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The aims of this report are firstly to raise awareness among kineticists and pharmacologists as to why pharmacokinetic-pharmacodynamic (PKPD) integration is essential for target validation (TV), optimizing development of lead compounds (lead generation [LG] and lead optimization [LO]) and scaling these to human. A related aim is to demonstrate strategic examples of PKPD collaborations that have improved the planning, execution and evaluation of experiments in primary and safety pharmacology. Examples include design of TV studies, design and data 'pruning' of PKPD studies in LO, analysis of data with marginal and substantial temporal (time) differences between exposure and response, design of safety pharmacology studies, assessment of safety margin and assessment of uncertainties in predictions of first dose in human.

Cardiovascular diseases are the leading cause of mortality worldwide and about 25% of cardiovascular deaths are due to disturbances in cardiac rhythm or "arrhythmias". Arrhythmias were traditionally treated with antiarrhythmic drugs, but increasing awareness of the risks of presently available antiarrhythmic agents has greatly limited their usefulness. Most common treatment algorithms still involve small molecule drugs, and antiarrhythmic agents with improved efficacy and safety are sorely needed. This paper reviews the model systems that are available for discovery and development of new antiarrhythmic drugs. We begin with a presentation of screening methods used to identify specific channel-interacting agents, with a particular emphasis on high-throughput screens. Traditional manual electrophysiological methods, automated electrophysiology, fluorescent dye methods, flux assays and radioligand binding assays are reviewed. We then discuss a variety of relevant arrhythmia models. Two models are widely used in testing for arrhythmogenic actions related to excess action potential prolongation, an important potential adverse effect of chemical entities affecting cardiac rhythm: the methoxamine-sensitized rabbit and the dog with chronic atrioventricular block. We then go on to review models used to assess potential antiarrhythmic actions. For ventricular arrhythmias, chemical induction methods, cardiac or neural electrical stimulation, ischaemic heart models and models of cardiac channelopathies can be used to identify effective antiarrhythmic agents. For atrial arrhythmias, potentially useful models include vagally-maintained atrial fibrillation, acute asphyxia with atrial burst-pacing, sterile pericarditis, Y-shaped atria surgical incisions, chronic atrial dilation models, atrial electrical remodelling due to sustained atrial tachycardia, heart failure-related atrial remodelling, and acute atrial ischaemia. It is hoped that the new technologies now available and the recently-developed models for arrhythmia-response assessment will permit the introduction of newer and more effective antiarrhythmic therapies in the near future.

Introduction: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles., Method: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms)., Results: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording., Discussion: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.

AZD7009 (tert-Butyl-2-(7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethylcarbamate) is an antiarrhythmic agent that increases atrial refractoriness, shows high antiarrhythmic efficacy and has low proarrhythmic potential. This study was primarily undertaken to determine the effects of AZD7009 on the late sodium current and to examine the impact of late sodium current inhibition on action potential duration in various myocardial cells. AZD7009 inhibited the late sodium current in Chinese Hamster Ovary K1 (CHO K1) cells expressing hNa(v)1.5 with an IC(50) of 11+/-2 microM. The late sodium current in isolated rabbit atrial and ventricular myocytes was also concentration dependently inhibited by AZD7009. Action potentials were recorded during exposure to 5 microM E-4031 (1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine), a compound that selectively inhibits the rapid delayed rectifier potassium current (I(Kr)), and to E-4031 in combination with AZD7009 or lidocaine in rabbit atrial and ventricular tissue and Purkinje fibres. In Purkinje fibres, but not in ventricular tissue, AZD7009 and lidocaine attenuated the E-4031-induced action potential duration prolongation. In atrial cells, AZD7009, but not lidocaine, further prolonged the E-4031-induced action potential duration. E-4031 induced early afterdepolarisations (EADs) in Purkinje fibres, EADs that were totally suppressed by AZD7009 or lidocaine. In conclusion, excessive action potential duration prolongation induced by E-4031 was attenuated by AZD7009 and lidocaine in rabbit Purkinje fibre, but not in atrial or ventricular tissue, most likely by inhibiting the late sodium current. Furthermore, the opposite effect by AZD7009 on action potential duration in atrial tissue suggests that AZD7009, in addition to inhibiting I(Kr), also inhibits other repolarising currents in the atria.

Introduction: Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model., Methods: The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval-heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval., Results: After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54+/-9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval., Discussion: To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval-heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.

