Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic.

BACKGROUND: Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class 2I), but paradoxically, it frequently is also proarrhythmic (torsade de pointes). METHODS AND RESULTS: The cardiac electrophysiological effects of 702 chemicals (class 2I or HERG channel block) were studied in 1071 rabbit Langendorff-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic beats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proarrhythmia. Agents that lengthened the APD by >50 ms, with induction of instability, triangulation, and reverse use-dependence (n=59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (n=19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (P<0.001). Shortening of APD, when accompanied by instability and triangulation, was also markedly proarrhythmic (primarily monomorphic ventricular tachycardia). In experiments in which instability and triangulation were present, proarrhythmia declined with prolongation of APD, but this effect was not large enough to become antiarrhythmic. Only with agents without instability did prolongation of APD become antiarrhythmic. For 20 selected compounds, it was shown that instability of APD and triangulation observed in vitro were strong predictors of in vivo proarrhythmia (torsade de pointes). CONCLUSIONS: Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.

Electrophysiological and inotropic effects of H 234/09 (almokalant) in vitro: a comparison with two other novel IK blocking drugs, UK-68,798 (dofetilide) and E-4031.

OBJECTIVE: The aim was to compare the electrophysiological and inotropic effects of the novel class III agents H 234/09, UK-68,798, and E-4031 in vitro. METHODS: The electrophysiological effects were investigated by recording transmembrane action potentials in the isolated ventricular muscle and Purkinje fibres of the rabbit; effects on force (adjusted to the maximum isoprenaline response) and refractoriness were investigated in the isolated cat papillary muscle. RESULTS: It was shown that all the drugs induced a concentration dependent prolongation of the action potential duration, which was much more pronounced in the Purkinje fibres than in the ventricular muscle. However, when compared at concentrations giving a 15% increase of the action potential duration in ventricular muscle, H 234/09 was significantly less effective in the Purkinje fibres than the other two drugs. In the cat papillary muscle all drugs induced an increase in force development. This increase tended to parallel the increase in effective refractory period. However, at prolongations of effective refractory period of more than approximately 50% the increase in developed force levelled off. CONCLUSIONS: All the class III agents investigated showed a positive inotropic effect, which may be of advantage when compared to conventional class I antiarrhythmic agents, which have cardiodepressant actions. Compared to UK-68,798 and E-4031, H 234/09 showed a less unfavourable profile in terms of dispersion of repolarisation, which theoretically may reduce the risk of arrhythmias associated with delayed repolarisation. However, this less unfavourable profile must, like the positive inotropic effect, ultimately be investigated in clinical trials.

Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations.

OBJECTIVE: The aim was to study factors contributing to torsade de pointes in the acquired long QT syndrome. METHODS: Anaesthetised rabbits or cats were given a continuous infusion of methoxamine and the class III agent almokalant (at a rate of 5 or 25 nmol.kg-1.min-1, respectively) and the effects on incidence of torsade de pointes and QT dispersion were examined. Effects of almokalant on action potentials recorded from Purkinje fibres and ventricular cells of rabbits and cats were also studied. RESULTS: "High rate" infusion of almokalant prolonged the QTc interval [from 162(SEM 6.2) ms to 211 (5.3) ms, p < 0.001] and initiated torsade de pointes in 9/10 rabbits after a dose of 391(116.3) nmol.kg-1. During "low rate" infusion, 1/8 rabbits developed torsade de pointes (p = 0.0029) despite infusion of 900 nmol.kg-1 almokalant and QTc prolongation from 162(3.6) ms to 230(12.6) ms (p < 0.01). In eight separate rabbits given the high rate infusion of almokalant, seven developed torsade de pointes and the QTc dispersion increased from 15(1.7) ms to 32(5.6) ms (p < 0.05). In six rabbits given the low rate infusion, none developed torsade de pointes (p = 0.0023), and the QTc dispersion was unaltered. In six cats, high rate infusion induced a QT interval lengthening from 241(6.0) ms to 349(8.0) ms (p < 0.001), but in only one cat was torsade de pointes initiated and preceded by a marked increase in QT dispersion (from 22 ms to 78 ms). In vitro, almokalant caused a marked lengthening of the action potential duration and early afterdepolarisations in Purkinje fibres but not in ventricular muscle cells of the rabbit. In the cat, however, almokalant induced a homogeneous prolongation of the action potential duration in both cell types, and early afterdepolarisations were never observed. CONCLUSIONS: The rate of infusion of repolarisation delaying agents may influence the dispersion of repolarisation and play a decisive role in the initiation of torsade de pointes.

