Effect of alpha-adrenergic stimulation on regional contractile function and myocardial blood flow with and without ischemia.

BACKGROUND. The effect of alpha-adrenergic receptor activation on regional contractile function and transmural myocardial blood flow is controversial. Accordingly, the effects of selective alpha 1-(methoxamine) and alpha 2-(BHT 933) receptor stimulation on regional contractile function and transmural myocardial blood flow distribution were studied in 15 anesthetized open-chest dogs. METHODS AND RESULTS. The alpha-adrenergic agonists were separately infused into the cannulated left circumflex coronary artery during control and ischemic conditions in the same animal. Mean coronary perfusion pressure was held constant by a servocontrolled pump in an extracorporeal circuit. Ischemia was created by reducing coronary perfusion pressure to the level at which percent systolic wall thickening (%WT) decreased by 54%. Contractile function during control conditions was unchanged, whereas under ischemic conditions a further significant decrease in %WT of 27% occurred with either alpha 1- or alpha 2-receptor stimulation without any change in the anterior (control) wall function. Both alpha 1- and alpha 2-receptor stimulations during control conditions resulted in a relatively uniform transmural decrease in blood flow with no change in the subendocardial-to-subepicardial blood flow ratio. With alpha 1-stimulation during ischemia (n = 13), there was a tendency toward decreased subepicardial blood flow with no change in subendocardial flow, resulting in an increased subendocardial-to-subepicardial blood flow ratio (0.61 +/- 0.23 to 0.82 +/- 0.40, p less than 0.05). alpha 2-Receptor stimulation during ischemia (n = 12) produced a significant decrease in subepicardial blood flow (0.45 +/- 0.20 to 0.35 +/- 0.12 ml/min/g, p less than 0.01) with no change in subendocardial blood flow, also resulting in an increased subendocardial-to-subepicardial blood flow ratio. CONCLUSIONS. These results indicate the selective vasoconstriction in outer wall layers during ischemia mediated by either alpha 1- or alpha 2-receptors can cause a decrease in regional contractile function despite unchanged subendocardial blood flow and improved subendocardial-to-subepicardial flow ratio. This suggests an adverse effect of alpha-adrenergic vasoconstriction during ischemia in this coronary perfusion pressure-controlled canine model.     

Myocardial contractile function during ischemia and hypoxia

There is good evidence that elevated [Ca2+]i, produced by an influx of Ca2+ in exchange for Na+, is the underlying pathology in reperfusion or reoxygenation damage. Further measurements of [Na+]i and [Ca2+]i during ischemia and reperfusion, coupled with information about metabolic levels, are needed to confirm or refute this hypothesis. Contributions to cell damage by other mechanisms, e.g., oxygen free radicals, certainly cannot yet be excluded.     

Energy metabolism in myocardial stunning.

We investigated the effect of reversible ischemia, leading to persistent contractile dysfunction (stunning), on myocardial energy metabolism. The balance of energy metabolism is expressed by the phosphorylation state of cytosolic nucleotides. This variable cannot be measured directly because of nucleotide compartmentation, but in the isolated heart it can be estimated by the release of purine catabolites. We have previously shown that increased energy consumption or impaired energy production cause purine release to increase, while primary reduction in energy consumption has the opposite effect. Isolated working rat hearts were reperfused after 10 min of global ischemia, measuring hemodynamic variables, tissue high energy phosphate compounds and purine release. In post-ischemic recovery, aortic flow and minute work decreased to 82 +/- 3% and 77 +/- 4% of control, adenine nucleotide pool was reduced by 4.6 mumol/g dry wt, phosphocreatine to creatine ratio increased significantly and purine release decreased to 42 +/- 6% (P < 0.01). The rate of purine salvage, as evaluated by the incorporation of exogenous 3H-adenosine and 14C-hypoxanthine into tissue nucleotides, was much lower than net purine release, and was unchanged after ischemia and reperfusion. The adenine nucleotide pool could be depleted to the same extent as in the stunned myocardium by prolonged (60 min) aerobic perfusion. In this group the hemodynamic variables were unchanged and purine release averaged 87 +/- 9% of control (P = NS). In other experiments prolonged perfusion was combined with preload reduction in order to decrease energy demand. This protocol reproduced the effects of ischemia-reperfusion: aortic flow and minute work averaged 79 +/- 4% and 73 +/- 9% of control, adenine nucleotide depletion was 4.4 mumol/g dry wt and purine release decreased to 38 +/- 5% (P < 0.01). Our findings support the view that stunning is not due to adenine nucleotide depletion or to impairment in energy production, which would cause purine release to increase, but rather to primary reduction in energy utilization.     