Introduction: To assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety., Method: On two separate occasions, four male and two female beagle dogs were given vehicle or the test substance, dofetilide (0.25 mumol/kg), over a 3-h intravenous infusion. Cardiovascular parameters, including QT intervals, were recorded for 24-h using radiotelemetry. The QT interval was corrected individually for heart rate, vehicle treatment, and serial correlation (QT(c)). Exposure (plasma concentration) to dofetilide was measured and described by a two-compartment model. The individual concentration-time course of dofetilide was linked to the QT(c) interval via an effect compartment and a pharmacodynamic E(max) model, to account for the observed hysteresis., Results: Dofetilide induced a concentration-dependent increase in the QT(c) interval, with an EC(50) of 9 nM (3-30 nM, 95% C.I.) and an E(max) of 59+/-9 ms. A hysteresis loop was observed by plotting plasma concentrations vs. QT interval in time order, indicating a delay in onset of effect. It was found to have an equilibrium half-life of 11+/-8 min. Based on the parameters potency and E(max), a representation was made of the drug-induced changes to the QT interval., Discussion: An effect compartment model was found to accurately mimic the QT interval prolongation following administration of the test substance, dofetilide. The assessment of the individual concentration-effect relationship and confounding factors such as hysteresis might provide a better prediction of the safety profiles of new drug candidates.

AZD7009 is a novel antiarrhythmic compound in early clinical development for management of atrial fibrillation. Electrophysiological studies in animals have shown high antiarrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. AZD7009 has previously been shown to inhibit hERG and hNav1.5 currents. The main objective of the present study was to characterize the effects of AZD7009 on hKv1.5 and hKv4.3/hKChIP2.2 currents to get a deeper understanding of the ion channel-blocking properties of the compound. hKv1.5 and hKv4.3/hKChIP2.2 currents were expressed in CHO cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited hKv1.5 and hKv4.3/hKChIP2.2 currents with equal potency: the IC50 for hKv1.5 block was 27.0 +/- 1.6 muM (n = 6), and the IC50 for hKv4.3/hKChIP2.2 block was 23.7 +/- 4.4 muM (n = 5). Block of the hKv4.3/hKChIP2.2 current was frequency dependent with larger block at higher frequency, whereas block of the hKv1.5 current was slightly decreased at higher frequency. In conclusion, AZD7009 inhibits both the hKv1.5 and the hKv4.3/hKChIP2.2 currents. These effects likely contribute to the effects described in animals in vivo.

Introduction: AZD7009 is a novel anti-arrhythmic compound under development for short- and long-term management of atrial fibrillation and flutter. Electrophysiological studies in animals have shown high anti-arrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. The main aim of this study was to characterize the blocking effects of AZD7009 on the human ether-a-go-go-related gene (hERG), the hNav1.5, and the hKvLQT1/hminK currents., Methods and Results: hERG, hKvLQT1/hminK, and hNav1.5 were expressed in CHO K1 cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited the hERG current with an IC50 of 0.6 +/- 0.07 microM (n = 6). AZD7009 1 microM hyperpolarized the potential for half-maximal activation from -8.2 +/- 0.1 mV to -18.0 +/- 0.6 mV (P < 0.001, n = 14) and induced pre-pulse potentiation at potentials near the activation threshold. The hNav1.5 current was blocked with an IC50 of 4.3 +/- 1.20 microM at 10 Hz (n = 6) and block developed use-dependently. Recovery from use-dependent block was slow, tau= 131 seconds. AZD7009 inhibited the hKvLQT1/hminK current only at high concentrations (IC50= 193 +/- 20 microM, n = 6)., Conclusion: AZD7009 inhibits both the hERG and the hNav1.5 current, and it is most likely this combined current block that underlies the prolongation of the refractoriness and the low proarrhythmic activity demonstrated in animals in vivo.

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.

In the present study the electrophysiological characteristics and the proarrhythmic potential of cisapride and a structurally related drug, mosapride, were compared. In the anesthetized guinea pig, cisapride and d-sotalol (0.01-10 micromol/kg i.v., n = 6) dose-dependently prolonged the duration of the monophasic action potential recorded from the left ventricle. The maximal lengthening was 18 +/- 3.2% at 1.0 micromol/kg (mean +/- S.E.M., P < .01 vs. base line) and 19 +/- 2.5% at 10 micromol/kg (P < .001) for cisapride and d-sotalol, respectively. In contrast, mosapride did not increase this variable. In a rabbit model of the acquired long QT syndrome, infusion of cisapride (0.3 micromol/kg/min for 10 min maximum, n = 6), but not mosapride or vehicle, was associated with a significant lengthening of the QTU interval (43 +/- 3.8 ms, P < .01). Furthermore, torsades de pointes appeared in two of the six rabbits given cisapride. In isolated rabbit Purkinje fibers (PF), cisapride increased the action potential duration (48 +/- 5.6% at 0.1 micromol/l, P < .01 vs. control, n = 4). Mosapride did not significantly influence the action potential duration (3 +/- 2.0% increase at 1.0 micromol/l, n = 6). However, after mosapride was washed out, the addition of cisapride (0.1 micromol/l) caused a 46 +/- 3.2% lengthening of the action potential duration (P < .01 vs. 1.0 micromol/l mosapride). Early afterdepolarizations and triggered activity appeared in four of eight cisapride-superfused PF stimulated at a very low frequency (0.1 Hz). In isolated rabbit cardiomyocytes, cisapride concentration-dependently blocked (IC50 = 9 nmol/l) the rapid component of the delayed rectifying K+ current (I(Kr)). Mosapride was approximately 1000-fold less potent in blocking I(Kr) (IC50 = 4 micromol/l). It is concluded that the electrophysiological characteristics of cisapride may explain the recently reported propensity to prolong the QT interval and to induce torsades de pointes in susceptible patients, although a structurally related benzamide, mosapride, did not appear to have electrophysiological features of relevance for induction of torsades de pointes in common with cisapride.

