Increase In Myocardial Contractility Research Articles

Role of adenosine and its interaction with adrenoceptor activity in ischaemic and reperfusion injury of the myocardium

Adenosine is recognised as an important regulator of myocardial function and coronary vascular tone in the ischaemic myocardium. It is produced by the enzymatic dephosphorylation of 5'-AMP by 5'-nucleotidase and the hydrolysis of SAH by SAH-hydrolase. 5'-Nucleotidase is thought to contribute to adenosine production aside from the accumulation of 5'-AMP in the ischaemic myocardium, while the hydrolysis of SAH plays a major role in adenosine production in the normoxic myocardium. 5'-Nucleotidase activity is reported to increase adenosine production through accumulation of ATP, ADP, H+, Mg2+ and inorganic phosphate during ischaemia. In addition, we have found that alpha 1 adrenergic receptors, activated in ischaemic hearts, increase both 5'-nucleotidase activity and adenosine production. Inactivation of adenosine deaminase and adenosine kinase may also contribute to adenosine production. On the other hand, the major role of endogenous adenosine is to increase coronary blood flow. This adenosine induced coronary vasodilatation is amplified by alpha 2 adrenoceptor stimulation. Adenosine induced vasodilatation is also enhanced by increasing H+ and opening ATP sensitive K+ channels, which occurs in the ischaemic myocardium. However, coronary vasodilatation is not the only effect of adenosine in the ischaemic myocardium. Stimulation of adenosine A2 receptors coupled to Gs proteins attenuates both free radical generation by activated leucocytes and aggregation of platelets. Adenosine A1 receptor activation coupled to G(i) proteins attenuates beta adrenoceptor mediated increases in myocardial contractility, Ca2+ influx into myocytes, and noradrenaline release from the presynaptic nerves. Any or all of these effects may attenuate ischaemic and reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Lusitropic changes induced by acid base alterations in cat papillary muscles.

The present work investigates the effects of acid-base alterations upon myocardial relaxation. Experiments were performed in cat papillary muscles contracting isometrically at constant frequency (0.2 Hz) and temperature (29 degrees C). To induce intracellular alkalosis at constant pH0, 20 mM NH4Cl were added to the perfusate. Alkalosis at variable pH0 was induced by switching from the control solution (5% CO2-95% O2, pH0 7.40) to a solution identical to the control one, equilibrated with 3% CO2-97% O2. Acidosis was induced by switching the control perfusate to a solution equilibrated with 12% CO2-88% O2 in which pH0 was either allowed to change or kept constant by manipulation of bicarbonate concentration. Alkalosis produced a negative lusitropic effect either when pH0 was kept constant or when it was allowed to increase. For an increase in myocardial contractility of 30%, half relaxation tme (T50) and time to peak tension (TTP) were prolonged 9.4 +/- 5% and 5.4 +/- 2% respectively at constant pH0 and 6.8 +/- 0.8 and 4.7 +/- 1% respectively at variable pHo. It is suggested that this negative lusitropic effect of alkalosis can be attributed to an increase in myofilament sensitivity to calcium. Either at constant or at variable pHo acidosis decreased myocardial contractility by approximately 50%. This decrease in contractility was accompanied by a positive lusitropic action only when pHo was allowed to decrease, or when acidosis at constant pHo was evoked in the presence of EIPA, a specific inhibitor of the Na+/H+ exchanger.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular actions of a new selective postjunctional alpha-adrenoceptor antagonist, SK&F 104856, in normotensive and hypertensive dogs.

1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.