Silent myocardial ischemia after acute myocardial infarction.

Silent ischemia after myocardial infarction has definite prognostic significance but should be interpreted within the context of other prognostic indicators. The rationale for therapeutic intervention is based on the prognostic implications of silent ischemia and the potentially deleterious effect of repeated episodes of ischemia on the integrity of the left ventricle. We measured parameters of ischemia in 20 patients who showed asymptomatic ischemic ST-T changes on exercise testing in the early phase after myocardial infarction. After diltiazem administration, a reduction of exercise-induced ST-T depression from 2.3 +/- 0.8 to 0.7 +/- 0.6 mm (p less than 0.01) occurred, and regional wall-motion score at exercise, determined by radionuclide angiography, improved significantly (p less than 0.02). These and other observations warrant further studies in which the duration, severity and frequency of the ischemic episodes should be quantified and correlated with prognosis after myocardial infarction.     

Influence of gender and diabetes on vascular and myocardial contractile function.

Premenopausal women have a lower cardiovascular risk than men or postmenopausal women. However, this "female advantage" is lost in diabetes, a condition characterized by cardiac and vascular contractile dysfunction. This study was designed to compare the influence of diabetes on vascular and myocardial contractile function between genders. Adult male and female rats were made diabetic with streptozotocin (55 mg/kg) and maintained for 8 weeks. Tension development was examined in thoracic aortic rings and left ventricular papillary muscles. KCl-induced vasoconstriction, acetylcholine (ACh)-induced endothelium dependent or sodium nitroprusside (SNP)-induced endothelium-independent vasorelaxation, duration and maximal velocity of myocardial contraction and relaxation duration (TPT/RT90 and +/- VT) were similar between males and females. Diabetes augmented KCl-induced vasoconstriction at low doses, reduced SNP-induced vasorelaxation and had little effect on ACh-induced vasorelaxation in aortic rings from both genders. Diabetes prolonged TPT and RT90 in both genders, and reduced +/- VT in males but not females. Acute increase in extracellular Ca2+ (2.7 mM to 5.4 mM) shortened TPT in diabetic myocardium from both genders, whereas it had no effect on other myocardial mechanical indices in normal or diabetic groups of either gender. In addition, acute exposure to the Na+/K(+)-ATPase inhibitor ouabain shortened TPT/RT90 and enhanced +/- VT in myocardium from normal female, whereas it had no effect on male or diabetic myocardium. In conclusion, these data suggest that in the vasculature, there is no difference in diabetes-induced contractile dysfunction between genders, however several gender-specific differences are evident in the myocardium.     

Ventricular ectopic activity after premature atrial beats in acute myocardial infarction.

Ventricular ectopic activity occurred only after premature atrial beats in a patient with an acute inferior wall myocardial infarction. The ventricular ectopic activity occurred only when the coupling interval between the premature atrial beats and preceding sinus beat was less than or equal to 0-44 s. The sinus cycle length, however, appeared to influence the form of expression of ventricular ectopic activity independent of coupling intervals, with single premature ventricular contractions occurring at cycle lengths greater than or equal to 0-72 s, couplets at cycle lengths of 0-68 to 0-71 s, and ventricular tachycardia at cycle lengths less than or equal to 0-67 s.     

Experimental myocardial ischemia. III. Protective effect of glucose on myocardial function

Glucose has been long known as an important substrate for muscle cells and a number of laboratories have demonstrated that carbohydrate metabolism can contribute significantly to energy production both in aerobic and anerobic heart muscle. It has been suggested that these findings may have additional application in localized myocardial ischemic and infarction. Accordingly, experiments were performed to determine the effect of glucose on the mechanical and electrical activity of the heart.Left ventricular pressure (LVP), left ventricular $\text{d}\text{p}\text{d}\text{t}$ ($\text{LVd}\text{p}\text{d}\text{t}$, left ventricular end diastolic pressure (LVEDP), and the incidence of ventricular premature beats (VPB) and ventricular fibrillation (VF) were determined before and after ligation of the anterior descending coronary artery in three different canine heart experimental models.Thirty minutes after ligation of the left anterior descending coronary artery, the mean left ventricular pressure and mean left ventricular $\text{d}\text{p}\text{d}\text{t}$ in the control group had decreased by 85 ± 6% and 74 ± 5% respectively. Under similar conditions glucose treatment produces an increase in left ventricular pressure and left ventricular $\text{d}\text{p}\text{d}\text{t}$ of 111 ± 5% and 123 ± 8% respectively. The simultaneously measured mean left ventricular end diastolic pressure was 7.2 ± 0.9 ml for the control group and 3.7 ± 1 for the glucose treated group. Eighty-three percent of the control dogs developed ventricular ectopic activity. Fifty-eight percent of the control hearts developed ventricular fibrillation. In contrast, only 10% of the glucose treated hearts demonstrated ventricular ectopic activity and only 10% developed ventricular fibrillation.Glucose, as a bolus, consistently improved myocardial contractility and prevented ventricular fibrillation even after serum osmolality and serum glucose levels had returned to normal. These results demonstrate that glucose has a protective effect on the electrical and mechanical function of the canine heart during acute segmental myocardial ischemia. These findings may have application in the treatment of acute myocardial infarction in man.     

