Arrhythmias In Rat Hearts Research Articles

Ventricular unloading causes prolongation of the QT interval and induces ventricular arrhythmias in rat hearts.

Ventricular unloading during prolonged bed rest, mechanical circulatory support or microgravity has repeatedly been linked to potentially life-threatening arrhythmias. It is unresolved, whether this arrhythmic phenotype is caused by the reduction in cardiac workload or rather by underlying diseases or external stimuli. We hypothesized that the reduction in cardiac workload alone is sufficient to impair ventricular repolarization and to induce arrhythmias in hearts. Rat hearts were unloaded using the heterotopic heart transplantation. The ECG of unloaded and of control hearts were telemetrically recorded over 56 days resulting in >5 × 106 cardiac cycles in each heart. Long-term electrical remodeling was analyzed using a novel semi-automatic arrhythmia detection algorithm. 56 days of unloading reduced left ventricular weight by approximately 50%. While unloading did not affect average HRs, it markedly prolonged the QT interval by approximately 66% and induced a median tenfold increase in the incidence of ventricular arrhythmias in comparison to control hearts. The current study provides direct evidence that the previously reported hypertrophic phenotype of repolarization during cardiac unloading translates into an impaired ventricular repolarization and ventricular arrhythmias in vivo. This supports the concept that the reduction in cardiac workload is a causal driver of the development of arrhythmias during ventricular unloading.

The Protective Effect of St. Thomas Cardioplegia Enriched With Zacopride on the Isolated Rat Heart

The activation of the heart inward rectifier potassium channel (I(K1) ) can reduce the injury of myocardial cells by shortening the action potential duration and reducing intracellular calcium overload. Zacopride is a selective I(K1) agonist and suppresses triggered arrhythmias in rat hearts. This investigation studied the effects of St. Thomas (ST) cardioplegia enriched with Zacopride on the isolated rat heart model. Sprague-Dawley rat hearts were harvested and perfused for 20 minutes with 37°C Krebs-Henseleit (KH) buffer followed by 15 minute perfusion with 4°C calcium-free KH buffer in the Control group (Con, n = 8), ST cardioplegia in the ST group (ST, n = 8) and ST cardioplegia with Zacopride in the STZ group (STZ, n = 8). After 45 minutes of arresting, all hearts were reperfused with 37°C KH buffer for 60 minutes. Hearts in the STZ group arrested faster than the Con and ST groups (9.25 ± 2.38 s vs. 72.25 ± 8.1 s, 12.75 ± 2.87 s). The recovery of the left ventricular developed pressure, ± dP/dtmax, heart rate, and coronary flow in the STZ group is significantly better than the other two groups during reperfusion. Compared with the Con and ST groups, the STZ group showed significant decreases in the maximum carciac troponin I level (P < 0.05) and the infarct size (P < 0.05). The superoxide dismutase level in the STZ group increased during the first 20 minutes of reperfusion (P < 0.05). ST cardioplegia enriched with Zacopride has beneficial effects against ischemia-reperfusion injury in this isolated rat heart model.

Stretch pulses and cardiac arrhythmias in rat hearts: is it a good model?

Stretch pulses and cardiac arrhythmias in rat hearts: is it a good model?

Hypercholesterolemia abrogates an increased resistance of diabetic rat hearts to ischemia-reperfusion injury

