Avile McCullen

Electrophysiologic and hemodynamic effects of propafenone, a new antiarrhythmic agent, on the anesthetized, closed-chest dog: Comparative study with lidocaine

The relative hemodynamic and electrophysiologic effects of a new antiarrhythmic drug, propafenone, and lidocaine were evaluated in eight closed-chest, anesthetized dogs. Propafenone (4 mg/kg intravenously) significantly (p less than 0.05) lowered aortic and pulmonary systolic pressures and caused a rise in heart rate (p less than 0.05). Cardiac output decreased from 4.5 +/- 1 to 3.8 +/- 0.7 L/min (p less than 0.05) during atrial pacing at 400 msec cycle length. Propafenone had no effect on pulmonary and aortic diastolic pressures. Lidocaine (5 mg/kg intravenously) caused a significant (p less than 0.05) decrease in aortic systolic pressure and a rise in heart rate. Lidocaine had no significant effect on the other measured hemodynamic parameters. Propafenone, unlike lidocaine, significantly (p less than 0.05) increased atrioventricular nodal functional refractory period and right ventricular endocardial (apex) cathodal (0.5 +/- 0.1 mA to 1.9 +/- 0.3 mA) and bipolar (1.4 +/- 0.3 to 2.2 +/- 0.4 mA) diastolic excitability threshold. Propafenone, unlike lidocaine, also caused a significant (p = 0.05) intraatrial conduction delay; however, neither drug caused conduction slowing in the His-Purkinje system. Both drugs had no effect on sinus nodal recovery time and on the effective refractory period of the right ventricular endocardium (apex). Mean plasma propafenone levels during hemodynamic and electrophysiologic measurement ranged between 3.2 +/- 1.8 micrograms/ml and 1.7 +/- 1.1 micrograms/ml. All of the propafenone-induced effects were reversible within 90 minutes. We conclude that propafenone differs from lidocaine in its atrial, AV nodal, and ventricular electrophysiologic properties, and thus these may explain propafenones greater efficacy over lidocaine against both certain atrial and ventricular arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular Effects of Nicotine in the Conscious Dog Modification by Changes in Autonomic Tone

Studies were performed in conscious dogs in which catheters had previously been positioned for long-term use in the right atrium, right ventricle, pulmonary artery and central aorta. Doses of less than 200 μ g of nicotine injected into the right atrium produced no significant hemodynamic effects. A dose of 200 μ g of nicotine produced initial tachycardia, a subsequent hypertensive response and reflex bradycardia. A 400 μ g dose of nicotine produced a triphasic response: (1) a 2 to 4 second sinus arrest, (2) subsequent sinus tachycardia and marked hypertensive response, and (3) reflex bradycardia with persistent increases in right ventricular end-diastolic pressure. Arterial administration of nicotine in similar doses produced only hypertension and reflex bradycardia. No asystole or tachycardia was observed. Pretreatment with atropine eliminated the asystole produced by intravenous administration of nicotine but did not alter the reflex tachycardia occurring after intravenous or intraarterial administration of nicotine. Pretreatment with propranolol did not prolong the asystole occurring after intravenous administration of nicotine and did not diminish the peak increase in heart rate during phase 2. However, the reflex bradycardia was more pronounced after nicotine was given either intravenously or intraarterially. We conclude that, in the conscious dog, nicotine (1) releases acetylcholine in the right atrium, (2) may depress myocardial function, and (3) produces significant hypertension and reflex bradycardia.

Spontaneous ventricular tachycardia associated with isolated right ventricular infarction, one day after right coronary artery occlusion in the dog: Studies on the site of origin and mechanism

The electrophysiologic and arrhythmic properties of isolated infarcted right ventricle (RV) were studied in 17 dogs during the first 24 hours after complete occlusion of the right coronary artery (RCA). During the 16-to-20-hour post occlusion period, spontaneously occurring sustained monomorphic ventricular tachycardia (VT) was present in all 17 dogs. Overdrive ventricular pacing (cycle lengths 200 to 250 msec) caused significant suppression of the VT when the rate of the VT was slower than 150 bpm (range 120 to 145 bpm) (n = 9), but had negligible effect when VT rate was higher than 150 bpm (range 160 to 245 bpm (n = 8). Overdrive pacing could not terminate either the slow or the fast type of VT. Bipolar intramural electrograms have showed electrical activity in the infarcted RV zone to precede Q wave of the VT by 15.4 +/- 5.8 msec regardless of VT rate. Microelectrode studies on isolated RV endocardial infarcted tissues 24 hours after RCA occlusions have shown the presence of spontaneous repetitive activity at a rate of 87 +/- 47 bpm, which was overdrive suppressed in dogs with slow VT, and spontaneous activity at a rate of 115.2 +/- 36 bpm (p less than 0.05) which was not overdrive suppressed in dogs with fast VT. Maximum diastolic potential, action potential amplitude, and Vmax of surviving subendocardial Purkinje fibers (SEPF) in the infarct zone were slightly but significantly depressed (p less than 0.05), and they manifested enhanced phase 4 depolarization, giving rise to automatic impulse initiation. Although action potential duration of these fibers was somewhat prolonged (p less than 0.05), no conduction delay occurred. Histopathologic examinations have shown necrosis of the basal two thirds of the RV, with no left ventricular involvement. Electron microscopy revealed lipid accumulation in the surviving SEPF as the sole abnormality. We conclude (1) that occlusion of the RCA in the dog is associated with high survival rate despite extensive necrosis involving exclusively the RV and (2) that VT seen during the 20 to 24 hours after occlusion arise in the infarcted zone of the RV, by an enhanced automatic mechanism in the surviving SEPF, possibly caused by cytoplasmic lipid accumulation. This model, by virtue of its high survival rate and frequency of late VTs, should be useful in providing clues to determine factors involved in the genesis of early VT/VF and for the evaluation of new pharmacologic agents during the 20- to 24-hour VT period.

