beta-Adrenoceptor Blocking Agents on Norepinephrine-lnduced Responses in Isolated and Perfused Rat Hearts

The effects of atenolol and another three beta-adrenoceptor blocking agents on norepinephrine (NE)-induced cardiac responses were examined in isolated and perfused rat hearts following a Langendorff method. Bolus injection of atenolol did not show significant inhibitory effects on NE-induced increases in myocardial contractile force (MCF) and heart rate. Bolus injections of metoprolol and timolol were also ineffective for inhibiting NE-responses. However, both bolus injection and infusion of propranolol or infusion of atenolol, metoprolol and timolol all significantly inhibited NE-responses. On sustained increase in MCF induced by infusion of NE, the inhibitory effect of atenolol was transient, while that of propranolol was continuous. From these results, it is concluded that atenolol displays a different time course of action on NE-induced cardiac responses by bolus injection or infusion because of its pharmacological properties, which may be due to its low lipophilicity.

Cardiovascular Profile of Ro 13–6438, a Novel Positive Inotropic Agent with Vasodilating Properties

The cardiovascular properties of Ro 13-6438 (R-6-chloro-1,5-dihydro-3- methylimidazo -[2,1-b] quinazolin -2[ 3H]-one), a novel nonglycoside , noncatechol cardiotonic agent, were investigated in vitro and in vivo by both intravenous and oral administration. Ro 13-6438 increased tension development of isolated guinea pig left atria in a concentration-dependent manner with an EC50 of 30 microM, but had no stimulant effect on the spontaneous rate of right atria. The positive inotropic effect of Ro 13-6438 was additive to that of ouabain (0.1 microM); Ro 13-6438 suppressed the arrhythmogenic activity of high concentrations of ouabain (10 microM). IN anesthetized open-chest dogs 10-300 micrograms/kg Ro 13-6438 i.v. produced a significant and dose-dependent increase in myocardial force, with a duration of action exceeding 60 min following the highest dose. It also slightly increased heart rate, cardiac output, and blood flow. Ro 13-6438 decreased systolic and diastolic blood pressure, left ventricular end-diastolic pressure, and total peripheral resistance. Thus, the direct positive inotropic effects of Ro 13-6438 were supported by a decrease in preload and afterload. In chronically instrumented, conscious dogs Ro 13-6438 increased myocardial contractility after administration of 0.03-0.3 mg/kg i.v. or 3-10 mg/kg p.o. The effects persisted for greater than 8 h after oral administration of 10 mg/kg. The inotropic effects were accompanied by a modest increase in heart rate, which, however, had a clearly shorter duration of action than the former.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine potentiates coronary flow and inhibits oxygen consumption during isoprenaline infusion in isolated perfused guinea pig hearts.

It has been shown that adenosine, a potent coronary vasodilator, is released during cardiac sympathetic stimulation and that infusion of adenosine reduces the increase in myocardial contractile force elicited by catecholamines. The purpose of our study was: 1) to examine if adenosine also attenuates the rise in O2 consumption (MVO2) induced by infusing isoprenaline; and 2) to determine whether such a fall in MVO2 occurs primarily because of a relative decrease in tissue O2 extraction or a change in coronary flow. We isolated guinea pig hearts, perfused the vasculature at constant pressure and measured coronary flow, inflow and outflow pO2, and isovolumetric left ventricular pressure (PLV) and its derivative (dP/dt). Before, during and after infusing isoprenaline, we infused adenosine at increasing rates; but both drugs were infused at rates which did not maximally increase flow. We observed that adenosine reduced the increases in PLV and +dP/dt due to isoprenaline from 52 to 24% and from 81 to 55%. Moreover, linear regression analysis showed that the rise in MVO2 by isoprenaline was antagonised as a function of adenosine. This relative fall in MVO2 resulted primarily because of a decrease in O2 extraction since coronary flow was enhanced as a function of adenosine. Thus, although adenosine enhances the increase in flow due to isoprenaline overall it attenuates tissue O2 extraction and MVO2. Our study suggests that during sympathetic cardiac stimulation, endogenously released adenosine may not only produce vasodilatation and enhance the delivery of O2, but may also attenuate cardiac muscle work and the extraction of O2 with a net inhibition of MVO2.