Exercise-induced T-wave normalization predicts recovery of regional contractile function after anterior myocardial infarction

Aims We investigated the ability of T-wave pseudo-normalization andST-segment elevation, which are demonstrated in infarct-relatedleads during submaximal exercise testing, to predict late recoveryof contractile function. Methods We studied 88 consecutive patients (73 males, mean age 59±8years) with anterior infarction, persistent T-wave inversionand a documented lesion of the proximal segment of the leftanterior descending coronary artery. They all underwent 2D-echocardiographyon admission, 4 weeks as well as 6 months after myocardial infarctionto evaluate the dysfunction score and the ejection fraction.Submaximal (75% of maximal predicted heart rate) exercise testingwas performed in 80 patients 2 weeks after myo-cardial infarctionfollowing discontinuation of treatment. Results During exercise testing, 59 of the 88 patients showing negativeT-waves on the resting electrocardiogram exhibited pseudonormalization(group A) in at least three adjacent precordial leads, whilst29 (group B) did not. Patients of group A more frequently exhibitedan early creatine kinase peak (41% vs 24%, P<0·05)and residual angiographic perfusion (97% vs 69%, P<0·05).The dysfunction score did not change in group B (from 19±7to 22±4), but decreased in group A (from 18±4to 11±6, P<0·05). The ejection fraction wassimilar in the two groups on admission (group A: 48±7%,group B: 45±10%), but was significantly different at4-week (52±99 vs 42±11%, P<0·05) and6-month follow-up (58±9 vs 44±10%, P<0·01).The concomitant presence of ST-segment elevation and T-wavenormalization showed the highest positive predictive value forleft ventricular function recovery (100%). Conclusions T-wave normalization induced by sub-maximal exercise test isfrequently associated with residual perfusion to the infarctarea and predicts progressive improvement in regional wall motion,especially if associated with ST-segment elevation. Therefore,these electrocardiographic findings may be used as easily obtainablemarkers of residual viability that predict late recovery incontractile function.     

The relation of contractile function to myocardial perfusion

During normoperfusion, both myocardial blood flow and contractile function are heterogeneously distributed throughout the left ventricle. Midwall segment shortening is greater at the apex than at the base of the left ventricle, and greater in the anterior than in the posterior wall. Also, transmural heterogeneity of myocardial deformation exists, with greater segment shortening and wall thickening in inner than in outer myocardial layers. Myocardial blood flow is greater in inner than in outer myocardial layers. Apart from transmural heterogeneities, there are adjacent regions with largely different resting flow in the same heart. While an increase in myocardial contractile function will lead to a metabolically mediated increase in myocardial blood, an increase in regional coronary perfusion within or above the autoregulatory range does not increase regional myocardial contractile function. During hypoperfusion induced by a proximal coronary stenosis, the reduction in subendocardial blood flow is more pronounced than that in subepicardial blood flow, and contractile function in the inner myocardial layers ceases more rapidly than in the outer myocardial layers. The reduced regional myocardial contractile function is closely matched to the reduced regional myocardial blood flow; however, such a coupling between reduced flow and function is lost when ischemia is prolonged for several hours in that function for a given flow is further reduced. Also, acute embolization of the coronary microcirculation induces a progressive loss of regional myocardial function at an unchanged regional myocardial blood flow, i.e. perfusion-contraction mismatch. During reperfusion, regional myocardial contractile function remains depressed for a prolonged period of time, depending on the severity, duration and location of the preceding ischemic episode, while regional myocardial blood flow is restored to almost normal. Recovery of contractile function in the outer myocardial layers is faster than in the inner myocardial layers.     