Cardiovascular reactivity assessment: effects of choice of difficulty on laboratory task responses

This laboratory study of cardiovascular reactivity was designed to examine how a choice of difficulty element in a mental arithmetic task would affect cardiovascular responses. 20 healthy male subjects were tested on a computer-controlled mental arithmetic task, designed to standardize performance across subjects by keeping constant the proportion of correct responses. This was achieved by automatic adjustment of problem difficulty according to ongoing performance. Subjects were led to believe that they could take either a ‘difficult’ or an ‘easy’ version of the mental arithmetic task and were asked to make a choice; in fact, all subjects were given the same task. Subjects who chose the ‘difficult’ mental arithmetic task ( N = 10) showed significantly greater increases in myocardial contractility, cardiac output and systolic blood pressure during task performance than those who chose ‘easy’ ( N = 10). However, subjects who chose ‘difficult’ were presented with more difficult problems presumably due to their exerting greater levels of effort during the task. The differences in cardiovascular responses associated with choice of difficulty were absent during testing on four subsequent tasks which did not incorporate any choice options (reaction-time, speech, mirror trace, cold pressor). These findings are interpreted as being provocative, rather than in any way conclusive. Nevertheless, they are suggestive of the possibility that choice of difficulty in laboratory tasks may be one strategy for improving the ecological validity of laboratory reactivity assessment procedures.

Adenosine, the heart, and coronary circulation.

Adenosine is known to regulate myocardial and coronary circulatory functions. Adenosine not only dilates coronary vessels, but attenuates beta-adrenergic receptor-mediated increases in myocardial contractility and depresses both sinoatrial and atrioventricular node activities. The effects of adenosine are mediated by two distinct receptors (i.e., A1 and A2 receptors). A1 adenosine receptors, located in atrial and ventricular myocardium and sinoatrial/atrioventricular nodes, are responsible for inhibition of adenylyl cyclase activity. A2 adenosine receptors, located in coronary endothelial and smooth muscle cells, are responsible for stimulation of this enzyme activity. During increased myocardial oxygen demand due to rapid pacing and exercise, although both coronary blood flow and adenosine concentrations in the myocardium and coronary efflux increased, there is no clear consensus explaining its cause and effect relation at present. However, ischemia/reperfusion-induced coronary hyperemia is believed to be mostly attributed to released adenosine, and it has been proven that adenosine attenuates the severity of ischemia due to its coronary vasodilatory action. The beneficial effects of adenosine during ischemia/reperfusion processes do not seem simple. This is because myocardial ischemia and reperfusion injury is caused by 1) activated leukocytes and platelets, 2) ATP depletion and calcium overload of myocardium, and 3) catecholamine release from the presynaptic nerves as well as 4) the impaired coronary circulation. Intriguingly adenosine attenuates all of these deleterious actions and thereby attenuates ischemia/reperfusion injury. Indeed, adenosine attenuates the severity of contractile dysfunction (myocardial stunning) and limits the infarct size. Thus, administration of adenosine or potentiators of adenosine production in the ischemic myocardium may be beneficial for the attenuation of ischemic and reperfusion injuries, although further clinical investigations are necessary.

Interaction between adenosine and beta-adrenoceptors.

Interaction between adenosine and isoproterenol (ISP) on myocardial inotropic action was studied in open-chest dog hearts. The local myocardial force and the left ventricular (LV) dP/dt were measured as indices of myocardial contractility. Isoproterenol [ISP, 9.47 microM (2 micrograms/ml)] was infused into the left circumflex coronary artery at rates of 0.05 ml/min (low dose ISP) or 0.2 ml/min (high dose ISP). Two mM adenosine or 0.5 mM N6-phenylisopropyl-adenosine (PIA) were infused into the coronary artery at rates of 0.2 (4 x 10(-7) mol/min), 0.5 (1 x 10(-6) mol/min) and 10 ml/min (2 x 10(-5) mol/min) in the presence of either a low or a high dose of ISP. Adenosine infusion at a rate of 0.2 ml/min did not modify myocardial contractility in the presence of the both doses of ISP. The larger doses of adenosine, 0.5 ml/min and 10 ml/min, decreased myocardial-developed tension and LVmax dP/dt dose-dependently. However, the dose of adenosine which affected myocardial contractility was inphysiologically high in comparison with the concentration in the ischemic myocardium. PIA, a potent agonist of adenosine A1-receptor, attenuated an increase in myocardial contractility in a dose-dependent manner which was caused by intracoronary ISP infusion. This indicates that A1-adenosine receptors exist, but a functional adenosine-catecholamine antagonism does not play a significant role in the canine left ventricle.