Both, diabetes mellitus (DM) and hypercholesterolemia (HCH) are known as risk factors of ischemic heart disease, however, the effects of experimental DM, as well as of HCH alone, on ischemia/reperfusion-induced myocardial injury are not unequivocal. We have previously demonstrated an enhanced resistance to ischemia-induced arrhythmias in rat hearts in the acute phase of DM. Our objectives were thus to extend our knowledge on how DM in combination with HCH, a model that is relevant to diabetic patients with altered lipid metabolism, may affect the size of myocardial infarction and susceptibility to arrhythmias. A combination of streptozotocin (STZ; 80 mg/kg, i.p.) and the fat-cholesterol diet (1% cholesterol, 1% coconut oil; FCHD) was used as a double-disease model mimicking DM and HCH simultaneosly occurring in humans. Following 5 days after STZ injection and FCHD leading to increased blood glucose and cholesterol levels, anesthetized open-chest diabetic, diabetic-hypercholesterolemic (DM-HCH) and age-matched control rats were subjected to 6-min ischemia (occlusion of LAD coronary artery) followed by 10 reperfusion to test susceptibility to ventricular arrhythmias in the in vivo experiments and to 30-min ischemia and subsequent 2-h reperfusion for the evaluation of the infarct size (IS) in the Langendorff-perfused hearts. The incidence of the most life-threatening ventricular arrhythmia, ventricular fibrillation, was significantly increased in the DM-HCH rats as compared with non-diabetic control animals (100% vs. 50%; p<0.05). Likewise, arrhythmia severity score (AS) was significantly higher in the DM-HCH rats than in the controls (4.9+/-0.2 vs. 3.5+/-0.5; p<0.05), but was not increased in the diabetic animals (AS 3.7+/-0.9; p>0.05 vs. controls). Diabetic hearts exhibited a reduced IS (15.1+/-3.0% of the area at risk vs. 37.6+/-2.8% in the control hearts; p<0.05), however, a combination of DM and HCH increased the size of myocardial infarction to that observed in the controls. In conclusion, HCH abrogates enhanced resistance to ischemia-reperfusion injury in the diabetic rat heart.

Effect of Cl− channel blockers on aconitine‐induced arrhythmias in rat heart

The effects of Cl- channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and niflumic acid (NFA) on aconitine-induced arrhythmias were investigated. Left ventricular pressure and electrocardiogram were monitored in Langendorff-perfused rat hearts. Whole-cell patch-clamp and current-clamp techniques were used to measure sodium current (I(Na)) and action potential (AP), respectively, in single rat cardiac ventricular myocytes. Addition of the Na+ channel agonist aconitine (0.1 microM) to the perfusion solution produced polymorphic ventricular arrhythmias with a latent period of 25.5 +/- 6.3 s. NPPB could reverse aconitine-induced arrhythmias. A similar effect was observed by using NFA. NPPB and NFA reversibly depressed the upstroke of the AP in a dose-dependent manner with IC50 values of approximately 12.3 and approximately 73.1 microM, respectively, without significantly affecting the resting potential of rat ventricular myocytes. Both Cl- channel blockers inhibited I(Na) and induced a leftward shift of the steady-state inactivation of I(Na). In conclusion, the results of this study demonstrate that NPPB as well as NFA can suppress aconitine-induced arrhythmias in rat hearts mainly by inhibiting cardiac I(Na).

Astragaloside IV fromAstragalus membranaceusShows Cardioprotection during Myocardial Ischemiain vivoandin vitro

Astragaloside IV is the major active constituent of Astragalus membranaceus, which has been widely used for the treatment of cardiovascular diseases in China. However, the effects of astragaloside IV on myocardial ischemia and its mechanisms of action remain largely unknown. In this study, we have examined the effects of astragaloside IV on myocardial infarction and coronary flow in vivo and in vitro. The possible roles of its antioxidative and nitric oxide-inducing properties were also explored. Astragaloside IV significantly reduced infarct size in dogs subjected to coronary ligation in vivo. Astragaloside IV also improved post-ischemic heart function and ameliorated reperfusion arrhythmias in rat hearts in vitro. The cardioprotection of astragaloside IV was accompanied by a significant increase in coronary flow both in vivo and in vitro. The nitric oxide synthase inhibitor, Nomega-nitro- L-arginine methyl ester partially abrogated astragaloside IV's protective effect on heart function. Myocardial antioxidative enzyme superoxide dismutase activity increased with astragaloside IV administration. These data suggest the potential roles of antioxidative and nitric oxide-inducing properties of astragaloside IV in its protection from myocardial ischemia.

Arrhythmias in rat hearts exposed to pulsed ultrasound after intravenous injection of a contrast agent.