Dispersion of QT interval following ventricular premature beats and mortality after myocardial infarction.

In a group of 193 postinfarction patients with ventricular premature beats on a resting 12-lead ECG, the dispersion of QT and JT intervals was calculated as a difference between maximum and minimum QT and JT intervals in ventricular premature beats. During a follow-up of 38 +/- 17 months, death from all causes was noted in 56 patients. Univariate predictors of mortality included QT dispersion >/=100 ms, JT dispersion >/=100 ms, left ventricular ejection fraction <40%, complete bundle branch block, 'R-on-T' index of ventricular premature beats <1 and age of patients >60 years. At multivariate Cox proportional hazards survival analysis, only QT dispersion >/=100 ms, left ventricular ejection fraction <40% and complete bundle branch block had an independent relation to postinfarction mortality. The final model selected increased QT dispersion as the prognostic factor which was the most strongly related to mortality (chi(2) = 23.60, p = 0.0000).     

The effect of lactate infusion on myocardial metabolism and ventricular function following ischemia and cardioplegia

Impaired myocardial fatty acid and glucose metabolism following ischemia and cardioplegia may limit the recovery of myocardial oxidative metabolism and ventricular function. Lactate, a simple three carbon compound, can be readily metabolized to pyruvate and is possibly the preferred substrate for aerobic metabolism. Therefore, increasing arterial lactate concentrations may improve myocardial metabolic recovery after ischemia and cardioplegia. Myocardial lactate metabolism and ventricular function were assessed in a canine model of 45 mins of global normothermic ischemia followed by 60 mins of cold potassium cardioplegic arrest. Thirteen dogs received a perioperative infusion of sodium lactate to elevate arterial concentrations (from 6 to 12 mmol/L) and 12 dogs received an equivalent amount of saline. The high arterial lactate concentrations were associated with an increased myocardial lactate consumption and oxidation (as assessed by 14C-labelled lactate) during reperfusion. Myocardial ATP concentrations fell during reperfusion despite improved myocardial oxidation. The recovery of ventricular function (as assessed by a compliant intraventricular balloon) was incomplete and only marginally better with the high arterial lactate concentrations. An infusion of lactate improved myocardial oxidative metabolism following ischemia and cardioplegia. However, the recovery of ventricular function was incomplete perhaps because of inadequate preservation of myocardial ATP.     

High-energy phosphates,myocardial contractile function and material properties after short periods of oxygen deficiency

Summary To investigate myocardial performance and diastolic properties after repeated periods of oxygen deficiency auxotonic and isovolumic measurements were performed after three periods (4 min) of asphyxia in Wistar rats (n=19). Additionally, the response of the peak isovolumic left ventricular pressure to postextrasystolic potentiation was measured. The hemodynamic results were compared to the levels of high-energy phosphates.Already after 15 min of recovery from asphyxia auxotonic measures of systolic function were completely normal compared to the control group (n=19). Isovolumic measurements after 20 min of postasphyctic recovery, however, demonstrated a considerable reduction of the peak left ventricular pressure (226.5±7.5 mm Hg vs. 262.6±3.4 mm Hg in controls, mean±SEM (p<0.01)) indicating persistence of decreased postischemic contractile performance. The relative effect of postextrasystolic potentiation was similar in both groups, but could not compensate for the reduced performance of the postasphyctic hearts: the absolute postextrasystolic peak isovolumic pressure of the postasphyctic hearts was lower than the value of the regular isovolumic peak pressure in the controls. Diastolic properties (pressure/volume and stress/strain relationships) of the postasphyctic myocardium remained unchanged. The total sum of the adenine-nucleotides decreased from 7.2±0.2 to 5.6±0.3 mol/gww (p<0.01). ATP was reduced from 4.8±0.2 to 3.9±0.3 mol/gww (p<0.01). Phosphocreatine was elevated to 7.0±0.6 mol/gww, x±SEM (p<0.01).Our results demonstrated normal postasphyctic basal hemodynamics and material properties. Thus, the energy supply was sufficient to maintain steady state conditions — in spite of decreased overall adenine-nucleotide levels. Isovolumic measurements and postextrasystolic potentation tests, however, indicated that the contractile performance of the postischemic myocardium was still reduced. This functional limitation cannot be explained by altered material properties and is probably not causally related to the decreased overall ATP content.Parts of the results were presented at the 10th World Congress of Cardiology, Washington D.C., USA, 1986Supported by the Deutsche Forschungsgemeinschaft (DFG), Bonn (Ho 1003/1-1)     

