The effect of haloperidol on ventricular fibrillation threshold in pigs.

Ventricular fibrillation has been observed in association with the administration of haloperidol. This study was designed to determine the effect of intravenous haloperidol on ventricular fibrillation threshold (VFT). VFT's were determined prior to and 15 min. following an intravenous infusion of haloperidol (50 mg administered over 10 min.) in five pigs anaesthetized with alpha-chloralose. VFT's were determined using a single stimulus method. Mean arterial pressure (MAP), heart rate (HR), and electrocardiogram (ECG) were monitored continuously. Mean VFT (mA) at baseline and following haloperidol infusion was 50.2 +/- 4.6 and 65.1 +/- 12.8, respectively (P less than 0.05). Mean MAP (mmHg) at baseline and following haloperidol infusion was 127 +/- 32 and 107 +/- 23, respectively (P less than 0.05). Haloperidol infusion did not significantly influence mean HR, QRS duration or corrected QT interval. Intravenous haloperidol increases VFT and decreases MAP in pigs. In this model, haloperidol may offer protection against ventricular fibrillation. Further study is required to determine the clinical significance of the antifibrillatory effect of haloperidol.     

Effects of encainide (MJ9067) on the ventricular fibrillation threshold in anesthetized dogs

The right ventricular epicardial ventricular fibrillation threshold (VFT) was determined during paced supraventricular rhythm using 100 Hz trains of stimuli at 15 min intervals in dogs before and during the intravenous administration of encainide, a new antiarrhythmic drug. With each VFT determination, simultaneous blood samples were obtained for determination of drug concentration. In 6 control dogs, VFT determined every 15 min during a 210 administered as a 90 min intravenous infusion at three successive rates (0.01, 0.02 and 0.04 mg/kg/min) for 30 min each. VFT measured at 5 and 20 min of each infusion increased from a mean control of 11.5 +/- 1.5 (+/-SE) to 20.2 +/- 2.2 mA (p less than 0.01) after 20 min of the third infusion. The maximal effect occurred during the second infusion with plasma concentration of 594 +/- 46 ng/ml and then reached a plateau. In group II (n = 6), encainide was administered in four successive sequences, each one including a bolus loading intravenous dose followed by a 45 min intravenous infusion. VFT measured at 30 and 45 min of each infusion when the encainide plasma concentration was close to a steady state increased significantly (p less than 0.01) after the second infusion from 11.8 +/- 2 to 27.3 +/- 4 mA. Two dogs in group II developed transient complete atrioventricular block at an encainide plasma concentration of greater than 800 ng/ml. These results show that the new antiarrhythmic drug encainide increases the VFT in anesthetized dogs.     

Effect of esmolol on the ventricular fibrillation threshold

The effect of esmolol on the ventricular fibrillation threshold (VFT) was determined in 11 open-chest dogs anesthetized with sodium pentobarbital. Since changes in VFT by antiarrhythmic drugs have been shown to depend on the method used to test vulnerability to fibrillation, two methods were studied. The vulnerable period was scanned with a train of pulses (100 Hz, 4 ms, 20 pulses) in nine experiments and a single pulse (10 ms) in eight experiments. Following control measurements, esmolol was administered as an intravenous bolus of 500 micrograms/kg followed by a continuous infusion of 300 micrograms/kg/min. After 15 min of infusion, the adequacy of beta-blockade was tested by the administration of 0.5 micrograms/kg of isoproterenol. Isoproterenol increased the heart rate by only 18 +/- 2 beats/min following esmolol administration which was significantly less than the control response (79 +/- 7 beats/min, p less than 0.01). Although the VFT measured with the single-pulse technique did not change in response to esmolol (14.1 +/- 1.1 mA vs. 14.3 +/- 1.2 mA), the VFT measured with the train-of-pulses technique significantly increased (3.7 +/- 0.5 mA to 14.5 +/- 2.8 mA, p less than 0.01). Twenty minutes after discontinuing esmolol, the VFT measurements were repeated and did not differ from control values with either technique. The increase in heart rate in response to isoproterenol also returned to control values (80 +/- 6 beats/min). The results suggest that the ability of esmolol to raise VFT as measured by the train-of-pulses technique is due to beta-adrenergic blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intravenous azimilide on cardiac performance, fibrillation threshold, and hemodynamics in anesthetized dogs

