Free radicals and cardioplegia: organic anti-oxidants as additives to the St Thomas' Hospital cardioplegic solution

The isolated perfused working rat heart model of cardiopulmonary bypass and ischaemic cardiac arrest has been used to investigate whether addition of various organic anti-oxidants to the St Thomas' Hospital cardioplegic solution can enhance the recovery of function of the rat myocardium after normothermic (37 degrees C) global ischaemic arrest. Five anti-oxidants were studied: (i) ascorbate (1.0 and 10.0 mmol.litre-1), (ii) methionine (1.0 and 10.0 mmol.litre-1), (iii) reduced glutathione (1.0 and 10.0 mmol.litre-1), (iv) dimethylthiourea (0.1, 1.0, 10.0 and 50.0 mmol.litre-1), (v) N-2-mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1). The recovery of aortic flow in control hearts which were free of anti-oxidant was 50.7(SEM 0.5)%; ascorbate (1.0 or 10.0 mmol.litre-1) improved this recovery to 72.1(1.7) and 70.2(0.3)% respectively; methionine (1.0 and 10.0 mmol.litre-1) improved the recovery to 74.1(5.7)% and 67.7(1.7)%, respectively; reduced glutathione (1.0 and 10.0 mmol.litre-1) improved the recovery to 66.7(1.4)% and 74.0(1.7)% respectively. In further studies, the addition of dimethylthiourea (0.1, 1.0 and 10.0 mmol.litre-1) to the cardioplegic solution failed to improve recovery of aortic flow [47.3(8.0), 24.6(7.3), 48.0(7.7)% respectively] when compared to its anti-oxidant free control value of 40.4(6.1)% and at a concentration of 50.0 mmol.litre-1 a very poor recovery of aortic flow of 7.7(4.8)% was observed. Mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1) also failed to improve the recovery of aortic flow [34.7(1.6), 34.7(7.7) and 25.6(5.4)% respectively.2+ Since biological membranes are highly permeable to dimethylthiourea and mercaptopropionyl glycine, it is possible that they accumulate in the intracellular compartment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of myocardial intracellular edema induced by St. Thomas' Hospital cardioplegic solution.

During cardiac surgery, the heart is infused with cold crystalloid cardioplegic solutions such as St. Thomas' Hospital (StT) solution, which contains high concentrations of K+ and Mg2+. The high K+ and Mg2+ block impulse conduction and inhibit Ca2+ influx, thereby arresting the heart and reducing cardiac oxygen consumption. Nevertheless, myocardial edema and post-operative abnormalities have been noted after cardioplegia and attributed to ischemia and reflow or to hypothermia. We found, however, that cold StT (9 degrees C) was hypotonic and induced cell swelling in the absence of ischemic injury. Cell swelling in cold StT was not due to hypothermia alone, but rather was caused by KCl influx and was prevented by partially replacing Cl- with an impermeant anion. After exposure to cold StT, cells transiently shrank to less than control volume on rewarming in physiological saline (Tyrode's solution, 37 degrees C). The transient shrinkage was blocked by ouabain suggesting that Na+ loading of depolarized hypothermic cells and Na(+)-K+ pump activation on rewarming were responsible. Hypothermic ventricular cells seem to follow Donnan equilibrium, and the product of [K+] x [Cl-] in cardioplegic solutions affects cell volume in the absence of ischemic injury.     

Protection of the immature myocardium during ischemic arrest: dose dependent effects of glucose and mannitol when added to St Thomas' cardioplegic solution