To develop an animal model suitable for characterizing electrocardiographic arrhythmias in hearts exposed to ultrasound after injection of a microbubble contrast agent. Conduction complex and heart lesion data were recorded from 20 rats that received intravenous injections of 0.25 mL of a contrast agent and were exposed to pulsed ultrasound (frequency, 3.1 MHz; pulse duration, 1.3 microseconds; pulse repetition frequency, 1700 Hz; and in situ peak rarefactional pressure, 15.9 MPa). The volume of the contrast agent based on body weight and the mechanical index (ultrasonic pressure) exceeded those used in echocardiography by 14 to 345 and 3 to 29 times, respectively. Premature atrial complexes, premature ventricular complexes, or polymorphic ventricular tachycardia occurred in 10 rats. When ultrasound exposure was halted, arrhythmias ceased but reoccurred in 4 of the 10 rats when exposure resumed. Myocardial degeneration identified by histochemical staining (hematoxylin-basic fuchsinpicric acid) was observed in 16 rats; however, only 10 rats had arrhythmias. There was no significant difference in the amount of histochemical staining in hearts from rats with arrhythmias when compared with rats without arrhythmias. An animal model suitable for characterizing electrocardiographic arrhythmias in rat hearts exposed to ultrasound after injection of a microbubble contrast agent was developed. Because arrhythmias were induced principally when the contrast agent interacted with ultrasound during exposure, the presence of myocardial degeneration alone was not a sufficient explanation for ectopic electrical activity. Under these extreme exposure conditions, the data suggest that pulsed ultrasound through its biomechanical interactions with contrast agents has the potential to induce arrhythmias.

Arrhythmias in Rat Hearts Exposed to Pulsed Ultrasound After Intravenous Injection of a Contrast Agent

ot only is the heart a challenging organ to image, with rhythm and motion fundamental to its design, but it lets you know when it is unhappy. Although contrast-enhanced sonographic techniques for vascular definition and for evaluation of perfusion have had an impact in liver and kidney studies,1–4 nonetheless, the heart as a functional organ in view of the wide prevalence of ischemic heart disease can be imaged and its function can be assessed by cardiac sonography. However, a sonographic method for describing myocardial perfusion directly has been lacking. With this “grail” in mind, a number of companies and investigators have actively been involved in the pursuit of agents and methods for imaging myocardial perfusion. There has been extremely clever science, not only from developers of contrast agents but also from scientists, investigators, and ultrasound engineers. The whole field of ultrasound has benefited vastly from the development of harmonic imaging strategies, and broadband, pulse inversion, and coded excitation implementations have yielded new energy delivery schemes almost as complicated as those used in magnetic resonance imaging. The concepts of intermittent imaging, burst imaging, and computation of the slope of the contrast wash-in curve as indicators of regional perfusion, either on gray scale or power mode images, use the indicator dilution theory and explore the difference between intravascular and extravascular contrast agent penetration. The ability to “break” bubbles, although requiring alterations of the indicator dilution theory, led to notable new horizons in the possibilities for targeted delivery of drugs and even genes loaded into bubbles. I remember in the early 1980s, when Doppler echocardiography required high pulse repetition frequencies, with multiple bursts occurring along individual lines of sight, the Bioeffects Committee of the American Institute of Ultrasound in Medicine became active in a dialogue with the Bureau of Radiologic Health and the Food and Drug Administration. Discussions especially related to the possibility of fetal risk occurred at the time. There was little clinical interest in contrast-enhanced echocardiography at the time; although Echovist had been licensed to Schering (Berlin, Germany), Levovist had not yet been developed. Nonetheless, in documents that preceded those referenced in the interesting article by Zachary et al5 in this issue of the Journal of Ultrasound in Medicine, a body of American Institute of Ultrasound in Medicine bioeffects statements,6–9 although emphasizing thermal effects, raised the possibility that mechanical effects could become amplified and consequential in the presence of gas nuclei, such as within

Sympathetic activation triggers ventricular arrhythmias in rat heart with chronic infarction and failure.