The class III antiarrhythmic azimilide (E-1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]-amino]-3-[4-(4-methyl-1- piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride; WHO No. 7299, CAS 149888-94-8), by slow infusion or stepwise bolus doses, was evaluated for effects on heart rate, blood pressure, and cardiac pump function, excitability, and refractoriness in anesthetized dogs. Infusion (0.6 mg/kg/min) in male beagles (n = 5) to a maximum dose of 54 mg/kg increased QTc more than 20 ms at 2.0 mg/kg. At a dose of 8.9 mg/kg i.v., QTc increased 34% above baseline and remained elevated throughout the subsequent infusion and for at least 60 min postinfusion. At this maximum class III dose, azimilide increased heart contractile force (HCF) 10% and +dP/dt 34% and decreased heart rate (HR) 12%, without significantly changing mean blood pressure (MBP), left ventricular end diastolic pressure, -dP/dt, stroke volume (SV), or cardiac output (CO). At the mean maximum 47 mg/kg i.v. dose, QTc remained elevated, but decreases were observed in HCF (-27%), +dP/dt (-24%), -dP/dt (-35%), SV (-16%), and CO (-52%). Cumulative intravenous bolus injections of azimilide (0.3, 1, 3, 10, and 30 mg/kg) in male mongrels (n = 5) increased effective refractory period (ERP) and +dP/dt (18% and 16%, respectively, at 10 mg/kg) as a function of dose and significantly decreased HR (-22% at 10 mg/kg). MBP decreased significantly (-23%) only at the highest dose. Ventricular fibrillation threshold (VFT) was unchanged at 30 mg/kg. Effects of dl- (n = 3) and d-sotalol (n = 4) on ERP and HR were similar to azimilide's, but both compounds caused a greater MBP depression and VFT elevation. These results suggest that azimilide is well tolerated by the cardiovascular system, providing an increase in contractility and a slight decrease in HR at intravenous doses that produced a large or maximum increase in cardiac refractoriness.     

The Effect of Cocaine on Ventricular Fibrillation Threshold in the Normal Canine Heart

We determined the effect of cocaine on ventricular vulnerability to fibrillation, as measured by ventricular fibrillation threshold (VFT), and cardiac electrophysiology in 20 anesthetized dogs with normal hearts. Animals were randomized in blinded fashion to receive a continuous 3-hour infusion of cocaine 0.11 mg/kg/minute (total dose 20 mg/kg) or placebo (lactose dissolved in normal saline). The VFT, systolic and diastolic blood pressures, ventricular effective refractory period (ERP), and electrocardiographic intervals were measured at baseline and every 30 minutes during infusion. Baseline mean ± SE VFT in cocaine and placebo groups was 57.0 ± 7.8 and 51.8 ± 7.6 må, respectively (p=0.64). Cocaine did not significantly decrease VFT, but actually increased it (i.e., reduced ventricular vulnerability to fibrillation) compared with placebo (84.6 ± 10.4 vs 55.8 ± 7.2 må, respectively, at 150 minutes, p=0.04). Cocaine prolonged ERP and PR, QRS, QT, QT_c, JT, and JT_c intervals. Cocaine does not increase ventricular vulnerability to fibrillation in anesthetized dogs with normal intact hearts. Its electrophysiologic effects are similar to those of class I antiarrhythmic agents in this model.     

The effect of amiodarone on the ventricular fibrillation threshold.

We evaluated the antifibrillatory effect of two different doses of amiodarone after cardiac arrest with a cardiopulmonary resuscitation (CPR) model in 19 pigs. Ventricular fibrillation was induced by pacing the right ventricle using a primary drive train at a cycle length of 270 msec for 8 beats. The minimum current strength necessary to induce sustained ventricular fibrillation was defined as the ventricular fibrillation threshold (VFT) measured in mA. Three VFT determinations were made at baseline, followed by 9 minutes of continuous CPR with two determinations of VFT, and three after stabilization. The pigs were placed into one of three groups: amiodarone 2 or 5 mg/kg, or placebo. The average poststabilization VFT in each group was compared with the average baseline VFT. Pigs receiving amiodarone 2 mg/kg had significantly higher VFT after stabilization than at baseline (22.88+/-12.76 to 27.10+/-10.18 mA, p=0.048), as did those receiving 5 mg/kg (17.03+/-7.01 to 28.08+/-11.58 mA, p=0.002). The deltaVFT was significantly greater with amiodarone 5 mg/kg than with vehicle (placebo), but not with 2 mg/kg. There were no changes in VFT in any group during CPR versus baseline. When active treatments were combined, the trend was toward better survival in the amiodarone groups (13/13) compared with the placebo group (4/6, p=0.076).     

