[Effects of single or combined administration of cedilanid and enalaprilat on visceral damages in early stage of severe scald in rats].

OBJECTIVE: To investigate the effects of single or combined administration of cedilanid and small-dose of enalaprilat on heart, liver, kidney and intestine damages at early stage of severe scald in rats. METHODS: Forty healthy male Wistar rats were enrolled in the study and randomly divided into: sham, burn control, cedilanid, enalaprilat, cedilanid + enalaprilat groups, with 8 rats in each group. Rats, except that of sham group (simulated scald with 37 degrees C water) were inflicted with 30% TBSA full-thickness scald, and were injected with Ringer's lactate solution (4 mLxkg(-1)x1% TBSA(-1)) intraperitoneally 30 minutes after burn. Then rats in cedilanid group were given cedilanid injection (0.2 mg/kg) intravenously, and those in enalaprilat group were given enalaprilat (1 mg/kg), and cedilanid + enalaprilat group with cedilanid and enalapril in the same dosage. At 6 post burn hour (PBH) or sham injury, parameters of myocardiac mechanics were recorded with the Multiple Channel Physiological Signal Collecting and Processing System. The blood flow of the liver, kidney and intestine was respectively detected with the Laser Doppler Flowmetry at 6 PBH. Serum contents of cTnI, TBA, beta2-MG and DAO were determined at 6 PBH to reflect visceral damages. RESULTS: Compared with those in sham group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine (158 +/- 32, 156 +/- 46, 119 +/- 30 PU, respectively) in burn control group were obviously decreased (P < 0.05), and the serum contents of cTnI, TBA, beta2-MG, DAO (5.0 +/- 0.3 microg/L, 82 +/- 23 micromol/L, 2.55 +/- 0.15 mg/L, 1.52 +/- 0.08 kU/L, respectively) in burn control group were obviously increased (P < 0.05). Compared with those in burn control group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine in the cedilanid or enalaprilat groups increased markedly, and their serum contents of cTnI, TBA, beta2-MG, DAO decreased significantly (P < 0.05). Compared with those in burn control group, the parameters of myocardiac mechanics and blood flow of liver, kidney, intestine (240 +/- 49, 239 +/- 75, 194 +/- 55 PU, respectively) in cedilanid + enalaprilat group increased significantly (P < 0.05), and the serum contents of cTnI, TBA, beta2-MG, DAO (3.43 +/- 0.21 microg/L, 47 +/- 8 micromol/L, 2.01 +/- 0.16 mg/L, 1.17 +/- 0.15 kU/L, respectively) were decreased (P < 0.05). CONCLUSION: Single administration of cedilanid or small-dose enalaprilat can ameliorate impairment of cardiac functions, prevent damages to liver, kidney and intestine in early stage of severe scald in rats. Combined administration of cedilanid and small-dose enalaprilat seems to be more effective.

Hemodynamic and plasma atrial natriuretic peptide responses to acute digitalis therapy in patients with normal and impaired left ventricular function.

BACKGROUND: Digitalis has a long history in the treatment of heart failure but its effects on cardiac hemodynamics and neurohormonal modulation are not well characterized. AIMS: The purpose of this study was to evaluate the relationship between atrial natriuretic peptide (ANP) and the hemodynamic responses to acute digitalis administration in patients with normal and impaired left ventricular function (LVD). METHODS AND RESULTS: Thirty patients were enrolled in the study, 20 with LVD (LVEF=22+/-8%) and 10 control subjects (LVEF=77+/-10%). Hemodynamics and plasma ANP concentrations were measured supine and with leg elevation before and after digitalis. In patients with normal ventricular function, the hemodynamic stress of leg elevation in the pre-digitalis state resulted in significant (P<0.05) increases in PAWP and MPAP. Digitalis administration in the supine position produced reductions in heart rate, PAWP, MPAP and CI; SVR was increased. In LVD patients leg elevation further increased PAWP, RAP and MPAP. Digitalis in the supine position, however, reduced RAP, MPAP and PAWP and increased CI. These improved hemodynamics were preserved during the stress of leg elevation. Leg elevation following digitalis resulted in increased ANP concentrations despite decreased cardiac filling pressures. CONCLUSIONS: Acute digitalis administration results in hemodynamic improvement in LVD patients which may in part result from digitalis stimulated release of myocardial ANP under conditions of hemodynamic stress.

Digitalis increases brain natriuretic peptide in patients with severe congestive heart failure.