Electrophysiologic effects of bretylium on canine ventricular muscle during acute ischemia and reperfusion

Electrophysiologic effects of bretylium were assessed on a recently developed animal model for analysis of conduction of premature impulses and excitation threshold. Bretylium was administered intravenously 10 mg/kg over 10 minutes followed by 2 mg/min of infusion immediately after coronary ligation. Conduction of the premature impulse was recorded in the epicardial and endocardial sites both in the base-to-apex and apex-to-base directions, in the normal, in the center, and across the border of ischemic myocardium. Compared to the control group of animals, bretylium did not cause any significant change in the conduction characteristics in the ischemic myocardium; however, it delayed the conduction of premature impulses in the normal myocardium. Thus the disparity in conduction times between the normal and the ischemic myocardium was lessened by bretylium. Further, conduction of impulses from normal tissue across the border of ischemia was also delayed. Bretylium also decreased the excitability threshold in the ischemic myocardium, although the normal myocardial excitation threshold was unaffected. These unique effects of bretylium on conduction and excitability in the normal, in the center, and across the border of ischemic myocardium, when a therapeutic dosage of the drug is used, further validate its antiarrhythmic potential and offer an insight into its mechanism of action in the setting of acute myocardial ischemia.

Effects of nifedipine on conduction delay during ventricular myocardial ischemia and reperfusion

Nifedipine has been suggested to have more potent slow channel blocking action than other agents of this type. However, its use in the treatment of cardiac arrhythmias has been limited. Electrophysiologic studies on AV conduction have shown that nifedipine lacks any significant effect. However, the action of the drug on intraventricular conduction has not been investigated with regard to its potential in the treatment of ventricular arrhythmias especially during ischemia. Therefore, the effects of nifedipine on conduction delay during ischemia and reperfusion were assessed in the present study. Sixteen dogs (eight control and eight nifedipine-treated dogs) were used. Transmural electrodes were positioned in normal, ischemic, and reperfused tissue, and at the border of these segments. The left anterior descending artery was initially ligated below the second diagonal branch (first ligation) and 30 minutes later below the first diagonal branch (second ligation); the second ligation was released 30 minutes later. Conduction of electrically induced premature impulses from the midwall of the left ventricle was recorded at epicardial and endocardial sites. Conduction delay was measured from the stimulus artifact to the first high-frequency deflection in each zone in the anterograde (base to apex) and retrograde (apex to base) directions. Intravenous nifedipine 0.1 mg/kg was given over 10 minutes immediately after the first ligation. Nifedipine slightly decreased the magnitude of conduction delay in the ischemic myocardium at 15 minutes of ischemia, which corresponded with the peak plasma nifedipine level. However, conduction delay throughout the remainder of the study was essentially unaltered by nifedipine. In conclusion, though nifedipine may improve ischemic myocardial metabolism, infarct size, and hemodynamics, the effect on the electrophysiologic parameters affecting conduction was insignificant. This lack of any further deterioration in conduction in the ischemic and reperfused tissue by the drug further attests to its safety during acute myocardial ischemia.

Effect of Renin and Plasma Protein Loading on Albumin Catabolism in the Isolated Perfused Kidney.

Summary Using the isolated perfused rabbit kidney preparation, the relationship between proteinuria and albumin catabolism was studied in the absence of all other tissues and humoral substances of the body. The rate of breakdown of I131 screened rabbit albumin was studied in both the normal and the proteinuric perfused kidney. Proteinuria was produced in the normal perfused kidney by administration of renin or by elevation of the plasma protein concentration of the perfusion media. It was found that albumin catabolism was markedly increased in the perfused kidney during renin and protein loading proteinuria.

Effect of ouabain and potassium on isolated perfused rabbit kidney.

Summary The effect of various doses of ouabain was studied on the isolated perfused kidney. A pronounced and consistent diuresis and natriuresis did not occur until a dose of 0.085 mg of ouabain was used. Within 2-20 min after the administration of ouabain, renal vascular resistance increased causing an increase in perfusion pressure and a reduction in renal blood flow, urine excretion, sodium excretion, and creatinine clearance. Plasma potassium always rose after the administration of ouabain. At 20-60 min after the addition of ouabain renal vascular resistance fell, causing the perfusion pressure to return to normal. There was an increase in renal blood flow, urine excretion (+220%) p<0.01 sodium excretion (+215%) p< 0.02 and the creatinine clearance returned to normal. Plasma potassium remained elevated. When potassium chloride (KCl) was added to the perfusion after 3-4 control periods, the plasma K level was raised from an average of 4.9 meq/liter to 8.6 meq/liter and leveled off at 8.1 to 7.8 meq/liter after the addition of ouabain. A diuresis and natriuresis was also produced by the addition of KCl, but when 0.085 mg of ouabain was added 20-40 min after the addition of KCl, even greater diuresis (+147%) p<0.001 and natriuresis (+138%) p<0.01 were produced. There was little evidence for a K-induced inhibition of the ouabain diuresis and natriuresis.