Change of a beneficial effect into an untoward effect by ischaemia: effect of quinidine-like drugs on vulnerability to ventricular fibrillation

The effects of three quinidine-like drugs, disopyramide, lidocaine and flecainide were investigated in anaesthetized, open-chest pigs on vulnerability to ventricular fibrillation under normal conditions and under myocardial ischaemia conditions. Vulnerability to fibrillation was evaluated by electrical ventricular fibrillation threshold (VFT), measured with 100 ms duration diastolic impulses the intensity of which was increased by steps of 1.0 or 0.5 mA. Impulses were delivered at the rate of 180 beats · min(-1). The ventricles were subjected to pacing at the same rate before the VFT determination, particularly throughout periods of ischaemia of increasing duration (30, 60, 90, 120, 150 s), separated by appropriate intervals for reproducibility of the results. Monophasic action potential (MAP) duration and conduction time were monitored in the ischaemic area under pacing. Ischaemia was obtained by complete occlusion of the left anterior descending coronary artery near its origin. The three drugs were i.v. administered in clinical dose range (1.00 mg · kg(-1) plus 0.04 mg · kg(-1) · min(-1)). In the absence of ischaemia, they increased almost equally VFT (from about 7 to 10 mA), despite 25% prolongation of conduction time. But, none of them was able to impede the increasingly marked fall of VFT caused by ischaemia: at 30 s, they had already lost any capacity for raising VFT and, beyond this time, they even aggravated its fall which led to spontaneous fibrillation when VFT approached 0 mA. The faster fall of VFT shortened time to onset of fibrillation (20 24 fibrillations for the three drugs at 150 s as against 12 24 in control period), the ischaemia-induced reduction of MAP duration (by 20%) being also hastened and slowing of conduction enhanced, given the addition of the depressant effects of ischaemia and drugs on conduction. Consequently, the antifibrillatory properties normally manifested by the studied drugs are first suppressed, then inverted by ischaemia.     

Prophylactic lidocaine: concentrations in plasma and myocardial tissue and antifibrillatoric efficacy during early ischemia in dogs and pigs

We investigated the antifibrillatoric efficacy of lidocaine and the time courses of lidocaine concentrations in plasma and nonischemic (NIM) and ischemic myocardium (IM) during early myocardial ischemia in anesthetized dogs and pigs. Lidocaine (2 or 3 mg/kg bolus + 50, 100, 150, or 500 micrograms/kg.min) was administered over 30 min to 29 dogs and 15 pigs. The left anterior descending coronary artery (LAD) was occluded 2 min after bolus application. Blood and myocardial biopsies were sampled for analysis by high-performance liquid chromatography (HPLC) up to 40 min. In 19 dogs and 6 pigs, we determined the ventricular fibrillation threshold (VFT) with and without lidocaine during acute LAD occlusion for 7-13 min. Dosages leading to therapeutic plasma levels (1.6-4.2 micrograms/ml) resulted in lidocaine concentrations always highest in the IM (IM greater than NIM greater than plasma). Under identical dosages, all lidocaine levels were higher in pigs than in dogs. The IM concentrations decreased less in the pigs. Lidocaine prevented the ischemic drop in VFT and spontaneous fibrillation only at persistent IM concentrations greater than 8 micrograms/g. With therapeutic dosages, this was achieved only in pigs, occluding the LAD as early as 2 or 10 min after bolus application. Lidocaine prophylaxis with clinically recommended dosages in humans will hardly result in myocardial concentrations sufficiently high to be antifibrillatorically effective during early acute ischemia.     

A comparison of the antifibrillatory effects of desethylamiodarone to amiodarone in a swine model.

We evaluated the effect of two different doses of desethylamiodarone (DEA) and amiodarone on the ventricular fibrillation threshold (VFT). We ascertained the VFT in 24 pigs randomized to intravenous DEA, amiodarone, or vehicle. Ventricular fibrillation was induced by pacing the right ventricle by using a primary drive train at a cycle length of 270 ms for eight beats of 2-ms duration each. A secondary train of 20 pulses of 4-ms duration (100 Hz) immediately followed this over a total duration of 200 ms synchronized to the primary drive train. The intensity of the secondary train stimuli current was initially 2 mA and was increased by 2-mA increments until sustained VF with hemodynamic collapse was induced. The minimal current strength needed to induce sustained VF was defined as the VFT measured in mA. DEA (10 mg/kg) increased the VFT significantly over baseline from 13.5+/-4.9 to 23.2+/-8.8 mA (p = 0.0076). Amiodarone, 10 mg/kg, increased the VFT significantly over baseline (mean +/- SD) from 14.4+/-3.6 to 23.8+/-6.1 mA (p = 0.0016). An additional dose of amiodarone (15 mg/kg) increased the VFT to 38.5+/-15.9 mA, which is significantly greater than the VFT derived from lower-dose amiodarone (p = 0.046). We showed that DEA (10 mg/kg) has a similar antifibrillatory effect as 10 mg/kg of amiodarone. We also demonstrated a dose-dependent effect on VFT for amiodarone.     