Induction of rhythm abnormalities in the fetal rat heart. A tentative mechanism for the embryotoxic effect of the class III antiarrhythmic agent almokalant.

OBJECTIVES: The aim was to test the hypothesis that the recently reported embryotoxic effect of class III antiarrhythmic agents may be a result of electrophysiological disturbances induced by these agents. METHODS: Comparative studies of drug effects in the adult and fetal rat were performed using three experimental models: (1) effects of almokalant upon pregnancy and fetal mortality in rats given daily doses of 0, 10, 50, 100, or 400 mumol.kg-1 orally in the diet on days 6-15 of pregnancy; (2) effects of d-sotalol (1-1000 microM), almokalant (0.1-100 microM) and dofetilide (0.01-10 microM) on the adult and fetal cardiac action potential in vitro; (3) voltage clamp recordings in single fetal and adult ventricular myocytes superfused with almokalant (0.5 microM). RESULTS: In the groups of rats treated with 100 and 400 mumol.kg-1, respectively, the body weight gain was decreased from day 12 of gestation, and there were no viable fetuses at termination of pregnancy. In atrial as well as ventricular tissue, the class III agents induced a concentration dependent prolongation of the fetal action potential duration, accompanied by a reduction in heart rate and eventually the appearance of rhythm abnormalities and/or early afterdepolarisations. The adult action potential duration remained unaffected. An almokalant sensitive current (probably the delayed rectifier, IK) could be evoked both in the fetal and in the adult ventricular cells. CONCLUSIONS: Class III antiarrhythmic agents were shown to induce fetal mortality and rhythm abnormalities in the rat heart. Although they do not prove a causal relationship between these effects, our observations may have implications for the clinical use of class III antiarrhythmic agents in women of childbearing potential.

Potassium and calcium current blocking properties of the novel antiarrhythmic agent H 345/52: implications for proarrhythmic potential.

OBJECTIVES: To study the blocking effects of H 345/52 on ionic currents of rabbit ventricular myocytes and how these features translate into a proarrhythmic potential. METHODS: The single electrode voltage clamp technique was used to study the effects of H 345/52 on the rapid component of the delayed rectifying potassium current, I(Kr), and the L-type calcium current (I(Ca)). Differential effects of H 345/52 and almokalant on APD prolongation were studied in a rabbit Purkinje fibre/ventricular muscle preparation. The temporal variability of the action potential duration (APD) and its relation to proarrhythmias was examined in Langendorff-perfused rabbit hearts administered H 345/52 or almokalant. Anaesthetised, methoxamine-sensitised rabbits were used to assess the propensity of intravenous H 345/52 and ibutilide to induce torsades de pointes (TdP). RESULTS: H 345/52 potently blocked I(Kr) (IC(50)=40 nM) without consequential use-dependency. The I(Ca) was also blocked, but at higher concentrations (IC(50)=1.3 microM). Block of I(Ca) was markedly frequency-dependent (positive) and influenced by membrane potential, such that H 345/52 was more effective following clamp steps from plateau potentials than from -80 mV. In the Purkinje fibre-ventricular muscle preparation, almokalant prolonged the Purkinje fibre APD preferentially, whereas H 345/52 homogeneously prolonged APD in both tissue types. In the perfused rabbit heart, H 345/52 (1 microM) and almokalant (0.3 microM) prolonged APD to a similar degree but increased the temporal variability of APD differently, from 3+/-0.4 ms in control hearts to 8+/-1.2 ms and to 38+/-7.5 ms (P<0.001 vs. H 345/52), respectively. Unequivocal early after-depolarisations were seen in 5/6 almokalant-perfused hearts but in no heart administered H 345/52 (P<0.05). In anaesthetised rabbits, H 345/52 (17.4 micromol/kg) or ibutilide (2.6 micromol/kg maximum), maximally lengthened the QT interval from 133+/-4.5 to 177+/-8.0 ms and from 125+/-5.1 to 166+/-9.3 ms (P<0.001, n=8). However, whereas ibutilide induced TdP in all animals at 0.06+/-0.009 micromol/kg, H 345/52 did not induce TdP (P=0.0002) at up to 17.4 micromol/kg. CONCLUSIONS: H 345/52 blocks I(Kr) with high potency and I(Ca) with somewhat lower potency and was found to delay ventricular repolarisation without substantially increasing temporal or spatial dispersion and without inducing early after-depolarisations or TdP.