Nonsteroidal cardiotonics. 3. New 4,5-dihydro-6-(1H-indol-5-yl)pyridazin-3(2H)-ones and related compounds with positive inotropic activities

A series of substituted indolyldihydropyridazinones and related compounds 1-18 were synthesized and evaluated for positive inotropic activity. In rats, most of these indole derivatives produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. Compound 13, 4,5-dihydro-5-methyl-6-(2-pyridin-4-yl-1H-indol-5-yl)pyrazin-3(2H) -one (BM 50.0430), was further investigated in cats. The increase in contractility in this animal model was not mediated via stimulation of beta-adrenergic receptors. After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h. However, the cardiotonic effect of 13 was at least 2-fold that of pimobendan after this period of time. The structural requirements necessary for optimal cardiotonic activity within this novel class of indole derivatives are a heterocyclic aromatic ring in position 2, a hydrogen or a methyl group in position 3, and a dihydropyridazinone ring system in position 5 of the indole.

Usefulness of Continuous Wave Doppler Measures as Indicators of Exercise-Induced Alterations in Myocardial Contractility

The authors examine the utility of using the CW Doppler measures of peak acceleration (PkA) and peak velocity (PkV) of blood flow in the ascending aorta as measures of alterations in myocardial contractility due to cardioselective β-blockade. Using upright cycle ergometry, 18 physically active men (mean age, years 25.2; VO2peak, 42.3 ml x kg-1 x min-1) exercised at 20, 40, and 60% VO2peak in three consecutive 6-minute stages after administration of either a placebo (P) or 100 mg of atenolol (A). CW Doppler measures were obtained, as was stroke volume (SV; CO2 rebreathing), heart rate (HR), and blood pressure. At 60% VO2peak, PkA averaged 37.0% less (P < 0.01) while PkV was 10.1% less (P < 0.05) with A than with P;SV was 22.5% higher (P < 0.01) while HR was 18.8% lower (P < 0.01) with A. Mean arterial pressure (MAP) was a significant covariate for PkA (P < 0.01) but not PkV. Absolute between-condition alterations in PkV (PkVp–a) shared a significant proportion of variance with SVp–a (R2 = 0.29, P < 0.05) while the amount of shared variance with PkAp–a was nonsignificant (R2 = 0.22). Since MAP was lower in A by 10.6% (P < 0.05), the increased SV in A was attributed to decreased afterload and not increased myocardial contractility. Approximately 68% of the variance in PkAp–a and 75% of PkVp–a cannot be explained by β1-blocker associated changes in either SV or MAP. Most likely, the majority of this unexplained variance is due to the suppression of catecholamine-induced increases in myocardial contractility seen with β1-blockade. Both PkA and PkV were significantly reduced (P < 0.01, P < 0.05, respectively) with A compared with P. These findings are consistent with the interpretation that Doppler measures of PkA and PkV are sensitive to changes in myocardial inotropic state when such measures are compared serially within the same subjects.

Experimental studies of the load reducing effects of nitroglycerin in heart failure.