Comparison of Intravenous Diltiazem and Verapamil for the Acute Treatment of Atrial Fibrillation and Atrial Flutter

Study Objectives . To compare the efficacy and safety of intravenous diltiazem and verapamil in controlling ventricular rate in patients with atrial fibrillation or flutter, and to evaluate the effects of these agents on left ventricular systolic function. Design . Prospective, randomized, double-blind, crossover study. Setting . University-affiliated hospital and Veterans Administration hospital. Patients . Seventeen men with atrial fibrillation or flutter with a ventricular rate of 120 beats/minute or higher and a systolic blood pressure of 100 mm Hg or greater. Interventions . Patients received up to two intravenous boluses of either diltiazem or verapamil, followed by an 8-hour continuous infusion if a therapeutic response was achieved (phase I). After a washout period, patients who responded were crossed over to receive the other drug in a similar fashion (phase II). Measurements and Main Results . At the end of each infusion, the patient's ejection fraction was assessed by gated angiography. Of the 17 men initially randomized, 8 successfully completed both phases I and II. In these patients, baseline mean (± SD) ventricular rates before treatment with intravenous diltiazem and verapamil were 138 ± 15 and 132 ± 9 beats/minute, respectively (NS). At 2 minutes after the initial bolus dose, the mean ventricular rate decreased to 100 ± 13 beats/minute in the diltiazem group compared with 114 ± 17 beats/minute in those receiving verapamil (p<0.05). Mean ventricular rates of 96 ± 11 and 97 ± 9 beats/minute were maintained during the 8-hour continuous infusion of diltiazem and verapamil, respectively (NS). On completion of the bolus dose(s) and during continuous infusions, there were no significant differences in blood pressures between the groups. Mean ejection fractions were 35.6 ± 13.6% and 35.5 ± 15.4% in the diltiazem and verapamil groups, respectively (NS). For the 17 patients, the mean maximum percentage decreases in blood pressure were not significantly different between groups. However, three patients developed symptomatic hypotension all of whom were randomized to receive verapamil initially. Conclusion . Intravenous diltiazem and verapamil are comparable in terms of efficacy and effect on systolic function in patients with rapid atrial fibrillation and flutter. However, hypotension may limit therapy with verapamil in some patients.     

Effects of intravenous ABT-870 (iron (III)-hydroxide oligosaccharide) on mean arterial pressure and heart rate in the anaesthetized beagle: comparison with other iron-containing haematinic agents

Iron-deficiency anaemia, a complication of end-stage renal disease (ESRD), is often treated with parenteral iron therapies that have been shown to produce dose-limiting hypotension in patients. ABT-870 (iron-(III)-hydroxide-oligosaccharide) is comprised of elemental iron complexed with oligosaccharide, a composition that we hypothesised would allow the hypotensive effects of parenteral iron therapy to be overcome, thus allowing a rapid rate of infusion to be well tolerated. Mean arterial pressure (MAP) and heart rate (HR) were monitored in anaesthetized dogs following the infusion of ABT-870 and iron sucrose administered at doses of 7.1 and 21.3 mg/kg using a rapid 30 s infusion. ABT-870 and iron sucrose were also monitored at doses of 7.1, 21.3 and 50 mg/kg administered over a 10 min period. Sodium ferric gluconate complex (SFGC) was administered in an identical fashion at doses of 12.5 and 31.2 mg/kg. A 30 s rapid infusion of ABT-870 at doses of 7.1 and 14.3 mg/kg or a 10 min infusion of ABT-870 at doses of 7.1 and 21.3 mg/kg produced little effect on MAP and HR. Infusion of the highest dose of ABT-870 (50 mg/kg) produced no consistent hypotension, but did produce an increase in HR (maximal increase 35 +/- 9 b.p.m.), an effect that lasted only 15 min. A 30 s rapid infusion of iron sucrose at 7.1 mg/kg produced modest increases in MAP and HR (5 +/- 1 mmHg and 5 +/- 2 b.p.m., respectively). However, rapid infusion of iron sucrose at 14.3 mg/kg produced hypotension (to -8 +/- 1 mmHg below baseline) and exerted variable, biphasic effects on HR ranging from -16 to +50 b.p.m. Although 10 min infusion of iron sucrose at 7.1 mg/kg exerted little effect on MAP and HR, at doses of 21.3 and 50 mg/kg iron sucrose elicited a profound dose-dependent decrease in MAP (-34 +/- 11 and -83 +/- 5 mmHg, respectively) and a pronounced increase in HR ranging from 32 to 49 b.p.m. above baseline. A 10 min infusion of SFGC at doses of 12.5 and 31.2 mg/kg produced a dose-dependent decrease in MAP (-28 +/- 18 and -67 +/- 12 mmHg below baseline) and a marked increase in HR (26 +/- 11 and 94 +/- 15 b.p.m. above baseline). In conclusion, unlike iron sucrose and SFGC, high doses of ABT-870 failed to exert consistent hypotensive effects. These data demonstrate that ABT-870 may have a substantial therapeutic window and considerable clinical potential for iron-replacement therapy.     