Effects of nitroglycerin on myocardial contractile force in the underperfused canine heart.

Effects of nitroglycerin (NG, 3 μg/kg/min, i.v.) on regional myocardial contractile force(MCF) during acute coronary stenosis were studied in 16 open-chest dogs using two strain-gauge arches: one in the normal perfused area and one in the underperfused area supplied by the left circumflex coronary artery (LC-area). MCF in LC-area fell precipitously at coronary perfusion pressures lower than 40 mmHg. The animals were divided into three groups. After complete constriction MCF almost disappeared in Groups I(n=7) and II (n=3), whereas it fell by only a half of control in Group III(n=6). Under normal perfusion, NG increased MCF in Groups I and III, and caused no change in Group II. At pressure 50 mmHg, NG caused an increase in MCF in Groups I and III along with decreases in left ventricular pressure and systemic blood pressure. In Group I, the increase reached to maximal level 2-3 min after NG infusion (130 ± 7 % in LC-area and 118 ± 6 % in normal area) and lasted for at least 10 min. At pressure 40 mmHg, MCF in LC-area decreased in Groups I and II and increased in Group III, although NG changed hemodynamic function to the same levels in the 3 groups. In Group I, 5 min after NG infusion MCF in LC-area decreased to about 70%. At this time, coronary perfusion pressure and coronary blood flow decreased to below 30 mmHg and 37 ± 8 %, respectively. Under these conditions, release of the constriction sufficient for retention of the coronary perfusion pressure at 40 mmHg resulted in significant improvement of MCF in LC-area without a further increase in coronary blood flow. In Group III, 2-3 min after NG infusion MCF in LC-area increased to 112 ± 3 %. The increase was reduced with propranolol; thus at least some participation of β-adrenoceptor is assumed.

Myocardial contractile force at high coronary arterial oxygen tension in dogs.

In 34 mongrel dogs, the left anterior descending coronary artery was perfused with the dog's own femoral arterial blood at a constant flow rate and the myocardial contractile force was measured using a myocardial strain gauge arch. When the femoral arterial blood was oxygenated (pO2 61.7 kPa (463 mmHg)) using an artificial lung, so that the perfused myocardium became hyperoxic, the myocardial contractile force was increased by 11.1 +/- 2.3%. When the perfusion rate was reduced by approximately 20%, there was a smaller increase in myocardial contractile force, 8.0 +/- 2.3%. If, in addition, oxygen inhalation was performed the myocardial contractile force decreased by 4.1 +/- 2.1%. In 10 mongrel dogs, the carotid arteries were perfused at a constant flow rate with femoral arterial blood from a donor dog. Oxygen inhalation by the donor dog caused a reduction in the myocardial contractile force of the experimental dog of 5.9 +/- 1.6%. It is suggested that oxygen has a direct effect in increasing myocardial contractile force. This increase is counteracted by oxygen-induced coronary vasoconstriction in some part and by a neurohumoral effect or suppression of chemoreceptor activity.

α-adrenergic blocking properties of quinine HCl

In the anesthetized dog, quinine HCl (50 mg/kg, i.v.) infused over a 20 min period produced a 22% maximum decrease in diastolic blood pressure, a 53% increase in pulse pressure and a 52% increase in myocardial contractile force. The initial positive inotropic response was maximal in the first 5–15 min of the quinine infusion and decreased to near control levels 40 min following the quinine infusion. Quinine caused a marked reduction in the noradrenaline (NA) pressor response, blockade of the adrenaline (A) pressor response, partial blunting of the angiotensin II (AII) pressor effect but no change in the depressor effect of isoprenaline (I). The positive inotropic effects of CaCl 2 were reduced and the duration of contractile action to both I and CaCl 2 was significantly prolonged by quinine. In isolated rabbit thoracic aortic strips, quinine produced a parallel, dose-related shift of the concentration-response curve for NA to the right but did not affect the maximum responses. A pA 2 of 4.91 was estimated by the method of Schild. The determined line had a slope of -0.84 which is similar to a theoretical slope of -1.0 and indicates a direct relationship between the number of receptors occupied and the contractile response. The responses to AII and histamine (H) were not altered by quinine. These results suggest that quinine HCl produces α-adrenergic blockade; additionally, quinine modifies catecholamine- and calcium-induced myocardial contractile force responses.