To seek direct evidence for a cause-effect relation between sympathetic activation and arrhythmogenesis. Rats underwent open-chest surgery with either coronary artery occlusion or sham operation, and were studied 8 weeks later using in situ heart perfusion and nerve stimulation methods. Infarcted rats showed cardiac functional impairment and increased heart and lung weight. The extent of these changes correlated well with infarct size (IS). In in situ perfused hearts, sympathetic nerve stimulation (2 and 4 Hz, 45 s duration) induced a frequency-dependent release of norepinephrine (NE). NE release was lower in MI than that in control groups. In hearts with large IS (> or = 40%, n = 19) ventricular arrhythmias were rare at baseline, but nerve stimulation evoked the onset of ventricular premature beats (95%), tachycardia (37%) and fibrillation (26%), IS and stimulation frequency were key determinants for the inducibility of arrhythmias. Lower K- concentration enhanced arrhythmia inducibility. beta-blockade inhibited the frequency of arrhythmias produced by nerve stimulation. In infarcted rat hearts sympathetic activation is a potent trigger for the onset of ventricular tachyarrhythmias.

Antiarrhythmic effects of cariporide, a novel Na +–H + exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts

Cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate: HOE642) is a novel Na +–H + exchange subtype 1 inhibitor and has antiarrhythmic effects on ischemia/reperfusion arrhythmias without apparent cardiovascular effects in dogs and rats when given before coronary occlusion. The aim of this study was to determine the minimum effective dose and to examine the dose related effects of cariporide when it was administered before and during coronary occlusion as well as simultaneously with reperfusion. In the pre-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 140 to 36 ( P<0.01), 59 ( P<0.05) and 23 s ( P<0.01) with 0.03, 0.1 and 1 mg/kg, respectively, and reduced the incidence of reperfusion-induced ventricular tachycardia from 100 to 50 and 58% ( P<0.01), ventricular fibrillation from 83 to 8 and 0% ( P<0.01), and mortality from 75 to 8 and 8% ( P<0.01) with 0.1 and 1 mg/kg, respectively. In the post-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 92 to 37, 40, 42 ( P<0.05) and 24 s ( P<0.01) with 0.03, 0.1, 0.3 and 1 mg/kg, respectively, and the incidence of ventricular tachycardia from 100 to 53% ( P<0.01) by 1 mg/kg, and ventricular fibrillation from 87 to 33, 7 and 7% ( P<0.01), and the mortality from 73 to 27 ( P<0.05), 0 and 7% ( P<0.01) with 0.1, 0.3 and 1 mg/kg, respectively. In the group with simultaneous injection, both doses of cariporide (1 and 3 mg/kg) reduced the incidence of ventricular fibrillation from 83 to 42% ( P<0.05). The heart rate, blood pressure and QT interval did not change after drug treatment.

Antiarrhythmic effects of DHA-As on ventricular arrhythmias in rat and dog hearts

DHA-Ascorbic acid (DHA-As), a new derivative of docosahexaenoic acid (DHA) was tested for its possible antiarrhythmic effects on coronary artery ligation/reperfusion arrhythmias in rat hearts, and adrenaline-induced arrhythmias in canine hearts. DHA-As (3 mg/kg i.v.) did not change the total duration of VT, and tended to suppress the incidence of VT, VF and mortality of reperfusion in rat hearts. The heart rate, QT90 and systolic blood pressure did not change, and the diastolic blood pressure was decreased by DHA-As in the rat hearts. DHA-As significantly decreased the arrhythmic ratio only at two time points (14 and 15 min after injection), and also decreased the heart rate and mean blood pressure in canine hearts. In conclusion, DHA-As tended to suppress the reperfusion-induced arrhythmias in rat hearts. However, the change was not statistically significant. In addition, DHA-As has a weak suppressing effect on adrenaline-induced arrhythmia.

Donors of nitric oxide mimic effects of ischaemic preconditioning on reperfusion induced arrhythmias in isolated rat heart.