The In-vivo Cardiovascular Effects of a Putative Class III Anti-arrhythmic Drug,AM 92016

AM 92016(1-(4-methanesulphonamidophenoxy)-3-(N-methyl-3–4-dichlorophenethylamino)-2-propanol benzoic acid salt), an oxypropanolamine analogue of sotalol, has been shown to possess Class III antiarrhythmic properties in-vitro at concentrations showing 1000 times more potency than sotalol. The aim of this study was to characterize the effects of AM 92016 in-vivo. When administered to anaesthetized guinea-pigs, AM 92016 (10 μg kg^?1-5 mg kg^?1) significantly increased heart rate, systolic arterial blood pressure, left ventricular systolic pressure and the contractile index dp/dt_max. AM 92016 also significantly decreased the QT interval of the electrocardiogram from 135 ± 10 to 105 ± 4 ms (5 mg kg^?1). The time to onset of the first arrhythmia and ventricular fibrillation, induced by intravenous infusion of ouabain, was shortened in the presence of AM 92016. Ouabain-induced ventricular fibrillation occurred at 18 ± 5 and 12 ± 3 min (P < 005) in control and AM 92016-(1 mg kg^?1) treated guinea-pigs, respectively. An infusion of AM 92016 (2.5 μg kg^?1 min^?1) to anaesthetized pigs significantly increased the total number of arrhythmias occurring following coronary artery occlusion from 266 ·26 in control pigs to 535 ± 148 (P < 005) in those receiving AM 92016. The time to onset of ventricular fibrillation was also significantly reduced in anaesthetized pigs from 24 ± 1 to 18 ± 3 min in the presence of AM 92016. The drug did not change haemodynamics in the anaesthetized pig. We conclude that AM 92016 exhibited proarrhythmic rather than antiarrhythmic activity when administered in-vivo to either guinea-pigs or pigs.     

槐果碱对犬室颤阈以及有效不应期的影响

目的：观察槐果碱静脉注射后对正常犬及急性心肌缺血犬心室有效不应期(ERP)、室颤阈(VFT)的影响。方法：测定犬静脉注射槐果碱(3 mg·kg~(-1))后5,20,40,60 min ERP和VFT,比较与氯化钠注射液对照组的差异。并且通过结扎犬左前降支冠脉(LAD)建立急性心肌缺血动物模型,比较对照组、槐果碱组用药前后ERP,VFT的变化。结果：正常犬用药后20 min及40 min,槐果碱组ERP较对照组有显著延长(P=0.028和P=0.02)；且VFT较对照组用药后有显著升高(P=0.013和P=0.026)。静脉注射槐果碱后20 min第2次结扎LAD,该组较对照组ERP有显著延长(P=0.043)；槐果碱组VFT较第1次结扎有提高,而对照组VFT有所下降,2组比较有显著差异(P=0.049)。结论：槐果碱用药后20,40 min能延长正常犬的ERP,提高VFT；用药后20 min槐果碱能提高急性心肌缺血犬的心室有效不应期和室颤阈。     

Alpha adrenergic activity and renal function in two-kidney deoxycorticosterone-acetate hypertensive swine