It has been suggested that immature hearts are less well protected by conventional cardioplegic solutions than are adult hearts. In an attempt to develop an improved cardioplegic solution for use in the immature ischemic heart the authors investigated whether the addition of various concentrations of glucose or mannitol to St Thomas' Hospital cardioplegic solution can improve its protective ability. Hearts from immature (three- to five-day-old) rats were perfused as Langendorff preparations with an indwelling left ventricular balloon. Contractile function (left ventricular developed pressure, maximum rate of development of pressure, heart rate, rate-pressure product and coronary flow) was recorded before and after a period of normothermic global ischemia with preischemic infusion (2 mins) of St Thomas' Hospital cardioplegic solution. In preliminary experiments the post ischemic recovery of contractile function was related to the duration of ischemia. With 60, 75, 90 and 120 mins of ischemia the post ischemic recovery of developed pressure was 47.6 +/- 3.9%, 17.4 +/- 5.5%, 15.0 +/- 5.4% and 13.8 +/- 4.8%, respectively, of its preischemic control. Comparable results were obtained with the other indices of cardiac function. The effect on the post ischemic recovery of function and tissue water content of the addition of mannitol or glucose (10, 20, 40, 60 or 80 mmol/L) to the cardioplegic solution was examined after 60 mins of ischemia. The mannitol groups tended to show consistently better recoveries at all concentrations studied but the improvement was small and rarely achieved a degree of statistical significance. In contrast glucose gave a U-shaped dose response profile with a significant deleterious effect at 10, 20 and 40 mmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative modification of antigen-induced bronchoconstriction by the calcium antagonists, nifedipine and verapamil

We compared the effects of the two calcium antagonists, nifedipine and verapamil, on baseline airway function and antigen-induced bronchoconstriction in asymptomatic subjects with ragweed hypersensitivity and a history of bronchial asthma. Twelve subjects received a single oral dose of 20 mg of nifedipine or 160 mg of verapamil before inhalation with ragweed antigen. Mean specific airway conductance, a measurement of airway obstruction, was not affected by either agent; nifedipine caused bronchodilatation in two subjects, and verapamil was followed by slight bronchoconstriction in another subject. Nifedipine partially or completely blocked the antigen-induced bronchoconstriction in 67 percent (8/12) of the subjects (p less than 0.05). Two of the subjects who were protected by nifedipine were also protected by pretreatment with verapamil, while this drug was without effect in the others. This study demonstrates that both nifedipine and verapamil in a single oral dose may attenuate antigen-induced bronchoconstriction in some subjects with allergic bronchial asthma and that nifedipine may be more effective than verapamil.     

Improved myocardial protection by creatine phosphate in cardioplegic solution. An in vivo study in the pig during normothermic ischemia

The effect of creatine phosphate in potassium cardioplegia was studied in a pig heart model in vivo. Fifteen pigs divided into two groups were placed on cardiopulmonary bypass and subjected to 1 hour of cardioplegic arrest at normothermia. In group I (control), in which a potassium cardioplegic solution was used, only two out of eight animals could successfully be weaned from bypass. In group II, on the other hand, in which creatine phosphate (10 mmol/l) was added to the cardioplegic solution, six out of seven animals could be weaned from bypass and the heart performance assessed by volume loading. Group II also exhibited better maintenance of high-energy phosphates during ischemia, with significantly higher adenylate charge potential, than group I. In all animals weaned from bypass--two in group I and six in group II--the ventricular performance was decreased compared with that before induction of ischemia. The results indicate that creatine phosphate could be an effective constituent in potassium cardioplegia.     

Randomized placebo-controlled comparative study of nifedipine, verapamil and isosorbide dinitrate in the treatment of angina at rest