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.

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 electromechanical properties of H 234/09 (Almokalant), a novel class III antiarrhythmic agent, was examined in isolated human ventricular muscle strips excised from patients undergoing mitral valve replacement. Using transmembrane microelectrode recording techniques, we demonstrated that H 234/09 markedly prolonged the action potential duration (APD) without affecting the maximal rate of depolarization or action potential amplitude. At 75 and 90% repolarization APD was prolonged to a similar extent, whereas the lengthening at 50% repolarization was somewhat less marked. In isometrically contracting muscle strips, H 234/09 increased peak developed force and its maximal rate of rise (dF/dt) and fall (-dF/dt) in a concentration-dependent manner, whereas time to peak developed force was unaltered. We conclude from these studies that H 234/09 is a class III agent in human ventricular muscle and that the class III effect is linked with a positive inotropic response.

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.

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 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.

Previous studies have shown that there are differences between hibernators and nonhibernators in the susceptibility to ventricular fibrillation. In an attempt to clarify these differences ventricular fibrillation was induced in isolated hearts of the hibernator, the woodchuck, Marmota monax by cooling, warming, puncture, and by norepinephrine administration. It was shown that the hearts of the winter animals were completely resistant toward the ventricular fibrillation inducing agents, which was not the case for the hearts from summer, active animals. Further, the hearts of another hibernator, the hedgehog, Erinaceus europaeus, and guinea pig, Cavia porcellus, were studied electrophysiologically in anesthetized animals with open chests and with bipolar electrodes attached to the epicardium. During pacing it was shown that the hedgehog had a higher stimulus threshold and a lower maximal following frequency than the guinea pig. The summer hedgehogs showed resistance toward both ventricular premature beats and ventricular fibrillation. Sixty percent of the summer hedgehogs and 100 percent of the winter hedgehogs and guinea pigs developed ventricular fibrillation. The threshold for ventricular fibrillation was highest for summer hedgehogs. The effective refractory period of papillary muscle of summer hedgehogs was shorter than that of guinea pigs. The force frequency relationship of the isolated papillary muscle showed a greater degree of independence in the hedgehog than in the guinea pig. Consequently, the results show that the heart of the hibernator is more arrhythmia resistant than the heart of the nonhibernator, although there are seasonal differences.

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.

The effect of two dihydropyridine derivatives, nifedipine and felodipine, on myocardial blood flow distribution 1 h after ligation of the left anterior descending coronary artery (LAD) was studied in open-chest dogs by means of radioactive microspheres. The myocardium normally perfused from the LAD was first labeled with 125I-labeled microspheres injected directly into the LAD before ligation. Microspheres used for blood flow measurements were given in the left atrium. An intravenous infusion rate of 0.3 nmol/kg/min felodipine slightly depressed mean aortic blood pressure (approximately 5 mm Hg) and decreased coronary vascular resistance in normal myocardium. Nifedipine, at three times the dose of felodipine, had a comparable hypotensive effect, but the decrease in coronary vascular resistance was not statistically significant. The two dihydropyridines were also compared in a dose range that was four times higher. The mean arterial blood pressure reduction (approximately 30% for both drugs) was counterbalanced by inflation of an intraaortic balloon to avoid a drastic decrease in afterload and coronary perfusion pressure. Under these circumstances, felodipine and nifedipine decreased coronary vascular resistance and increased blood flow to nonischemic myocardium comparably. However, in severely ischemic, truly collateral-dependent myocardium without admixture of interdigitating healthy myocardium, the blood flow was unaffected after administration of both felodipine and nifedipine. Although felodipine was three times more potent than nifedipine with regard to vasodilatation in the normal myocardium, the difference in vascular selectivity between the two agents did not influence the effect on the "true" collateral blood flow in acute myocardial ischemia.

The antiarrhythmic effects of dl'propranolol, d-propranolol, metoprolol and lidocaine against ouabain-induced cardiac arrhythmias were studied. It was found that contrary to earlier findings in the dog, the effects of the adrenergic beta-blockers against ouabain-arrhythmias in guinea pigs were due to beta-blocking activity and not the membrane-stabilizing activity of the compounds. The cardioselective beta-blocker, metoprolol, was more or equally effective as dl-propranolol against ouabain-induced arrhythmias in guinea pigs.

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.