To evaluate the role of alpha-adrenergic activity in deoxycorticosterone-acetate (DOCA) hypertensive swine, eight two-kidney Yucatan miniature swine were implanted with DOCA silicone strips (100 mg/kg) for 12–16 weeks. Mean arterial pressure (MAP) in these animals increased progressively from control values of approximately 1 15 mm Hg to 173 ± 5 mm Hg. Treatment of four conscious animals with phenoxybenzamine (POB) (1 mg/kg) resulted in a significant decrease in MAP from 190 ± 3 to 157 ± 5 mm Hg (P < 0.05). This decline was due to a 21% decrease in total peripheral resistance (TPR) (P < 0.05), while cardiac output (CO) and heart rate (HR) remained unchanged. Pentobarbital anesthesia caused a small insignificant decrease in MAP to 165 ± 5 mm Hg. While under anesthesia, infusion of POB into the left renal artery (0.04 μg/kg/min) caused a slight increase in left renal blood flow (P > 0.05), without affecting MAP, HR, TPR, or CO. Left kidney urine flow and sodium excretion also increased during intra-renal POB infusion. Potassium excretion was unchanged and GFR decreased slightly. When POB (1 mg/kg) was infused systemically during anesthesia, MAP decreased to 82 ± 6 mmHg (P < 0.05). This was due to a 34% and 14% decrease in TPR and CO, respectively (P < 0.05). Whole animal urine flow, sodium excretion, and GFR all decreased significantly with systemic POB. These findings suggest that alpha-adrenergic activity plays a role in the maintenance MAP and the determination of renal function in DOCA hypertensive swine.     

Comparative effects of antiarrhythmic drugs on the ventricular fibrillation threshold

The purpose of this study was to compare the effects of several different antiarrhythmic drugs on the ventricular fibrillation threshold (VFT). Experiments were performed on open-chest dogs anesthetized with pentobarbital. The VFT was measured on the right ventricle by scanning the vulnerable period with a single 10-ms electrical stimulus. The following antiarrhythmic drugs were each given intravenously to eight different dogs: procainamide (25 mg/kg), lidocaine (2 mg/kg + 70 micrograms/kg/min), flecainide (3 mg/kg), timolol (0.1 mg/kg), clofilium (1 mg/kg), dl-sotalol (5 mg/kg), and bethanidine (4 mg/kg). The drugs resulted in the following increases in the VFT: procainamide, 33 +/- 13%; lidocaine, 21 +/- 5%; flecainide, 38 +/- 10%; timolol, 19 +/- 6%; clofilium, 14 +/- 6%; sotalol, 33 +/- 10%; and bethanidine, 69 +/- 15%. The changes in VFT were all significant (p less than 0.01) except for clofilium. Only procainamide and sotalol caused stimulus-induced runs of nonsustained polymorphic ventricular tachycardia that spontaneously reverted to sinus rhythm after 4 s or more. In individual experiments, the occurrence of nonsustained polymorphic tachycardia that resembled ventricular fibrillation could not be correlated with a change in the VFT. In addition, there appeared to be no relationship between a drug-induced increase of the VFT and alterations in the QRS duration, the QT interval, or the ventricular effective refractory period. Bethanidine had the greatest effect on the VFT, in spite of the fact that this drug shortened the ventricular effective refractory period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic action of B-type natriuretic peptide substantially outlasts its plasma half-life in conscious dogs

1. The objective of the present study was to determine the plasma half-life of B-type natriuretic peptide (BNP) in conscious dogs after intravenous administration and to compare this with its haemodynamic effects. In six chronically instrumented dogs, plasma BNP concentrations were measured under basal conditions, during a constant infusion of canine BNP-32 (10 pmol/kg per min; 25 min) to steady state and at nominated time points up to 75 min after stopping the infusion. Concomitant, continuous measurements of mean arterial blood pressure (MAP), heart rate (HR), central venous pressure (CVP) and mesenteric blood flow (MBF) were obtained. 2. Baseline plasma BNP levels were 15.0 +/- 2.3 fmol/mL and rose approximately 10-fold to 159 +/- 23 fmol/mL after 20-25 min BNP infusion. When the infusion was turned off, plasma BNP levels declined in a biphasic manner, with an initial half-life of 1.57 +/- 0.14 min and a terminal half-life of 301 +/- 85 min. The metabolic clearance rate of BNP was 2.29 +/- 0.34 L/min. 3. The infusion of BNP reduced MAP (approximately 10%), CVP (approximately 65%) and MBF (approximately 25%), whereas haematocrit (approximately 4%) and mesenteric vascular resistance (MVR) increased (approximately 40%; all P < 0.05). Plasma BNP levels returned to baseline by 20 min after BNP infusion had been stopped, whereas none of the haemodynamic variables returned to normal by this time. Mean arterial pressure returned to resting levels within 10-15 min after plasma BNP returned to normal. However, CVP, haematocrit and MBF remained substantially below baseline values for more than 20 min after circulating BNP levels had returned to pre-infusion levels. Of these, only mesenteric vascular changes were returned to baseline within 60 min of plasma BNP levels normalizing. 4. These results demonstrate that the removal of BNP from the canine circulation is rapid, similar to observations made regarding the metabolism of circulating atrial natriuretic peptide in dogs. The half-life of BNP in dogs was shorter than that in rats, sheep or humans. However, the haemodynamic actions of BNP substantially outlasted its plasma half-life. Whether this disparity in plasma level and haemodynamic activity of BNP reflects long-lasting activation of second messenger systems or slow recovery from the hydraulic changes at the capillary level, reflected in the haematocrit and CVP, remains to be answered.     