Direct and reflex cardiostimulating effects of hydralazine

Increased cardiac output and heart rate after administration of hydralazine have been attributed to reflex activation of the cardiac sympathetic nerves secondary to the decrease in arterial pressure. However, some studies suggest that hydralazine has an additional direct cardiostimulatory effect. The present study was designed to investigate this possibility. Mean arterial pressure, percent change in myocardial contractile force using a Walton-Brodle strain gauge and heart rate were measured in eight open chest dogs anesthetized with sodium pentobarbital. After intravenous administration of hydralazine, 20 mg, myocardial contractile force increased on average by 27 percent and heart rate by 7 percent; mean arterial pressure decreased less than 10 percent. The same reduction of mean arterial pressure with sodium nitroprusside resulted in increases of only 10 percent in myocardial contractile force and 2 percent in heart rate. The differences between the drugs were statistically significant for heart rate ( P < 0.05) and myocardial contractile force ( P < 0.01). After reductions in mean arterial pressure exceeding 10 percent, the increases in heart rate and myocardial contractile force with either hydralazine or sodium nitroprusside were insignificantly different. Direct injection of 0.8 mg of hydralazine into a coronary artery in four dogs consistently increased myocardial contractile force in the area perfused whereas administration of sodium nitroprusside even in large doses exerted no local inotropic activity. The local effect of hydralazine was blocked by intravenous administration of propranolol. These results suggest that the increase in myocardial contractile force and heart rate after administration of hydralazine is the result not only of a reflex response to a decrease in blood pressure, as occurred with sodium nitroprusside, but also of direct beta adrenergic stimulation of myocardium.

Nutritional Circulation in the Heart

The effect of a constant intracoronary infusion of potassium chloride and calcium chloride upon myocardial hemodynamics and clearance of 86Rubidium in the heart was studied in the isolated supported dog heart preparation (ISHP). In the ISHP with a constant coronary blood flow, potassium chloride in doses up to 4mg/min had no significant effect upon either the myocardial hemodynamics (MH), clearance of 86Rubidium (C86Rb) or the capillary transport coefficient, PS. Calcium chloride in small doses had no effect upon the MH, C86Rb or PS. A higher dose of calcium chloride (4mg/min) produced an increase in myocardial contractile force, left ventricular peak systolic pressure, myocardial oxygen consumption and a decrease in C86Rb and PS. Pretreatment of the ISHP with practolol (0.25mg/Kg), an agent which blocks adrenergic β-receptors, did not modify the effects of calcium chloride upon the MH, C86Rb or PS. It is concluded that the effects of calcium chloride are exerted directly, independent of a β-receptor mediation.

Cardiac inotropic and coronary vascular responses to countershock.

These experiments were designed to examine the role of excitation of intracardiac nerves in the response to countershock with either alternating current (ac) or direct current (dc). Studies were performed on intact anesthetized dogs and on isolated perfused hearts. In intact dogs a-c and d-c countershock produced transient sinus arrest and an increase in myocardial contractile force. Sinus arrest could be prevented with atropine, and the positive inotropic response could be prevented with propranolol or prior surgical denervation of the heart. In isolated hearts, a-c and d-c countershock produced sinus arrest which could be prevented with atropine or hemicholinium-3. Alternating-, but not direct-, current countershock increased contractile force of the isolated heart. The inotropic response to ac could be blocked with propranolol and was absent in hearts removed from dogs which had undergone prior cardiac denervation. Both a-c and d-c countershock produced a decrease in coronary vascular resistance which could be prevented with atropine. Cholinergic responses to countershock persisted after surgical denervation of the heart. These observations provide evidence for excitation of intracardiac cholinergic and adrenergic nerves by countershock. Direct-current countershock excites cardiac sympathetic nerves in intact dogs, but not in isolated hearts. Intracardiac cholinergic nerves persist after surgical denervation of the heart.