Twenty-nine patients with angina at rest took part in a randomizedplacebo-controlled short-term study to assess the relative effectivenessof different dosages of nifedipine (N), verapamil (V) and isosorbidedinitrate (ISDN) versus placebo and to evaluate the antianginaleffects of a sustained-release preparation of ISDN (sr), ofN retard form (r) and of V retard form (r). The 29 patients were divided into 3 groups: the first groupof patients (10 patients, group A) was treated with N10 mg sixtimes daily, V 80 mg three times daily and ISDN 10 mg six timesdaily; the second group of patients (9 patients, group B) wastreated with N 20 mg six times daily, V 120 mg four times dailyand ISDN 20 mg six times daily; the third group of patients(10 patients, group C) was treated with N r 20 mg four timesdaily, V r 120 mg three times daily and ISDN sr 40 mg four timesdaily. The daily frequency of ischaemic episodes (IE) was assessedby Holter monitoring. The effect of each drug on the mean frequencyof IE was compared with the placebo using a one-way analysisof variance and the Newman-Keuls test. In group A, the mean daily frequency of IE per patient was 8.1± 5.9 with the placebo, 1.4 ± 1.9 with N (P>0.001;–82%), 4 ± 3.6 with V (P: NS; –50%) and 4.3± 3.6 with ISDN (P: NS; –46%). In group B it was6.4 ± 3.4 with the placebo, 0.5 ± 1.6 with N (P>0.01;–91%), 0.3 ± 0.5 with V (P>0.01; –95%)and 1.2 ± 1 with ISDN (P>0.01; –82%). In groupC it was 10.3 ± 8.7 with the placebo, 0.7 ± 1.6with N r (P>0.01; –93%), 1 ± 2.5 with V r (P>0.01;–90%) and 5.1 ± 7.7 with ISDN sr (P: NS; –50%). In group A a reduction of 100% in the number of recorded IESwas achieved in 5/10 patients by using N, in none by V, andin 1/10 by ISDN. In group B, in 8/9 patients by N, in 6/9 byV and in 3/9 by ISDN. In group C, in 8/10 patients by both Nr and V r in 4/10 patients by ISDN sr. It is concluded that calcium antagonist drugs at adequate dosagesare substantially more effective than ISDN in relieving anginaat rest and thus they may be considered as first choice therapyin the management of angina at rest. Furthermore, long-actingpreparations of both nifedipine and verapamil were comparablyeffective in reducing the frequency of IE whereas isosorbidedinitrate, in the sustained release form, was again less effective.     

Mechanisms of angina relief after nifedipine: a hemodynamic and myocardial metabolic study

To elucidate the mechanisms of action of nifedipine in angina pectoris, 14 patients were studied before and after sublingual administration of 10 mg nifedipine. Systemic and coronary hemodynamic and myocardial metabolic measurements were taken at rest and during pacing. At the pacing rate that induced pain in the control situation, no patient experienced angina after nifedipine administration. Lactate production during control turned into extraction after nifedipine administration (p less than .05), and the double product was reduced (p less than .001). Systemic and coronary vascular resistance were reduced by 26% (p less than .001) and 19% (p less than .005), respectively. Systolic blood pressure fell from 160 +/- 29 to 127 +/- 25 mm Hg (p less than .001) and diastolic from 100 +/- 14 to 79 +/- 11 mm Hg (p less than .001). Pulmonary artery diastolic blood pressure fell from 14 +/- 4 to 10 +/- 3 mm Hg (p less than .01). When the pacing rate was further increased after nifedipine administration until pain developed, the double product and the degree of lactate production were the same as during pain before nifedipine was administered. The pacing rate was 131 +/- 12 compared with 119 +/- 13 during control (p less than .001). Both the systolic and diastolic blood pressures were still significantly reduced compared with control pacing values, 131 +/- 26 mm Hg (p less than .01) and 84 +/- 13 mm Hg (p less than .01), respectively. Our data demonstrate that the antianginal efficiency can be partly explained by afterload reduction, which decreases myocardial oxygen consumption. The data also suggest additional mechanisms, possibly an increase in collateral flow, direct dilatation of stenotic parts of epicardial arteries, or a decrease in myocardial back pressure secondary to reduced left ventricular filling pressure.     

Myocardial protection during ischemic cardiac arrest. Hemodynamic study of the effects of allopurinol in a cardioplegic solution

The effects of the addition of 20 mg sodium allopurinate to a litre of ionic cardioplegic solution were studied. The experimental model was the working isolated perfused rat heart in oxygenated Krebs-Henseleit solution. The cardiac outputs were compared after 1 hour of ischaemia with three different methods of myocardial protection; group I: protection by hypothermia at 4 degrees C, group II: protection by ionic cardioplegic solution A, group III: by ionic cardioplegic solution B (with 20 mg Allopurinol). The results were expressed in percentage of the preischemic cardiac output. The best results were obtained in group III, especially after 15 minutes recovery (80.7 +/- 4.5 p. 100 at 15 minutes, 90.6 +/- 3.1 p. 100 at 30 minutes., 88.3 +/- 4.6 p. 100 at 1 hour). The results in group II were significantly better than in group I after 10 minutes recovery. Myocardial protection bu ionic cardioplegia associated with hypothermia at 4 degrees C gives a better post ischaemic recovery than hypothermia alone. When allopurinol is added to the cardioplegic solution, the protection is increased. These effects are similar to the haemodynamic effects of allopurinol on ischaemic myocardium together with the possible limitation of experimental myocardial infarction with regression of the oedema that has been observed with this drug.     