NO has been implicated in the mechanism of ischaemic preconditioning. To verify this hypothesis further we have attempted to reproduce effects of ischaemic preconditioning by nitric oxide donors administration prior to the ischaemia. The effect of glyceryl trinitrate (GTN) and 3-morpholino-sydnonimine-hydrochloride (SIN-1), NO donors, on reperfusion induced ventricular tachycardia (VT) and ventricular fibrillation (VF) in Langendorff perfused rat hearts subjected to 10 min regional ischaemia followed by 10 min reperfusion were examined. GTN, 500 microM and SIN-1, 10 microM, administered for 5 min and washed for another 5 min prior to ischaemia (to mimic ischaemic preconditioning), almost completely abolished reperfusion induced VF. GTN and SIN-1, administered at the time of reperfusion, increased the incidence of sustained VF and the duration of VT and VF. When given 5 min before the ischaemia and throughout the ischaemia and the reperfusion, SIN-1 abolished VF. Adenosine, 10 microM, applied according to the above three protocols, did not affect reperfusion arrhythmias, although adenosine induced changes in coronary flow and post-ischaemic reflow were similar to those produced by the NO donors. In conclusions: (1) NO is able to mimic the effect of ischaemic preconditioning on reperfusion arrhythmias in rat heart, supporting the view that NO may be one of the endogenous substances triggering ischaemic preconditioning; (2) In crystalloid-perfused heart, NO may be deleterious when its administration is restricted to the reperfusion period.

Relation between ischemic preconditioning and the duration of sustained ischemia.

It has been reported that repetitive brief periods of ischemia and reperfusion (ischemic preconditioning, IP) cause a significant reduction in the extent of myocardial necrosis or in the incidence of reperfusion arrhythmias in rat heart. However, recent reports have stated that IP effect is diminished or lost in the canine or bovine heart if ischemia (mostly regional) is sustained for 40 min or longer. The main objective of this study is to assess whether IP provides myocardial protection in prolonged sustained ischemia under the condition of global ischemia in isolated rabbit heart. The hearts were subjected to 10-60 min sustained ischemia (SI) followed by 60 min reperfusion with (IP heart) or without IP (ISCH heart). IP was induced by 4 cycles of 5 min global ischemia and 5 min reperfusion. Left ventricular function (LVF), extent of infarction (EI) and ultrastructural changes were examined. As a whole, the LVF began to recover on reperfusion but there was no significant difference in the functional parameters. However, extracellular Ca2+ concentration was lower in the ISCH hearts (p < 0.05) and the EI was significantly different between the hearts which had received 60 min SI (67% in the ISCH versus 32% in the IP heart, p < 0.01). Ultrastructural changes were homogeneous in the ISCH hearts and became irreversible in accordance with increase of the duration of ischemia, while these changes were heterogeneous and restricted in the IP heart. These results suggest that IP does not attenuate the postischemic dysfunction in prolonged ischemia but it can provide an infarct size-limiting effect and delay ultrastructural changes. This cardioprotective effect may be related to calcium homeostasis.

Differential Effects of Various Oil Diets on the Risk of Cardiac Arrhythmias in Rats