Differential cardiovascular and neuroendocrine effects of epinine and dopamine in conscious pigs before and after adrenoceptor blockade.

1. The effects of epinine or dopamine (both 1-10 micrograms kg-1 min-1) on systemic haemodynamics and plasma concentrations of catecholamines and prolactin were studied in conscious pigs before and after combined non-selective alpha- and beta-adrenoceptor blockade. 2. The plasma concentrations of the two compounds did not differ from each other over the entire dose-range. 3. Epinine increased aortic blood flow (AoBF, 24 +/- 6%), which was due to an increase in heart rate (HR) for doses less than 10 micrograms kg-1 min-1. At 10 micrograms kg-1 min-1, HR decreased slightly (10 +/- 3%, as compared to the value obtained at 5 micrograms kg-1 min-1) and stroke volume increased up to 15% (P < 0.05). Mean arterial pressure (MAP, 99 +/- 3 mmHg at baseline) decreased dose-dependently (14 +/- 2%, P < 0.05) up to the infusion rate of 5 micrograms kg-1 min-1, but increased by 4.0 +/- 1.8 mmHg during infusion of 10 micrograms kg-1 min-1. Systemic vascular resistance (SVR) decreased up to 23 +/- 3% for doses less than 10 micrograms kg-1 min-1, but did not change further during infusion of the highest dose. LVdP/dtmax increased during the two highest infusion rates up to 22 +/- 6% (P < 0.05). After the infusion was stopped there was an abrupt increase in HR (18 +/- 4%, P < 0.05) and a further decrease in SVR before all parameters returned to baseline. 4.(ABSTRACT TRUNCATED AT 250 WORDS)     

靶控输注瑞芬太尼改善七氟醚吸入诱导插管条件的临床观察

目的评价靶控输注瑞芬太尼改善七氟醚诱导用于无肌松药气管插管的临床效果。方法将拟行择期手术全身麻醉的患者46例随机分为2组,复合瑞芬太尼组(Ⅰ组)靶控输注1 ng/mL瑞芬太尼,单纯吸入组(Ⅱ组)输注等量生理盐水。进行七氟醚吸入诱导,气体监测仪监测出呼吸末七氟醚达2.5 MAC,稳定3 min后行气管插管。分别记录诱导前(T0)、诱导后插管前(T1)、插管后1 min(T2)、插管后2 min(T3)和插管后5 min(T4)的MAP、HR和SpO2。结果Ⅰ组患者意识消失时间和插管时间显著短于Ⅱ组,Ⅰ组呼气末七氟醚浓度达2.5 MAC时间较Ⅱ组延长(P<0.05)。Ⅰ组插管条件评分优于Ⅱ组(P<0.05)。Ⅰ组诱导后MAP和HR显著下降。Ⅱ组诱导后MAP下降,插管后1 min,MAP、HR较基础值显著升高,与Ⅰ组比较差异有统计学意义(P<0.05)。结论瑞芬太尼1 ng/mL靶控输注复合七氟醚吸入诱导,能较好地控制气管插管的血流动力学反应,在无肌松药条件下,可达到满意的气管插管条件。     

Assessment of the role of the renin-angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren.