Cardiovascular responses to cyclohexylamine

The cardiovascular effects of cyclohexylamine have been studied in cats. In appropriate doses, cyclohexylamine produced a rise in arterial blood pressure, an increase in myocardial contractile force, and tachycardia. Higher doses caused a vasodepressor response, bradycardia, and a reduction in myocardial contractile force. Repeated injections of cyclohexylamine led to tachyphylaxis, but the pressor effect could be partially restored by injection of norepinephrine. The pressor response could be reduced with cocaine or phenoxybenzamine and increased by iproniazid. It was unaffected by ganglion blockade, α-adrenergic receptor blockade, reserpine, bilateral adrenalectomy, nephrectomy, and it persisted in decerebrate and in spinal cats. These observations suggest that cyclohexylamine caused its cardiovascular effects by direct stimulation of α-adrenergic receptors, but it may also release endogenous catecholamines from sites other than the adrenal medulla.

THE EFFECT OF RESERPINE ON PHOSPHORYLASE ACTIVITY IN THE ISOLATED RABBIT ATRIA

The increase in myocardial contractile force after administration of epinephrine is closely related to the activation of cyclic 3', 5'-AMP with a subsequent conversion of phosphorylase b to a (1-5). Further, it seems likely that there exists a close relationship between the level of circulating catecholamine and the activity of phosphorylase in the heart, based on the finding that the injection of ganglionic stimulating agents produces the simultaneous increase in myocardial contractile force and augmentation of phosphorylase activity (6). The observation of Nakatani (7) that physostigmine augments phosphorylase activity in the heart and this augmentation is prevented by prior reserpine is compatible with the view that endogenously liberated catecholamines increase phosphorylase a. However, there are controversial reports regarding the effect of reserpine on heart phosphorylase activity: no significant change (3, 8), increase (5) and decrease (9), and there is no conclusive evidence that reserpine decreases heart phosphorylase. This is incompatible with the concept that there is a positive correlation between the amount of endogenous catecholamines and heart phosphorylase a activity. All these expriments, however, were conducted in the in situ preparations. To our knowledge, the one exceptional observation was made by Giotti (10), who reported insignificant effects of reserpine in vitro on phosphorylase activity in guinea pig atria. The present study was undertaken to investigate the relationship between reserpine and phosphorylase activity in the isolated rabbit atria.

CARDIAC VERSUS PERIPHERAL EFFECTS OF LEFT STELLATE GANGLION STIMULATION.

The direct effects of left stellate ganglion stimulation were studied in dogs with an intact circulation and with the left ventricle bypassed. In both preparations left stellate stimulation was associated with an increase in myocardial contractile force, an elevation in pulmonary arterial pressure, and no change or a slight fall in right atrial pressure. Before left ventricular bypass, left stellate stimulation was accompanied by a rise in both systolic (+46 mm Hg) and diastolic (+22 mm Hg) pressure. With the left ventricle eliminated from the circulation and systemic flow controlled with a mechanical pump, changes in systolic (+13 mm Hg) and diastolic (+7 mm Hg) pressure were negligible. These observations confirm that the hypertensive response is due predominantly to augmented cardiac output and that peripheral vasoconstriction plays a minor role.

The effect of ouabain on cardiac automaticity in reserpine-pretreated dogs

The findings reported in this study suggest that the increase in cardiac automaticity and the increase in myocardial contractile force due to ouabain are not dependent on the release of catecholamines from the heart, adrenal glands, or stores which mediate the response of certain adrenergic nerves.