(+)-sotalol causes significant occupation of beta-adrenoceptors at concentrations that prolong cardiac repolarization.

The racemate (+/-) and the two enantiomers of sotalol were studied with regard to the effects on cardiac repolarization. In addition, the affinity to cardiac beta-adrenoceptors was investigated for the enantiomers. The effect on left ventricular monophasic action potential duration was assessed in the isolated perfused guinea-pig heart and the beta-adrenoceptor affinity of the compounds was studied, using a radioligand binding technique, in cellular membranes prepared from the left ventricular free wall of the cat. Moreover, the beta-adrenoceptor blocking potency of (+)-sotalol was studied in isolated strips of guinea-pig papillary muscles. Both the racemate and the two enantiomers of sotalol caused a concentration-dependent prolongation of the ventricular monophasic action potential duration. The maximal effect and the concentration causing half maximal effect (EC50 = 13 mumol/l) were similar for the racemate and the enantiomers, indicating lack of stereoselectivity for this effect. The beta-adrenoceptor affinity (equilibrium dissociation constant) of (+)-sotalol was 11 mumol/l and 4 mumol/l as estimated by the binding technique and in the isolated muscle strips, respectively. The affinity for (-)-sotalol, estimated by binding, was 0.6 mumol/l. Thus, at concentrations of (+)-sotalol required for a significant prolongation of cardiac repolarization, this isomer may cause significant beta-blockade. In this study the enantiomeric purity was better than 98%, so that the degree of beta-blockade may be even more pronounced if the enantiomeric purity of the (+)-enantiomer is less than 98%.

[The DA240-4 discrete biochemical autoanalyser]. / Diskretnyi biokhimicheskii avtoanalizator DA240-4.

The principle of operation, design and main technical characteristics are described of a discrete biochemical autoanalyzer DA240-4 jointly elaborated by the USSR and GDR. This unit can be employed in big biochemical laboratories and in prophylactic institutions.

Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes.

BACKGROUND AND PURPOSE: Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) could be used to identify pro-arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and specificity for evaluating the pro-arrhythmic properties of I(Kr) blockers, using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds). EXPERIMENTAL APPROACH: Assays included the anaesthetized remodelled chronic complete AV block (CAVB) dog, the anaesthetized methoxamine-sensitized unremodelled rabbit, multi-cellular hESC-CM clusters, isolated CM obtained from CAVB dogs and isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models and early afterdepolarizations (EADs) in the cell models. KEY RESULTS: At clinically relevant concentrations (5-12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (≥100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). Dofetilide and E-4031 induced EADs or TdP in all assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization. CONCLUSION AND IMPLICATIONS: Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the I(Kr) blocking drugs moxifloxacin and dofetilide or E4031.

Gender disparity in cardiac electrophysiology: implications for cardiac safety pharmacology.

BACKGROUND: Gender differences in cardiac electrophysiology were reported for the first time almost a century ago. The importance for safety pharmacology became significant when modern medicine came into use and women appeared to be more susceptible to drug-induced Torsade de Pointes (TdP). To unravel the underlying mechanisms, the effect of sex hormones on cardiac electrophysiology has been studied in humans, animals and cell models. In this review, these data have been summarized and discussed in regard to possible consequences for safety pharmacology testing. RESULTS: In man, electrophysiological differences become apparent during adolescence when the QTc interval shortens in males. This protective effect for long-QT related arrhythmias can be correlated to testosterone levels. Testosterone likely suppresses I(Ca,L) and enhances I(K) which increases the repolarization reserve. Though progesterone may have similar effects in women, these effects are probably balanced out by the small but opposite effects of estrogen. Progesterone levels, however, vary importantly throughout the different phases of the human menstrual cycle, implying that the sensitivity for drug-induced TdP changes too. The consequences for drug safety testing and TdP have not been assessed. CONCLUSION: The testosterone-mediated increase in repolarization reserve in men is a likely cause for their lower susceptibility to drug-induced TdP. For the female population, the shifting balance in estrogen and progesterone creates temporal variation in the lability of repolarization to drug-induced TdP. This is a possible confounding factor in the evaluation and comparison of drugs that has to be further tested.