The load-reducing effect of nitroglycerin (NTG), a vasodilator, was studied in dogs with heart failure. The chordae tendineae of the mitral valve were transected to induce acute mitral regurgitation (MR) for hemodynamic evaluation. By such surgical treatment, preload indices such as left ventricular end-diastolic pressure (LVEDP) and left atrial pressure (LAP) increased significantly, and subsequent cardiac dysfunction and heart failure were indicated by another decrease in stroke volume, myocardial contractility, forward flow, and myocardial oxygen consumption. To dogs with artificially established acute MR, 3 micrograms/kg/min of NTG was administered intra-arterially by means of a continuous infusion, that resulted in decrease of LVEDP, LAP and central venous pressure (CVP). Thus, a reduction of preload was determined. Simultaneously, afterload indices such as aortic systolic pressure (Aos), aortic mean pressure (Aom) and total peripheral resistance (TPR) decreased remarkably. Afterload reduction depended on the amount of venous return; therefore, an extra-corporeal circulation system was applied in order to supply a constant venous return before NTG administration. This caused a significant decrease in aortic diastolic pressure (Aod), Aos, Aom, left ventricular systolic pressure (LVSP) and TPR, and an increase in myocardial contractility and cardiac output. This suggested that afterload reduction might be realized by the vasodilatory effect of NTG on the resistance vessels.

Central and peripheral adrenergic receptor agonists in heart failure

The subtypes of alpha- and beta- and dopaminergic receptors have been identified along with specific agonists and antagonists. The effects of alpha-receptor agonists on haemodynamics results from the interaction of relative changes in vascular tone and increase in myocardial contractility. Predominantly, beta 1 agonists improve cardiac performance by increasing contractility which is usually accompanied by increased myocardial oxygen consumption. Dopaminergic receptor agonists improve left ventricular function primarily by reduction in systemic vascular resistance usually without a change in myocardial oxygen consumption. beta 2-receptor agonists improve cardiac function both by increasing contractility and by peripheral vasodilation usually without an increase in metabolic cost. The effects of various adrenoreceptor agonists such as dobutamine, dopamine, prenalterol, levodopa and dopexamine on systemic and coronary haemodynamics and on myocardial energetics in heart failure are reviewed.

Cardiotonic agents. 1-Methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3 (2H)-isoquinolinones and related compounds. Synthesis and activity.

A series of 1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinones and related compounds were synthesized and evaluated for positive inotropic activity. Most members of this series exerted a dose-dependent increase in myocardial contractility in the dog acute heart failure model, whereas they caused only slight changes in heart rate and blood pressure. Several derivatives, especially those with cyano, acetyl, and ethyl substituents at the 4-position, were more potent than milrinone, which was used as a reference. 4-Acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone (MS-857) is one of the most potent positive inotropic agents in this series.

New alpha 1-adrenergic receptor antagonists for the treatment of hypertension: Role of vascular alpha receptors in the control of peripheral resistance

The pharmacology, clinical efficacy and safety of new alpha-adrenergic receptor antagonists for the treatment of hypertension was reviewed (Table XIV). Although all these agents block alpha 1 receptors, some of them have additional effects on histamine, serotonin, dopamine, and alpha 2 receptors. These other actions account for the differences in the side effect profiles observed, i.e., increased incidence of central nervous system side effects found with indoramin, ketanserin, and urapidil, as well as for some additional beneficial effects of ketanserin (i.e., antiplatelet aggregation activity). The magnitude of BP reduction observed with antagonists of alpha 1-adrenergic receptors is modest. In most studies, the degree of BP reduction is comparable to that of prazosin, but less than that achieved with thiazide diuretics, beta-receptor antagonists, or methyldopa. Studies on the comparative efficacy and safety of new alpha 1 antagonists with converting enzyme inhibitors or calcium-channel blockers are not available. In general, alpha 1 antagonists produce greater reductions in standing than in supine BP, an effect due to the venodilatory action of these drugs. New alpha 1 antagonists appear to have equal efficacy in black and white hypertensive individuals. Their comparative efficacy and safety in young vs elderly hypertensive individuals requires further investigation. No information about the possible development of tolerance during treatment with new alpha 1 blockers was encountered. The effects of alpha 1 antagonists on HR are variable and depend on how long after the oral dose the measurements were obtained. In most studies, no significant HR changes are noticed for readings obtained 24 hours post dose; whereas tachycardia has been observed at the time of peak hypotension. Since alpha 1 antagonist-induced tachycardia is most likely of reflex nature, i.e., mediated to an increase in sympathetic activity, the increased HR may be associated with increases in myocardial contractility and in myocardial oxygen consumption. Consequently, a 24-hour HR monitoring during treatment with alpha 1 antagonists should be required for evaluation of new agents. The hemodynamic, humoral, and hormonal effects of the newer alpha 1-receptor antagonists are comparable to those of prazosin. The most consistent finding is a reduction in total peripheral resistance associated with either no change or with only small increases in cardiac index. These agents have been shown either not to change or to increase renal blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Alifedrine, a positive inotropic agent that moderately reduces the severity of ischaemia and reperfusion-induced ventricular arrhythmias