Independently of the problem of atherogenesis, the amount and type of fat intake influences the risk of cardiac arrhythmias. However, the relative effectiveness of different fats and the underlying mechanisms are controversial. The aim of the present study was to compare the effects of various oil-enriched diets on the risk of ventricular arrhythmias in rat hearts under conditions of ischaemia and reperfusion and to help clarify the mechanisms underlying the differing effects of the oils on the occurrence of arrhythmias. Over a 10-week period, we studied five groups of young male Wistar rats given a low-fat chow diet or one enriched with 10% hydrogenated coconut oil, corn oil, linseed oil or sardine oil. Electrocardiograms were recorded from the isolated hearts (Langendorff preparation) perfused with a modified Krebs-Henseleit solution. Ischaemia was induced by a 20 min occlusion of the left anterior descending coronary artery. In another series of experiments, a 10 min occlusion was followed by a 20 min reperfusion period. The times between the first occurrence of extrasystole and the incidence of ventricular tachycardia and fibrillation were determined. The size of the ischaemic zone was assessed using malachite green. The fatty acid composition of the myocardial tissue was analysed using gas chromatography. An increase in the risk of ventricular arrhythmias under conditions of both ischaemia and reperfusion was obvious in the rats that consumed large quantities of saturated fatty acids (coconut oil) and in the group with a very low intake of fat. Polyunsaturated fatty acids (PUFAs), particularly fish oil, exerted a protective effect. The incidence of ventricular fibrillation was 75% in the low-fat group, 67% in the coconut-oil group, 44% in the corn-oil group, 40% in the linseed-oil group and 10% in the fish-oil group. The time until the first occurrence of extrasystole, the incidence of ventricular tachycardia and the incidence of reperfusion-induced ventricular fibrillation were influenced in a similar manner. The size of the ischaemic zone was significantly reduced in the groups given diets enriched with PUFAs. All protective effects were abolished, however, by cyclooxygenase inhibition with aspirin. The fatty acid composition of myocardial tissue, the ratio of n-3 to n-6 fatty acids and the double-bond index were significantly affected by the various diets. Whereas saturated fatty acids are obviously proarrhythmic, diets enriched with n-6 or n-3 PUFAs both exert antiarrhythmic effects. Although n-3 fatty acids seem to be more effective, cardioprotection cannot simply be related to the replacement of n-6 by n-3 fatty acids in cardiac membrane phospholipids, given the beneficial effects of corn oil. In any case, replacement of n-3 by n-6 fatty acids is not the underlying mechanism. The overall reduction of prostaglandin formation cannot be the primary mechanism because the beneficial effects of diets rich in PUFAs were abolished by cyclooxygenase inhibition. We conlcude that, besides prostacyclin (PGI2 or PGI3), membrane fluidity and accompanying alterations in functional membrane proteins (e.g. protection from calcium overload) are key factors apart from vascular effects that influence the size of the ischaemic zone.

"Dose"-dependency and Temporal Characteristics of Protection by Ischaemic Preconditioning against Ischaemia-induced Arrhythmias in Rat Hearts

Brief episodes of ischaemia and reperfusion (preconditioning) can increase the resistance of the myocardium to ischaemic injury. We investigated the temporal characteristics of anti-arrhythmic protection by preconditioning. Rat hearts underwent regional ischaemia (± reperfusion) of the left coronary territory. Control isolated blood-perfused hearts underwent 40 min ischaemia; in the preconditioned groups this was preceded by one, two or three cycles of 5 min ischaemia and 5min reperfusion. Control anaesthetized rats underwent 60 min ischaemia; this was preceded by three cycles of 3 min ischaemia and 3 min reperfusion in the preconditioned group. Preconditioning led to: (i) the abolition of ventricular fibrillation in both in vivo and in vitro preparations; (ii) a reduced incidence of ventricular tachycardia (from 100% to 8% in vitro and 100% to 25% in vivo); and (iii) a reduced incidence of ventricular premature beats (from 246 ± 36 to 8 ± 5 in vitro and 85 ± 21 to 24 ± 13 in vivo). In isolated hearts protection was proportional to the number of preconditioning cycles. Although preconditioning caused a dramatic reduction in the severity of arrhythmias it did not result in any significant alteration in their temporal profiles. We conclude that protection by preconditioning against ischaemia-induced arrhythmias is "dose"-dependent in rat hearts in vitro and results in an absolute reduction in the severity of ischaemia-induced arrhythmias rather than an alteration in their time-course, both in vivo and in vitro.

Halothane prevents reperfusion-induced arrhythmia in rat heart

Halothane prevents reperfusion-induced arrhythmia in rat heart

Reduction of ischemic K+ loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulfonylurea.