Electrophysiologic and hemodynamic effects of H 234/09 (almokalant), quinidine, and (+)-sotalol in the anesthetized dog.

The electrophysiologic and hemodynamic effects of H 234/09 (Almokalant), a novel class II antiarrhythmic agent, were studied in the anesthetized dog. H 234/09 (1.0 mumol/kg i.v.) significantly prolonged the atrial and ventricular effective refractory periods, the ventricular monophasic action potential duration, and the paced QT interval. At this dose, atrial, ventricular, and atrioventricular conduction was not affected, aortic blood pressure was not changed, and contractile force was transiently increased. The effects on cardiac repolarization and refractoriness induced by H 234/09 were both larger and more long lasting than the effects observed after quinidine (11.8 mumol/kg) and (+)-sotalol (9.7 mumol/kg). However, both quinidine and (+)-sotalol significantly reduced the aortic blood pressure and (+)-sotalol also decreased cardiac contractility. The effect of H 234/09 on atrial refractoriness was very little influenced by the paced heart rate and was twice as large as the corresponding effect in the ventricle. In conclusion, H 234/09 has electrophysiological properties suggestive of a class III antiarrhythmic. H 234/09 may have a favorable therapeutic profile compared to both quinidine and (+)-sotalol, especially for the treatment of atrial arrhythmias.

The healing of autologous spongiosa and heterologous materials in the periodontal bone pocket. An animal experimental study.

In animal experiments with fully-grown beagle dogs we followed the healing of autologous spongiosa, collagen and binding gelatine by the use of polychrome sequential labelling. We found that when autologous spongiosa is transplanted into the periodontal intrabony pocket, the new material is fully remodelled after 6 weeks. When collagen is implanted, there is also a large amount of bone formed during this time. There was very little new bone formation after 6 weeks when binding gelatine was implanted.

Lidocaine and nisoldipine attenuate almokalant-induced dispersion of repolarization and early afterdepolarizations in vitro.

INTRODUCTION: Treatment with Class III antiarrhythmic agents may lead to increased dispersion of repolarization and early afterdepolarizations (EADs), which are both likely substrates for torsades de pointes. Recent studies in vivo have shown that the prevalence of proarrhythmias induced by Class III agents may be reduced by Na(+)- or Ca(2+)-blocking agents. In the present study, tentative mechanisms for this protective effect were investigated in vitro. METHODS AND RESULTS: Transmembrane action potentials were recorded simultaneously from rabbit isolated ventricular muscle (VM) and Purkinje fibers (PF). At a basic cycle length (BCL) of 500 msec, the Class III agent almokalant (0.1 microM) increased the dispersion by prolonging the action potential duration (APD) significantly more in the PF (33% +/- 4.2%, n = 18) than in the VM (17% +/- 5.9%, n = 18, P < 0.05). In six of the preparations, addition of 1, 5, and 25 microM lidocaine reduced the almokalant-induced prolongation in a concentration-dependent manner mainly in the PF, thereby decreasing the dispersion. At 5 microM lidocaine, the remaining prolongation was 7% +/- 12.2% (P < 0.05 vs time controls) in the PF and 14% +/- 6.4% in the VM, respectively. In six other preparations, the addition of 0.01, 0.05, and 0.25 microM nisoldipine did not reduce the almokalant-induced prolongation in the PF and VM, but attenuated the spike-and-dome appearance of the action potential in the PF. In separate experiments performed at a BCL of 1000 msec, EADs developed in 2 of 6 and 5 of 6 PF during superfusion with almokalant (0.3 and 1 microM, respectively) at an APD of 828 +/- 41.4 msec. In six separate preparations pretreated with lidocaine (5 microM), the almokalant-induced prolongation in the PF was less pronounced and EADs were not observed. Pretreatment with nisoldipine (0.05 microM) did not influence the response to almokalant, and in 4 of 6 preparations the APD exceeded 1000 msec. Despite this extensive prolongation, EADs did not appear. CONCLUSION: At concentrations that did not affect the APD in the VM but reduced the APD in the PF, lidocaine suppressed almokalant-induced dispersion and the development of EADs. Nisoldipine, on the other hand, inhibited almokalant-induced EADs directly. Hence, the primary APD-prolonging effect of a Class III agent may be preserved, but the risk of proarrhythmias reduced, during concomitant treatment with low concentrations of a Na(+)- or Ca(2+)-blocking agent.