The effects of alifedrine, a positive inotropic agent, were examined in greyhounds anaesthetised with chloralose. An intravenous dose of 0.3 mg kg −1 resulted in a substantial increase in myocardial contractility (increased dP/dt max, cardiac output and stroke volume) without significantly affecting heart rate. The effects of alifedrine on the severity of arrhythmias resulting from both coronary artery occlusion and reperfusion were also determined. A mild anti-arrhythmic effect was observed during early ischaemia when the incidence of ventricular tachycardia was reduced from 90% in controls to 50% in treated dogs. There was also a significant reduction in the number of extrasystoles appearing as ventricular tachycardia (from 511 ± 138 to 151 ± 84). The total number of extrasystoles during the first 30 min of ischaemia was also reduced, although not significantly, from 846 ± 193 to 527 ± 86. Following release of a 40 min coronary artery occlusion there was a marked reduction in reperfusion-induced ventricular fibrillation from 75% in controls, to 37% in the alifedrine-treated dogs. The overall survival from the combined occlusion-reperfusion insult was increased from 20% in controls to 50%. These results suggest that alifedrine has an unusual and useful spectrum of pharmacological activity in that it combines antiarrhythmic activity with an ability to improve cardiac function.

Effects of calcium channel blockers on systemic hemodynamics in hypertension

Increased total peripheral resistance is the hemodynamic abnormality that characterizes established essential hypertension. Therefore, an antihypertensive agent should reduce arterial pressure by decreasing total peripheral resistance while maintaining systemic flow as well as flow to the target organs of hypertensive disease: the brain, heart, and kidney. Drugs that reduce total peripheral resistance have been used for many years. However, their stimulation of renal and humoral responses counteracts the antihypertensive effect and thereby limits their efficacy. Thus, when total peripheral resistance is reduced, the sympathetic nervous system and the renin-angiotensin system are activated. Increases in myocardial contractility, sympathetic tone, and angiotensin-mediated vasoconstriction; sodium and fluid retention; and tachycardia may result, thereby blunting the drug-induced decrease in arterial pressure and producing so-called “pseudoresistance” to the antihypertensive regimen. Most calcium channel blockers appear to differ from other vasodilators because neither the renin-angiotensin system nor the sympathetic nervous system is stimulated during long-term treatment. Moreover, in patients with left ventricular hypertrophy, certain calcium channel blockers allow left ventricular hypertrophy to regress.

Role of cyclic AMP in regulating cardiac muscle contractility: Novel pharmacological approaches to modulating cyclic AMP degradation by phosphodiesterase