Enzyme release during myocardial anoxia: a study of metabolic protection.

In studies with the isolated perfused anoxic rat heart, myocardial enzyme release was used as an index of cellular damage. Anoxic damage (with K⁺ arrest) was characterized by measuring the release of four enzymes (creatine phosphokinase, α-hydroxybutyrate dehydrogenase, glutamate oxaloacetate transaminase and adenylate kinase). The possibility of protecting the myocardium against anoxic damage by using potential metabolic protective agents was investigated. The inclusion of glucose as an anaerobic energy source in the perfusion fluid during the entire anoxic period afforded considerable metabolic protection, the period of anoxia that could be tolerated without significant enzyme release was extended and the overall release was reduced. In addition, glucose during anoxia was able to confer protection against the exacerbation of enzyme release induced by reoxygenation. The results with graded hypoxia were similar to those with glucose and the two were additive. An increasing availability of oxygen afforded an increasing degree of protection. The membrane stabilizing drug methyl prednisolone had a variable effect upon enzyme release but was unable to confer true protection with increased viability upon the myocardium.The exacerbation of enzyme release induced by reoxygenation was further investigated. Potential protective agents (glucose, methyl prednisolone and the anti-oxidant ascorbate) introduced at the time of reoxygenation had little protective effect. Stepwise reoxygenation studies revealed that the extent of exacerbation was determined by the concentration of O₂ used in the reoxygenation process, the higher the O₂ tension the greater the exacerbation of release.It is proposed that the onset of major myocardial enzyme release reflects the transition from reversible to irreversible cellular damage and that the action of metabolic protective agents is to prevent the deterioration of the cells to a point where they become susceptible to irreversible damage. Once the cells enter a state of irreversible damage and major enzyme release occurs then metabolic protection becomes ineffective. The results underline the importance of the need for the rapid introduction of protective agents to the anoxic myocardium. In this experimental model, protection must be initiated before the transition from reversible to irreversible cellular damage and this may possibly be best achieved either by reducing cellular energy demands or by maximizing cellular energy production.     

Differential therapy with calcium antagonists in pulmonary hypertension secondary to COPD. Hemodynamic effects of nifedipine, diltiazem, and verapamil

In 53 patients with COPD and precapillary pulmonary hypertension, we investigated the effect of three typical calcium antagonists on hemodynamics at rest and during bicycle ergometer exercise. In the responders, the decrease in pulmonary vascular resistance following nifedipine was 23 percent at rest (p less than 0.0005) and 35 percent during exercise (p less than 0.0005); following diltiazem, it was 10 percent at rest (p less than 0.05) and 23 percent during exercise (p less than 0.025); following verapamil, it was 22 percent at rest (p less than 0.005) and 11 percent during exercise (p less than 0.025). The cardiac index rose significantly at rest and under exercise only after the administration of nifedipine (+16 percent and +8 percent, resp). Nifedipine caused the most distinctive peripheral vasodilation. The heart rate increased slightly following nifedipine and decreased slightly following diltiazem and verapamil. After long-term therapy with nifedipine (13 +/- 5 months), the decrease in pulmonary artery pressure and pulmonary vascular resistance was no longer significant. In our opinion, the different hemodynamic action profiles will have consequences for the differential therapy in patients with COPD and pulmonary hypertension.     