Rhythm anomalies related to delayed repolarization in vivo: influence of sarcolemmal Ca++ entry and intracellular Ca++ overload.

The present study examined how Ca++ entry and intracellular Ca++ overload may contribute to the appearance of torsades de pointes in the setting of delayed repolarization. In anesthetized rabbits, the infusion of methoxamine and the selective I kappa s blocker almokalant (8.8 micrograms/kg.min) was associated with a lengthening of the QTU interval (37 +/- 2.6 ms, P < .001) and the appearance of torsades de pointes in 9/10 rabbits. In rabbits pretreated with nisoldipine (7.7 or 37 micrograms/kg i.v.), the incidence of almokalant-induced torsades de pointes was reduced to 7/10 (P = .5820 vs. vehicle) and 1/10 (P = .0006) rabbits, respectively. This occurred without attenuating the QTU-prolonging effect of almokalant (47 +/- 7.0 ms and 56 +/- 8.6 ms, respectively). Likewise, pretreatment with flunarizine (0.5 or 3.0 mg/kg i.v.) reduced the incidence to 1/6 (P = .0076) and 0/6 animals (P = .0009), respectively. In 10 of the rabbits that were given nisoldipine or flunarizine and did not experience torsades de pointes with almokalant, BAY K 8644 (0.11 mg/kg) was injected. In six of these rabbits, BAY K 8644 promptly induced torsades de pointes. In four vehicle-pretreated rabbits that experienced torsades de pointes with almokalant, acute injection of nisoldipine (37 micrograms/kg) abruptly suppressed the proarrhythmia. In separate experiments, rabbits were treated with ryanodine or BAPTA-AM and were subsequently administered almokalant. Compared with the vehicle-pretreated rabbits, these interventions did not significantly reduce the incidence of torsades de pointes (from 6/5 rabbits to 3/8 and 3/8 rabbits, respectively, P = .1776). The results demonstrate that Ca++ entry through the L-type Ca++ channel may be of crucial importance for the induction of torsades de pointes in the acquired long QT syndrome.

Recording of monophasic action potentials in the horizontally perfused guinea pig heart. An in vitro method to study drug-induced changes in cardiac electrophysiology.

An in vitro technique has been developed for the recording of monophasic action potentials to enable the measurement of changes in the duration of repolarization and in rise time produced by known concentrations of drugs and ions. Guinea pig hearts were perfused horizontally at constant pressure (60 cm H2O) and temperature (37 degrees C) with Krebs-Henseleit buffer. Epicardial monophasic action potentials were recorded from the right ventricular base using a bipolar Ag/AgCl electrode to which a suction pressure of 400 mm Hg was applied. The monophasic action potential signals had smooth depolarization and repolarization phases with amplitudes of 25-65 mV; repeated measurements of monophasic action potential duration at the 50, 75, and 90% repolarization levels (MAPD 50, 75, and 90) and rise time, determined by computer analysis, were reproducible for at least 150 min of perfusion. There was an excellent linear correlation between heart rate and monophasic action potential duration. The ability of the method to detect drug-induced changes was confirmed using clofilium (10(-9) to 10(-5) M), which significantly prolonged monophasic action potential duration 50, 75, and 90 in a concentration-dependent manner, and tocainide (3 x 10(-4) M), which significantly decreased monophasic action potential duration 50, 75, and 90 and increased rise time.

QTU-prolongation and torsades de pointes induced by putative class III antiarrhythmic agents in the rabbit: etiology and interventions.

When low doses of clofilium were administered to conscious rabbits, ventricular tachyarrhythmia (VT) with features typical of torsades de pointes developed. This arrhythmia was further studied and characterized in chloralose-anesthetized rabbits. In 20 of 20 rabbits, VT developed after a mean cumulative dose of 0.53 +/- 0.04 mumol/kg clofilium, provided an infusion of the alpha 1-agonist methoxamine (15 micrograms/kg/min) was given concomitantly. The arrhythmia was preceded by a marked prolongation of the QTU interval and the monophasic action potential duration, as well as signs of early afterdepolarizations (EADs). In seven of 10 rabbits receiving only clofilium (cumulative dose, 20.8 mumol/kg), no VT occurred (p less than 0.001 compared to the incidence in animals given both methoxamine and clofilium). In animals given both methoxamine and clofilium, pretreatment with prazosin (1 mg/kg i.v., n = 4) attenuated the arrhythmia, whereas diltiazem (0.5 mg/kg i.v., n = 4) or propranolol (0.5 mg/kg i.v., n = 8) was ineffective. Acute intervention with prazosin, isoproterenol, pinacidil, or magnesium sulfate promptly regularized the rhythm in animals with VT. Prazosin and pinacidil were equally effective in beta-blocked rabbits. When other agents known to retard the repolarization currents (sematilide, UK-68,798, LY97119, amperozide, and cesium chloride) were examined, a strong correlation (r = 0.99, p less than 0.001) between the potency of the drug to prolong the QTU interval and the proarrhythmic potential was obtained. This experimental model may represent an appropriate alternative for studying the acquired ("pause-dependent') long QT syndrome.