AbstractThe role of cyclic AMP in modulating the contractile function of cardiac muscle has been the subject of intensive investigation for more than two decades. These studies have shown that the positive inotropic response to cyclic AMP involves multiple components, including adenylate cyclase, the enzyme that catalyzes the conversion of ATP to cyclic AMP, activation of cyclic AMP‐dependent protein kinases, which are responsible for phosphorylating key intracellular proteins, and phosphodiesterase, the enzyme that hydrolyzes cyclic AMP, thereby terminating the response. Several reports have shown, however, that increases in intracellular cyclic AMP are not always accompanied by increases in myocardial contractility, suggesting that cyclic AMP may be compartmentalized within cardiac cells and that only certain compartments are involved in modulating contractility. In addition, although cardiac muscle contains only one form of adenylate cyclase, multiple forms of phosphodiesterase have been identified in ventricular muscle, which vary in their substrate specificity and their response to allosteric effectors such as calmodulin. Recent studies have also shown that these various forms of phosphodiesterase can be located in different regions within the cardiac cell and that only certain forms of the enzyme are involved in modulating the inotropic response to cyclic AMP. This review summarizes the current state of knowledge regarding the involvement of cyclic AMP with cardiac contractile function and also explores several controversial aspects of this involvement.

Comparison Between the Effects of MDL 72567 and Nifedipine on Various Cardiovascular Parameters in Conscious Sinoaortic-Denervated Rats and Sham-Operated Controls

In this study the effects of a new calcium entry blocking agent, 2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(2-furoyl)-1, 4-dihydropyridine (MDL 72567), were compared with those of nifedipine on blood pressure, heart rate, ECG, and cardiac contractility indices in conscious sinoaortic baroreceptor-denervated (SA-denervated) rats and their sham-operated controls. In sham-operated rats, the calcium-entry blocking agents (0.1-2 mg/kg i.v.) produced equivalent falls in blood pressure. However, nifedipine caused a much greater reflex tachycardia which was accompanied by a negative inotropic effect, and with the highest dose (2 mg/kg), a prolongation of the PQ interval. MDL 72567 induced an increase in myocardial contractility. In SA-denervated rats, both drugs produced an enhanced fall in blood pressure accompanied by a negative inotropic effect. Nifedipine did not change heart rate in SA-denervated rats, whereas MDL 72567 caused bradycardia. Thus, in these experiments, MDL 72567 caused less reflex tachycardia for a given fall in blood pressure than nifedipine and was less likely to cause myocardial depression. These effects of MDL 72567 may represent valuable, clinically relevant advantages over nifedipine.

Effects of chronic myocardial infarction on responsiveness to isoprenaline and the state of myocardial beta adrenoceptors in rats.

Responsiveness to catecholamines and alterations in myocardial beta adrenoceptors were determined in rats with chronic myocardial infarction. Myocardial infarction was produced by ligating the left main coronary artery. Three weeks after myocardial infarction, when left ventricular function was impaired, catecholamine responsiveness was determined by measuring the effects of isoprenaline in the conscious animal, the isolated perfused heart, the isolated right atria, and the right papillary muscles. The catecholamine content and the density and affinity of beta adrenergic receptors [( 3H]dihydroalprenolol binding) were determined in non-ischaemic myocardium (ventricular septum). In conscious rats isoprenaline induced the same tachycardia in the sham operated as in the rats with infarction, but it induced only a slight increase of myocardial contractility because of a high basal sympathetic tone. In isolated perfused hearts, right atria, and right papillary muscles isoprenaline increased contractile force and heart rate with the same EC50 in both groups. However, in the infarcted group the maximal increase of contractile force induced by isoprenaline was smaller because of mechanical limitation due to the infarction. The catecholamine content was decreased in non-ischaemic myocardium and beta adrenergic density was increased by 30% (p less than 0.02) without any change of affinity. Thus in rats chronic myocardial infarction does not change the responsiveness of the non-ischaemic myocardium to isoprenaline and is not associated with a downregulation of the beta adrenoceptors.

Cardiac and microcirculatory effects of different doses of prostaglandin E1 in man.