States of myocardial metabolism related to ischemia

Energy metabolism of the heart in ischemia is mainly characterized by oxygen deficiency and lack of lactate removal. However, under certain circumstances substrate deficiency might contribute to disturbances of energy supply as well. Capillary permeability was determined from tracer washout kinetics of isolated hearts. Regulation of mitochondrial respiration was estimated from the relationship of phosphorylation potential vs. oxygen consumption. The results obtained suggest that at least under experimental conditions substrate supply at the level of capillary exchange can be a rate-limiting figure, as well as substrate supply at the mitochondrial level, i.e., NADH supply. The latter was inferred from the effects of cobalt and strontium ions on the regulation of respiration.     

Progressive loss of myocardial contractile function despite unimpaired coronary blood flow after cardiac surgery

Objective Mild to moderate transient contractile dysfunction is frequently observed after cardiac surgery on cardiopulmonary bypass (CPB) but may also lead to low–cardiac–output (LCO) failure especially in patients with unstable angina, and is often referred to represent myocardial stunning. Whether time course of contractile dysfunction after cardiac surgery is similar to that of myocardial stunning was investigated in pigs. Methods After baseline measurements of systemic hemodynamics (micromanometry), myocardial contractile function (sonomicrometry), cardiac output and coronary flow (ultrasonic probe), CPB was instituted. Control animals (n = 7) were weaned after 3 h from CPB. In LCO animals (n = 8), global ischemia was induced for 10 min by aortic crossclamping, followed by 1 h of cardioplegic cardiac arrest. After declamping and reperfusion, CPB was terminated after a total of 3 h. Measurements were repeated at 15 min, 4 h and 8 h after CPB. Systemic TNF–plasma concentrations were measured (ELISA) and left ventricular biopsies were analyzed with respect to myocardial TNF (immunohistochemistry) and irreversible cellular damage (light/electron microscopy). Results Contractile function decreased in LCO (75 ± 12%) and control (83 ± 17%) at 15 min compared to baseline (p < 0.05). Thereafter, contractile function remained unchanged in control, but progressively decreased in LCO (52 ± 12% at 4 h; 36 ± 5% at 8 h; p < 0.05). Coronary flow remained unchanged in both groups. Cardiac output progressively decreased to 2.8 ± 0.9 l/min at 8 h in the LCO group compared to baseline (5.9 ± 1.1 l/min, p < 0.05) and control (5.7 ± 1.4 l/min, p < 0.05). There was no evidence for myocardial infarction. TNF–plasma concentrations and myocardial TNF–staining were increased at 8 h after CPB in the LCO group compared to baseline and control (p < 0.05). Conclusions The progressive pattern of myocardial dysfunction apart from ongoing ischemia after cardiac surgery suggested underlying mechanisms at least partially different from those of myocardial stunning.     

Energy metabolism,intracellular Na+ and contractile function in isolated pig and rat hearts during cardioplegic ischemia and reperfusion:23Na- and31P-NMR studies

The purpose of the study was to compare the role of Na ions in the damage caused by cardioplegic ischemia in fast (rat) and slow (pig) hearts. Changes in intracellular Na⁺ (Na⁺ _i), high energy phosphates, and contractile function were assessed during ischemia (36°C) and reperfusion in KCl-arrested perfused hearts using³¹P-NMR and shift reagent (DyTTHA^3–)-aided²³Na-NMR spectroscopy. In the pig hearts the rates of decrease of phosphocreatine (PCr), ATP and intracellular pH (pHi) were 3–4 times slower than the rates observed in the rat hearts. In the pig hearts PCr was observable (10%) during first 80 min of the ischemic period (90 min). Comparable decreases in ATP (32.0±6 vs. 38±15% of initial) and pH_i, (to 6.14±0.06 vs. 6.10±0.15) observed after 90 and 20 min ischemia in pig and rat hearts, respectively, were associated with a smaller Na⁺ _i increase in the pig hearts (to 175±31%) than in the rat hearts (to 368±62%). This Na⁺ increase in the rat hearts preceded development of ischemic contracture (41±6 mmHg at 23.6±0.7 min) while no contracture was observed in pig hearts. Reperfusion of the rat hearts (at 30 min ischemia) was followed by partial recovery of PCr (44±3%) and Na⁺ _i (234±69%) and poorer recovery of the pressure-rate product (PRP, 9±4%) and end-diastolic pressure (EDP, 72±5 mm Hg) compared to the pig hearts (PCr, 106±25%; Na⁺ _i, 82±17%; PRP, 24±3%; EDP, 4.6±2.5 mmHg). The loss of function in the pig hearts was reversed by increasing Ca⁺⁺ in the perfusate from 1 to 2.3 mM and resulted in a rise in both PRP and oxygen consumption rate, V(O₂), from 24±3.3 to 64.5±5.8% and from 55±10 to 74±10% of the control levels, respectively. The PRP/V(O₂) ratio was halved in the post-ischemic pig hearts and returned to the pre-ischemic level following Ca⁺⁺ stimulation. It is suggested that the higher stability of Na⁺ homeostasis to ischemic stress in the pig heart may result from: 1) a lower ratio of the rate of ATP hydrolysis to glycolytic ATP production; 2) differences in the kinetic properties of the Na⁺ transporters. Reduced Na⁺ accumulation during ischemia and reperfusion is benefical for metabolic and functional preservation of cardiomyocytes.     

Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia

The effects of 1 hour of mild and moderate reductions in coronary blood flow on myocardial high-energy phosphate levels were evaluated. Thirty anesthetized pigs were instrumented with left anterior descending arterial and venous catheters, crystals for instantaneous wall thickness, and a fluid-filled occluder. Measurement of myocardial blood flow was performed with microspheres, and a series of myocardial biopsies also was performed. In 10 pigs, overall coronary blood flow was lowered by 22%, with a fall in subendocardial-to-subepicardial flow ratio from 1.11 to 0.54 and in wall thickening from 33% to 15%. Subendocardial flow fell 48%. Coronary blood flow and thickening were constant during 1 hour of ischemia. Phosphocreatine (mumol/g wet wt) in the subendocardial third of the ischemic zone fell from 7.6 to 3.8 at 5 minutes of ischemia (p less than 0.005 versus control) and returned to normal (7.9) at 60 minutes (p = NS), despite ongoing ischemia. Subendocardial ATP (mumol/g wet wt) fell slowly from 4.3 and leveled off at 2.1 at 60 minutes of ischemia (p less than 0.001 versus control). Similar regeneration of phosphocreatine was found in seven additional pigs, with a 43% transmural reduction in coronary blood flow and a 66% reduction in subendocardial flow. No significant changes in ATP and phosphocreatine were noted in two different control groups (n = 13 pigs). The regeneration of phosphocreatine despite ongoing ischemia and low ATP levels was not related to changes in myocardial oxygen demand or consumption, or in regional function during the period of ischemia. This may reflect 1) a successful downregulation of the energy needs of the ischemic myocardium to maintain cell viability, or 2) a metabolic abnormality in the ability of the cells to produce ATP primarily or by use of phosphocreatine.     

Effect of preliminary adaptation to moderate and intensive physical loads on cardiac electrical stability and contractile function in experimental myocardial infarct

Preliminary adaptation of animals to a moderate swimming exercise prevented the fall of ventricular fibrillation electrical threshold and limited drastically the heart ectopic activity in acute myocardial infarction. Adaptation to intense stress, i.e. prolonged swimming with a load, had less preventive effect. The rationing of preventive exercise, to be used for the prophylaxis of myocardial infarction, is discussed.     

Effect of procainamide on myocardial contractile function and digoxin inotropy

The effect of procainamide and digoxin, singly and together, on peak active force and rate of force development of isolated right ventricular papillary muscles from adult cats was examined. Procainamide (1.5 X 10(-5) M) increased force and rate of force development in each muscle with further increments in performance up to 2.4 X 10(-4) M in most muscles. The maximal increases in force (+/- SEM) averaged 75 +/- 13% above control values. Essentially no response to procainamide was observed when basal levels of contractile state were increased by increasing stimulus frequency or calcium concentrations of the bathing solution. Propranolol (10(-6) M) markedly reduced and verapamil (10(-7) M) abolished the inotropic effect of procainamide. Exposing muscles to procainamide (1.5 or 3 X 10(-5) M) before or after the administration of digoxin (2 or 4 X 10(-7) M) did not alter the inotropic action of either drug. Thus, procainamide in concentrations that are in the therapeutic range in human patients has potent positive inotropic effects that may be masked at high levels of contractile state. This action of procainamide appears to be due to an effect on calcium channels, which in part may be due to beta-adrenergic receptor stimulation. These concentrations of procainamide do not alter the inotropic response to digoxin.