Computerized evaluation of drug-induced changes in guinea-pig epicardial monophasic action potentials.

The monophasic action potential (MAP) has been widely used for the study of drug effects on cardiac repolarization in vivo. There is, however, no study of drug-induced effects on MAP depolarization, i.e. effects on MAP Vmax and/or MAP rise-time. For this study, we developed a method in the anesthetized open chest guinea-pig. MAP signals were recorded and subjected to on-line computerized analysis, in which parameters describing both depolarization and repolarization were calculated. With the MAP electrode kept at the same epicardial position the MAP rise-time did not vary with time. If the influences of heart rate were eliminated, the intra- and interindividual variation in the MAP duration was very low. Sotalol significantly and dose-dependently prolonged MAP duration, but did not affect rise-time, whereas tocainide significantly and dose-dependently shortened MAP duration and increased rise-time. The effect of tocainide on rise-time is most likely secondary to a reduction in conduction velocity due to a decrease in Vmax in the single cell action potential. These results suggest that monophasic action potential recordings coupled with an on-line computerized analysis may be used for rapid and simple evaluation of drug effects, both on cardiac depolarization and repolarization.

Effects of induced hypothermia on organ blood flow in a hibernator and a nonhibernator.

Regional blood flow and hemodynamic variables during induced hypothermia were compared in six guinea pigs and four hedgehogs. Tracer microspheres were used for blood flow measurements, since this technique is more accurate than the earlier method (86Rb+ distribution) used for cardiac output distribution measurements in hibernators. Heart rate and blood pressure decreased with reduced temperature in a comparable fashion in the two species, while cardiac output was less affected in the hedgehogs than in the guinea pigs. Total peripheral resistance increased in both species. At 34 degrees C the hedgehogs had a higher myocardial blood flow per gram tissue than the guinea pigs and it was not reduced in the hedgehogs when the body temperature was lowered to 22 degrees C, whereas in the guinea pigs it was markedly reduced. The brown adipose tissue of the hedgehogs showed a fourfold increase in blood perfusion at 22 degrees C when compared with 34 degrees C. In the hedgehogs the fractional distribution of cardiac output to the myocardium increased with decreasing body temperature, while the renal fraction decreased. In the guinea pigs, on the other hand, the fractional distribution of cardiac output to the myocardium remained unchanged but increased to the kidneys.

Effects of felodipine, a new dihydropyridine vasodilator, on regional myocardial blood flow during acute coronary occlusion in the pig.

We studied the effects of felodipine [4-(2,3-dichlorophenyl)-1,4-dihydropyridine-2,6-dimethyl 3,5-dicarboxylic 3-ethylester and 5-methylester] on the coronary vascular bed of pig hearts with an ischemic region in the left ventricle following ligation of the left anterior descending coronary artery. At an infusion rate of 0.12 nmol X kg-1 X min-1, felodipine caused a slight reduction in mean arterial blood pressure and a decrease in coronary vascular resistance in both normal myocardium and partly ischemic myocardium of the border zone. In another series of experiments, felodipine was infused at a higher rate (0.38 nmol X kg-1 X min-1). The resultant decrease in mean arterial blood pressure, which was about 30%, was counterbalanced by inflation of an aortic balloon to keep the afterload and the coronary perfusion pressure constant. In this situation, felodipine caused a pronounced increase in blood flow to all parts of the heart except the central ischemic zone, where blood flow was extremely low. We conclude that felodipine has a coronary vasodilator action which is at least of the same magnitude as its peripheral vasodilator action, and that it markedly increases coronary blood flow in the border zone of an ischemic area.