Glibenclamide, one of the antidiabetic sulfonylureas, is known to block ATP-dependent K+ channels. We used this drug to determine to what extent K+ loss from acutely ischemic myocardium is mediated via these channels. We also investigated whether glibenclamide would influence ischemic arrhythmias. Isolated rat hearts rendered globally ischemic showed no correlation between early lactate and K+ efflux rates. Cumulative K+ loss during 11 minutes of global ischemia (0.5 ml min-1 g-1) was reduced, from 3.2 +/- 0.3 to 2.5 +/- 0.1 mueq/g (p less than 0.025) by 1 microM glibenclamide and from 3.3 +/- 0.2 to 1.9 +/- 0.2 mueq/g (p less than 0.005) by 10 microM glibenclamide, while lactate efflux was unaltered by the drug. Glibenclamide also exhibited potent antifibrillatory activity, abolishing irreversible ventricular fibrillation during regional ischemia (0/6 vs. 5/6 controls; p less than 0.02) and during global ischemia (0/7 vs. 9/9 controls; p less than 0.01). Heart rate, coronary flow rate, peak systolic pressure, and myocardial oxygen consumption were unaltered by the drug (1 microM). Similarly, glibenclamide (1 microM) did not alter myocardial ATP, phosphocreatine or lactate content, or glucose utilization. Ventricular fibrillation threshold during normoxia was also unaltered by glibenclamide (1 microM). We conclude that K+ loss during acute myocardial ischemia is mediated partly by ATP-dependent K+ channels, and not by a tightly coupled co-efflux with anionic lactate.

Effects of promethazine on ischemic and reperfusion arrhythmias in rat heart.

The effects of the H1-receptor antagonists promethazine, mepyramine, and chlorpheniramine on ischemic and reperfusion arrhythmias were studied in the isolated perfused rat heart. Promethazine reduced both ischemic and reperfusion arrhythmias (2 x 10(-6)M-7.5 x 10(-6)M). Mepyramine and chlorpheniramine decreased these arrhythmias but at concentrations about 10 times higher. The H2-blockers cimetidine and ranitidine had no antiarrhythmic effect. Promethazine also: (i) increased release of noradrenaline by the heart; and (ii) increased coronary flow in the reperfusion period and in some mildly ischemic zones. It is proposed that promethazine exerts most of its antiarrhythmic effects by a nonspecific mechanism, possibly membrane stabilization; in addition, enhanced coronary flow may play a role.

Protective effect of transient calcium reduction against reperfusion-induced arrhythmias in rat hearts.

By using the isolated rat heart with regional ischemia and a perfusate Ca2+ of 2.4 mM, we have observed a bell-shaped relationship between the incidence of reperfusion-induced ventricular fibrillation (VF) and the duration of preceding ischemia. With 5, 10, 20, 30, and 40 min of ischemia, 8, 83, 58, 25, and 8% of the hearts (n = 12 per group) exhibited irreversible VF. In additional studies (10 min ischemia) perfusate Ca2+ was reduced (to 0.1, 0.4, 0.8, 1.2, 1.6, and 2.0 mM) for 1 min before coronary occlusion (to trap low Ca2+ in the ischemic zone) and for 1 min before and throughout reperfusion. VF fell in a dose-dependent manner from its control incidence of 83% (2.4 mM Ca2+) to 17 (P less than 0.01), 25 (P less than 0.01), 41, 58, 91, and 83%, respectively. In further studies Ca2+ was reduced to 0.4 mM just before ischemia and also just before and during reperfusion, and the ischemic time was varied (5, 10, 20, 30, or 40 min), VF was reduced from its time-matched control (2.4 mM Ca2+) values of 8, 83, 58, 25, and 8% to 0, 25 (P less than 0.01), 8 (P less than 0.05), 0, and 0%, respectively. In a final series of experiments, Ca2+ reduction (to 0.4 mM) was carried out only during reperfusion (1 min before and throughout reperfusion). When time-vulnerability curves were constructed some protection was observed after 20 min of ischemia (VF fell from its control incidence of 58 to 8%). We conclude that extracellular Ca2+ concentration can influence vulnerability to reperfusion-induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the enantiomers of the dihydropyridine derivative 202–791 on contractility, coronary flow and ischemia-related arrhythmias in rat heart

The (+)-enantiomer of the dihydropydine 202–791 produced coronary constrictor and positive inotropic effects in Langendorff-perfused rat hearts whereas (-)-202-791 showed coronary dilator and negative inotropic effects. Both enantiomers showed the vascular effects at lower concentrations than the myocardial effects. Furthermore, the (+)-enantiomer significantly increased whilst the (-)-enantiomer reduced the number of ventricular ectopic beats occurring during coronary ligation. Arrhythmia-enhancing effects must therfore be considered when the potential therapeutic uses of calcium channel activators are discussed.