A cumulative dose response to intravenous PGE1 was established in 12 healthy volunteers. Systolic time intervals, including pre-ejection period (PEP), the ventricular ejection time (VET) and the RR-interval, were continuously determined, and transcutaneous oxygen pressure (tcpO2) was recorded. RR-intervals fell in a dose dependent manner, reaching a significantly lower level at 128 ng.kg-1.min-1 of PGE1 (basal value 842 ms falling to 756 ms). PEP decreased from 89 ms to 74 ms and the ratio PEP/VET decreased from 35% to 30%, indicating increased myocardial contractility. The maximal increase in tcpO2 was 125% on the calf and 60% on the foot. The peak tcpO2 was observed at an infusion rate of 16 ng.kg-1.min-1 PGE1. A decline in tcpO2 was seen at infusion rates greater than 64 ng.kg-1.min-1 PGE1 indicating a decrease in skin perfusion. The results indicate that the effects of intravenous PGE1 on skin perfusion occur at a lower threshold than the increase in myocardial contractility. A maximal increase in skin perfusion can be achieved with doses of PGE1 devoid of systemic haemodynamic effects.

Variability of positive inotropic response to acute amrinone administration in chronic cardiac failure.

To determine the factors conditioning the variability of positive inotropic response after intravenous acute amrinone administration, 14 patients with chronic cardiac failure were studied by quantitative M-mode and cross-sectional echocardiography. Six patients had idiopathic dilated cardiomyopathy and 8 patients had severe chronic aortic insufficiency. Myocardial contractility (evaluated as peak arterial systolic pressure/end-systolic volume ratio: PAP/ESV) did not change in patients with idiopathic cardiomyopathy, a significant increase of myocardial contractility occurred in patients with aortic regurgitation only if the control value of PAP/ESV was greater than 1. Mean systolic wall stress decreased significantly in all patients, independent of aetiology of cardiac failure and was the factor determining the improvement of left ventricular performance (evaluated as fractional shortening) in patients without changes in myocardial contractility. Maximum improvement in left ventricular performance occurred 10 minutes after amrinone administration. It is concluded that the possibility of detecting the positive inotropic properties of amrinone in man depends on the aetiology of the cardiac failure and on the basal level of myocardial contractility.

Reflex hypotension due to regional activation of left ventricular mechanoreceptors to explain the hypotension noted in clinical myocardial ischaemia or reperfusion.

To determine if regional increases in myocardial contractility, as may occur clinically in angina pectoris, myocardial infarction, or coronary thrombolysis, can initiate the reflex hypotension that sometimes accompanies these conditions, regional injections of positive inotropic agents were made into 32(3)% of the left ventricular myocardium in seven pneumonectomised dogs on total cardiac bypass. The coronary and systemic circulations were isolated and perfused separately. The systemic circulation was perfused at a constant rate so that changes in systemic pressure reflected changes in resistance. Regional injections of doses from 0.001 to 1.0 micrograms noradrenaline in a 0.1 ml volume appreciably increased regional contractility, detected visually and by strain gauge arches, whereas global contractility (left ventricular peak dP/dt) was increased much less. This caused a fall in the systemic pressure (resistance) of 14(2)% below the control value of 78(5)mm Hg, at the largest dose. The decreases in resistance were abolished by bilateral vagotomy, proving their reflex nature. The smaller (0.0001-0.01 micrograms) doses of noradrenaline and the smallest (0.25 micrograms) dose of veratridine increased regional contractility almost without increasing global contractility, indicating that the increase in regional contractility was the major cause of the reflex decrease in systemic resistance. In one animal a decrease in contractility in a control myocardial region occurred simultaneously with the experimentally produced increase in regional left ventricular contractility. This decrease may be analogous to the increase in contractility in the non-ischaemic left ventricular myocardium that occurs simultaneously with the decrease in contractility in the ischaemic region in clinical or experimental myocardial infarction. Left ventricular mechanoreceptors in the region with increased contractility probably initiate the reflex hypotension that sometimes occurs in both circumstances. Thus in angina pectoris or acute myocardial infarction the reflex hypotension probably originates in the hyperactive non-ischaemic myocardial region, whereas in coronary arterial thrombolysis it probably originates in the newly reperfused, formerly ischaemic, region.