Ionic bases of cardioplegic solutions. II. Influence of the ionic composition of a cardioplegic solution on the metabolic and functional preservation of ischemic myocardium. Experimental evaluation with phosphorus 31 nuclear magnetic resonance and applications to cardiac surgery

The object of this study was to establish whether the protective effects of a cardioplegic solution could be improved by ionic or pharmacological intervention aimed at reducing cellular Ca++ overload resulting from myocardial ischaemia. The experimental model was the isolated perfused working heart of the rat submitted to 60 or 120 minutes of hypothermic ischaemia (15 degrees C) followed by 30 minutes of reperfusion at 37 degrees C. The high energy phosphates were measured every 2,5 or 5 minutes by Phosphorus 31 (P31) nuclear magnetic resonance and correlated with haemodynamic data. Our results showed that the best metabolic (75,5 +/- 9,7 p. 100 preservation of ATP after 60 minutes ischaemia) and functional protection (91,8 +/- 4,7 p. 100 recovery of aortic output after 30 minutes reperfusion) was obtained with a solution with the following ionic properties: 1) high Mg++ concentration (13 mM); 2) low Ca++ concentration (0,25 mM); 3) high Na+ concentration (100 mM). The protective effects of this solution were further improved by the addition of a calcium blocking agent (nifedipine 0,2 micrograms/ml). This preserved 85,5 +/- 3,2 p. 100 of basal ATP values after 120 minutes of ischaemia and was associated with a 92,9 +/- 2,8 p. 100 recovery of aortic output at the end of reperfusion. We conclude that: 1) limitation of cellular Ca++ overload is one of the major objectives to be considered when making up cardioplegic solutions; 2) the use of P 31 nuclear magnetic resonance on the isolated working heart is the technique of choice for comparing methods of myocardial protection because it provides a non-invasive, sequential and simultaneous assessment of the parameters of metabolic and haemodynamic function.     

Biochemical and functional effects of creatine phosphate in cardioplegic solution during aortic valve surgery--a clinical study.

During myocardial ischemia there is a drop in high-energy phosphates in the myocardium. Cold potassium cardioplegia decreases but does not altogether prevent this reduction. Supplementation of cardioplegic solutions with the high-energy compound creatine phosphate (10 mmol/L) compared to plain cardioplegic solutions was investigated in this study. Thirty patients scheduled for aortic valve replacement were included. The patients were randomized to group I (creatine phosphate) or group II (control). Postoperative hemodynamic evaluation revealed no significant differences between the groups. However, group I exhibited a tendency toward a better stroke-work index (135 +/- 18% vs. 102 +/- 5% recovery 15 minutes after bypass and 145 +/- 16% vs. 119 +/- 11% recovery 105 min after bypass). There were fewer patients in group I (5/15) needing inotropic support compared to group II (9/14). The myocardial content of ATP and creatine phosphate showed no significant differences during ischemia and reperfusion. It is concluded that the myocardial protection during ischemia was sufficient to prevent significant reductions of myocardial ATP and creatine phosphate irrespective of supplementation with CP.     

Calcium antagonists and beta blockers in the control of mild to moderate systemic hypertension, with particular reference to verapamil and propranolol

The antianginal and antiarrhythmic role of calcium antagonists is well established. Recent preliminary studies have indicated that, like beta blockers, calcium antagonists may produce short- and long-term hypotensive effects in patients with mild to moderate essential hypertension. The pharmacologic properties of calcium antagonists provide a clear rationale for their use in the control of essential hypertension. The comparative hypotensive effects of verapamil (80 to 160 mg 3 times a day) and propranolol (40 to 120 mg 3 times a day) were evaluated over 4 weeks, preceded by a 4-week placebo phase, in a double-blind protocol in 17 patients with mild to moderate hypertension. Verapamil (n = 10) reduced the mean sitting systolic blood pressure by 10.7% (p less than 0.01) and standing by 7.6% (p less than 0.04). The corresponding data for propranolol (n = 7) were 4.8% (not significant) and 5% (p = 0.04). Verapamil reduced the sitting diastolic blood pressure by 10.8% (p less than 0.01), propranolol by 7.5% (p = 0.01); the standing diastolic blood pressure was reduced by 10.7% with verapamil (p less than 0.01) and by 8.6% (p = 0.01) with propranolol. With verapamil the mean heart rate fell from 77.60 +/- 8.42 to 70.20 +/- 4.85 beats/min (p = 0.03); with propranolol it fell from 76.85 +/- 6.91 to 66.29 +/- 4.54 beats/min (p less than 0.01). Although a trend towards a slightly greater hypotensive effect was apparent with verapamil compared with propranolol, the difference was not statistically significant. It is concluded that verapamil and propranolol exert comparable hypotensive potency in patients with mild to moderate hypertension.     