1. The role of the renin-angiotensin system in the regulation of myocardial contractility is still debated. In order to investigate whether renin inhibition affects myocardial contractility and whether this action depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c.) infusions of the renin inhibitor remikiren, were compared and related to the effects on systemic haemodynamics and circulating angiotensin II in open-chest anaesthetized pigs (25-30 kg). The specificity of the remikiren-induced effects was tested (1) by studying its i.c. effects after administration of the AT1-receptor antagonist L-158,809 and (2) by measuring its effects on contractile force of porcine isolated cardiac trabeculae. 2. Consecutive 10 min i.v. infusions of remikiren were given at 2, 5, 10 and 20 mg min-1. Mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), systemic vascular resistance (SVR), myocardial oxygen consumption (MVO2) and left ventricular (LV) dP/dtmax were not affected by remikiren at 2 and 5 mg min-1, and were lowered at higher doses. At the highest dose, MAP decreased by 48%, CO by 13%, HR by 14%, SVR by 40%, MVO2 by 28% and LV dp/dtmax by 52% (mean values; P < 0.05 for difference from baseline, n = 5). The decrease in MVO2 was accompanied by a decrease in myocardial work (MAP x CO), but the larger decline in work (55% vs. 28%; P < 0.05) implies a reduced myocardial efficiency ((MAP x CO)/MVO2). 3. Consecutive 10 min i.c. infusions of remikiren were given at 0.2, 0.5, 1, 2, 5 and 10 mg min-1. MAP, CO, MVO2 and LV dP/dtmax were not affected by remikiren at 0.2, 0.5 and 1 mg min-1, and were reduced at higher doses. At the highest dose, MAP decreased by 31%, CO by 26%, MVO2 by 46% and LV dP/dtmax by 43% (mean values; P < 0.05 for difference from baseline, n = 6). HR and SVR did not change at any dose. 4. Thirty minutes after a 10 min i.v. infusion of the AT1 receptor antagonist, L-158,809 at 1 mg min-1, consecutive 10 min i.c. infusions (n = 5) of remikiren at 2, 5 and 10 mg min-1 no longer affected CO and MVO2, and decreased LV dP/dtmax by maximally 27% (P < 0.05) and MAP by 14% (P < 0.05), which was less than without AT1-receptor blockade (P < 0.05). HR and SVR remained unaffected. 5. Plasma renin activity and angiotensin I and II were reduced to levels at or below the detection limit at doses of remikiren that were not high enough to affect systemic haemodynamics or regional myocardial function, both after i.v. and i.c. infusion. 6. Remikiren (10(-10) to 10(-4) M) did not affect contractile force of porcine isolated cardiac trabeculae precontracted with noradrenaline. In trabeculae that were not precontracted no decrease in baseline contractility was observed with remikiren in concentrations up to 10(-5) M, whereas at 10(-4) M baseline contractility decreased by 19% (P < 0.05). 7. Results show that with remikiren i.v., at the doses we used, blood pressure was lowered primarily by vasodilation and with remikiren i.c. by cardiac depression. The blood levels of remikiren required for its vasodilator action are lower than the levels affecting cardiac contractile function. A decrease in circulating angiotensin II does not appear to be the sole explanation for these haemodynamic responses. Data support the contention that myocardial contractility is increased by renin-dependent angiotensin II formation in the heart.     

Antiarrhythmic effects of the angiotensin converting enzyme inhibitor perindoprilat in a pig model of acute regional myocardial ischemia.

Previous studies on the possible antiarrhythmic effects of angiotensin converting enzyme (ACE) inhibitors during early ischemia in pigs have been inconclusive or negative; however, proof of adequate ACE inhibition was not provided. Perindoprilat, 0.06 mg/kg, i.v., was administered 30 min prior to ligation of the anterior descending coronary artery (CAL) in anesthetised open-chest pigs. Plasma ACE activity was decreased by 95.0 +/- 1.9% when measured 5 min before CAL. Within 5 min of CAL, the ventricular fibrillation threshold (VFT) in the control group was decreased from 11.8 +/- 1.9 to 7.2 +/- 1.2 mA (p less than 0.01). Perindoprilat prevented the fall in the VFT and the increase in left ventricular end-diastolic pressure caused by CAL. Perindoprilat decreased arterial pressure. Cardiac output (thermodilution) was decreased by 23 +/- 3% after CAL in the control group and by only 10 +/- 5% (p less than 0.05) in the perindoprilat group (both versus pre-CAL values). In the control group cyclic AMP was increased from 0.97 +/- 0.04 (pre-CAL) to 1.16 +/- 0.04 nmol/g (p less than 0.05) in the central ischemic zone 20 min after CAL. Perindoprilat prevented this increase in cyclic AMP. Twenty minutes after CAL blood flow (microsphere method) in the nonischemic zone of the perindoprilat group was increased, whereas blood flow in the central ischemic zone was decreased compared to the control group. However, levels of tissue metabolites (ATP, phosphocreatine, lactate) measured in drill biopsies in the same zones of the two groups were similar.(ABSTRACT TRUNCATED AT 250 WORDS)