Intracellular pH, Na+- and K+-activities at the onset of St. Thomas' cardioplegia: a study with ionselective microelectrodes

Cellular edema and cardiac arrhythmias are often closely related to intracellular ionic alterations and, moreover, are an actual problem of clinical cardioplegia and ischemia of the heart. In order to investigate whether the clinically widely used cardioplegic solution of the St. Thomas' Hospital may predispose for these complications, membrane potential (EM), intracellular pH (pHi), and intracellular sodium and potassium activity (aiNa- and aiK) in sheep heart Purkinje fibres were directly measured by means of neutral-carrier ion-selective microelectrodes during equilibration of the fibres' extracellular space with the cardioplegic solution. The experimental temperature was 35 degrees C throughout. During control conditions under superfusion of a HEPES-buffered Tyrode solution EM was -74.4 +/- 5.1 mV (n = 39), pHi was 7.18 +/- 0.05 (n = 16), and aiNa and aiK were 7.6 +/- 1.4 mmol/l (n = 15) and 118.9 +/- 4.6 mmol/l (n = 15) respectively. Superfusing the Purkinje strand for 10 minutes with the cardioplegic St. Thomas' solution led to a depolarization to -57.3 +/- 4.7 mV (n = 21), a slight aiNa decrease to 6.7 +/- 1.6 mmol/l (n = 15; p less than 0.01; cardioplegic solution without procaine) and an increase of aiK to 127.1 +/- 4.4 mmol/l (n = 6; p less than 0.01). pHi needed 15 minutes to reach a steady state value of 7.25 +/- 0.05 (n = 9). The alterations on post-cardioplegic reperfusion with Tyrode solution were reversible within 15 minutes. Simulation of the clinical situation of ice-cold application of the solution by inhibiting the cellular Na/K pump via 0.1 mmol/l dihydroouabaine added to the St. Thomas' solution resulted in a marked increase of aiNa to 10.7 +/- 1.5 mmol/l (n = 6; p less than 0.01; no procaine) during cardioplegic superfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the antianginal effectiveness of nifedipine, verapamil, and isosorbide dinitrate in patients receiving propranolol: a double-blind study

Ten men with stable angina not fully relieved by optimal doses of propranolol were given on each of four mornings a single dose of 10 mg nifedipine, 120 mg verapamil, isosorbide dinitrate (5 to 30 mg, previously titrated to lower systolic blood pressure by 15 to 20 mm Hg), or placebo, in double-blind fashion. Bicycle exercise to angina was performed hourly for 8 hr thereafter. All three vasodilators increased exercise time by at least 50% by the first hour (p less than .001), with a gradually diminishing effect persisting for 6 to 8 hr (p less than .01). Although for the group there were no differences in magnitude and duration of effect among the three drugs, in five of the individual patients there were important differences in response favoring one or another vasodilator. We conclude that nifedipine, verapamil, and isosorbide dinitrate are equally effective and reasonably long-acting antianginal supplements to propranolol, although some patients may benefit more from one than another of the three.     

Comparison of the protective effects of verapamil, diltiazem, nifedipine, and buffer containing low calcium upon global myocardial ischemic injury

This study was designed to compare the effects of the Ca2+ slow channel blocking agents verapamil (2 X 10(-6) M), diltiazem (7.5 X 10(-7) M), and buffer containing reduced Ca2+ content (0.95 mM) on myocardial ischemic injury. These treatments were equiactive, reducing cardiac function to 20% of the control value, and fully reversible in nonischemic, isolated, working rat hearts. Hearts which were reperfused (30 min) following 27 min of global ischemia recovered 17% of control cardiac function and had a markedly reduced ATP and creatine phosphate content and ATP/ADP ratio compared to nonischemic hearts. When verapamil, diltiazem, nifedipine, or low Ca2+ treatments were given before and during ischemia, equal improvement in cardiac function was observed upon reperfusion, and tissue ATP levels, creatine phosphate levels, and ATP/ADP ratio were significantly higher than in hearts which did not receive the treatments or which received the drug vehicle. Large increases in recovery of contractile function were observed with a partial preservation of ATP reserves. These treatments, which were equiactive in nonischemic hearts, provided equivalent preservation of cardiac function, ATP, and creatine phosphate in the reperfused ischemic hearts. When the ischemic period was increased to 33 min and the effective concentrations reduced to depress cardiac function to 40% of the control value (4.5 X 10(-7) M verapamil, 2.5 X 10(-6) M diltiazem, 3 X 10(-7) M Nifedipine, 1.25 mM Ca2+), equal improvement in cardiac function was again observed. Thus, major differences among these Ca2+ slow channel blockers or low Ca2+ treatment were not detected in this experimental system.     

Calcium antagonists and acute myocardial ischemia: Comparative effects of gallopamil and nifedipine on ischemia-induced and reperfusion-induced ventricular arrhythmias,epicardial conduction times,and ventricular fibrillation thresholds

Summary The comparative effects of the calcium-antagonists gallopamil and nifedipine on ischemia-induced and reperfusion-induced ventricular arrhythmias, particularly ventricular fibrillation (VF), were assessed in a total of 40 mongrel dogs in two experimental preparations. In part I of the study, changes in the time course of spontaneous ventricular arrhythmias and VF parallel to changes in epicardial conduction following acute coronary artery occlusion lasting 20 minutes and followed by subsequent reperfusion were determined. In part II, repeated coronary artery occlusions (20 min) followed by reperfusion (60 min) were performed, and changes in ventricular fibrillation threshold (VFT) were assessed. Gallopamil proved to be highly effective in preventing ventricular arrhythmias and VF following coronary artery occlusion. Simultaneously, peak epicardial conduction delay was reduced. The ischemia-induced fall in VFT occurring during the first few minutes after occlusion (phase Ia) was significantly reduced. In contrast, nifedipine failed to influence the incidence of ventricular arrhythmias and VF. Following reperfusion, neither drug reduced the incidence of VF nor the associated fall in VFT at the onset of reperfusion. The time course of recovery of epicardial conduction was not affected by either drug. However, the increase in the VFT during the early postreperfusion period was significantly enhanced by both agents. The effects of gallopamil were more pronounced than those of nifedipine. Delayed reperfusion ventricular arrhythmias arising 5 to 10 minutes after release of coronary artery obstruction were significantly reduced by gallopamil whereas nifedipine proved ineffective. The results show that calcium antagonists display direct antiarrhythmic and cardioprotective actions in acute transient myocardial ischemia. The different effectiveness of gallopamil compared to nifedipine can be explained by differences in electrophysiological properties of the drugs. Enhanced ventricular vulnerability following acute transient coronary artery occlusion and subsequent release of coronary artery obstruction, first described by Tennant and Wiggers [1], has been extensively investigated over the past decade in a variety of experimental and clinical settings. However, the basic mechanisms underlying ischemia- and reperfusion-induced ventricular arrhythmias and ventricular fibrillation (VF) have not yet been fully elucidated. Furthermore, the results of pharmacological approaches to prevent ventricular arrhythmic activity are conflicting. The present study aimed to evaluate the antiarrhythmic efficacy of calcium antagonists in acute myocardial ischemia and reperfusion. We have examined the effects of gallopamil and nifedipine on the time course of ventricular arrhythmias during the first 20 minutes after acute coronary artery occlusion and subsequent reperfusion. We have studied the underlying mechanisms by mapping epicardial conduction and by assessing the electrically induced ventricular fibrillation threshold (VFT) both within and outside ischemic areas.