Ouabain can cause increased secretion of atrial natriuretic peptide (ANP) from atrial cardiocyte culture, but the effects of digitalis in a therapeutic range on the secretion of cardiac natriuretic peptide including ANP and brain natriuretic peptide (BNP), mainly from the ventricle, in patients with congestive heart failure remain to be investigated. Therefore we studied the acute effects of intravenous infusion of a relatively low dose of digitalis or placebo on hemodynamics and neurohumoral factors including the plasma levels of ANP and BNP and cyclic guanosine monophosphate, a second messenger of cardiac natriuretic peptide, in 13 patients with severe congestive heart failure. No significant change in the hemodynamic parameters or neurohumoral factors was observed with placebo. After 1 hour of intravenous administration of deslanoside (0.01 mg/kg), there was a significant decrease of plasma renin activity and angiotensin II, aldosterone, and norepinephrine levels but no significant change of plasma levels of vasopressin and a significant decrease of the pulmonary capillary wedge pressure but no significant change in cardiac index. In addition, plasma levels of ANP (217 +/- 47 vs 281 +/- 70 pg/ml, p < 0.05), BNP (628 +/- 116 vs 689 +/- 132 pg/ml, p < 0.05), and cyclic guanosine monophosphate (9.7 +/- 1.1 vs 10.9 +/- 1.5 pmol/ml, p < 0.05) increased despite the decrease of pulmonary capillary wedge pressure (19.7 +/- 2.3 vs 16.8 +/- 2.3 mm Hg, p < 0.05). These results indicate the acute intravenous low dose of digitalis resulted in a significant increase in plasma levels of ANP, BNP, and cyclic guanosine monophosphate concomitant with the significant decrease of pulmonary capillary wedge pressure, suggesting the acute direct action of digitalis on the cardiac natriuretic peptides released from the heart in patients with severe congestive heart failure.

Determination of deslanoside in antemortem and postmortem specimens. Unusual case report.

One case of the erroneous administration of deslanoside and high level of drug in antemortem plasma and postmortem specimens has been reported owing to the unusual surrounding circumstances. Deslanoside in antemortem plasma was determined by FPIA and the analysis was done by HPLC in the postmortem tissue samples. The analytical results and methods used in the examinations are discussed in the following paper.

Cardiovascular effects of digitalis on intact dogs and isolated cross-perfused atria.

The chronotropic effects of digoxin and deslanoside were studied in canine atria cross-perfused with heparinized arterial blood from donor dogs. Intravenous injections of either drug (100 micrograms/Kg) into the donor dog produced bradycardia followed by ventricular tachyarrhythmia, with or without hypertension, in the donor dog. A significant increase in the developed tension was observed in the isolated atria, with or without slight sinus acceleration. These effects continued over 150 min after the injection. Digoxin (200 micrograms/Kg, i.v.) caused an immediate bradycardia followed by ventricular tachycardia. In addition, ventricular fibrillation occurred in 3 out of 5 donor dogs within 20 min of the drug administration. In isolated atria, there was a marked increase in the developed tension, usually with a little sinus tachycardia. Deslanoside (200 micrograms/Kg, i.v.) caused almost the same response patterns as digoxin. However, this dose of deslanoside caused ventricular fibrillation in all 6 experiments. Drug concentrations in the donor's arterial blood decreased rapidly for 15-20 min and then decreased slowly in all experiments. It is concluded that digoxin and deslanoside have no significant direct accelerating action on the SA node in doses which produced marked increases in the developed tension; only extremely high doses cause a direct, slight sinus acceleration.

Direct effects of digoxin and deslanoside on sinoatrial conduction in isolated, blood-perfused dog atria.

We studied the direct effects of digitalis on sinoatrial conduction time (SACT), atrial rate (AR) and developed tension (DT) in isolated atrial muscle, using an isolated dog atrial preparation perfused with heparinized blood from the carotid artery of an anesthetized donor dog. After digoxin or deslanoside (100 micrograms or 200 micrograms/Kg) was given intravenously to the donor dog, SACT, AR and DT of the isolated atrium were continuously measured. Following administration of 100 micrograms/Kg of digoxin, an immediate sinus bradycardia followed by various kinds of ventricular arrhythmias was observed in the donor dog, and the DT of the isolated atrium was augmented without any effects on the SACT and AR in all 3 experiments. With 200 micrograms/Kg of digoxin or deslanoside, ventricular fibrillation was induced in all 5 donor dogs within 75 min after digitalis administration. In these cases, the DT of the isolated atrium was immediately increased to over 200% of control DT, but SACT and AR were not affected until 20 min later, at which time increases in SACT and AR were finally induced. From these results, it is concluded that a large amount of digitalis has no distinct direct effect on SA nodal pacemaker activity and SA conductivity. Moreover, extremely large doses of digitalis which cause ventricular fibrillation might also induce a prolongation of SACT in addition to sinus tachycardia.

Changes in diastolic time with various pharmacologic agents: implication for myocardial perfusion.

Diastolic time (DT) is calculated as the cycle length (RR) minus electromechanical systole (QS2). The ratio of DT (RR-QS2) to RR interval times 100, or the percent diastole (%D), varies nonlinearly with heart rate (HR), increasing rapidly with decreasing HR. The effect of commonly used cardioactive agents on %D was studied in five groups of normal subjects. In group 1 (n = 12), propranolol (160 mg daily) increased %D from 55.9 +/- 1.7 to 64.7 +/- 1.3 (p less than 0.001) by slowing HR. In group 2 (n = 12), dobutamine (2.5 micrograms/kg/min) increased %D from 56.4 +/- 1.4 to 61.8 +/- 1.3 (p less than 0.005) by shortening the QS2. In group 3 (n = 10), Cedilanid-D (1.6 mg i.v.) increased %D from 55.5 +/- 1 to 63.2 +/- 0.7 (p less than 0.001), both by slowing the HR and shortening the QS2. In group 4 (n = 12), isoproterenol (2 micrograms/min) increased HR and shortened the QS2 significantly. The net result was a significant reduction of %D from 56.1 +/- 1.4 to 53.5 +/- 1.1, (p less than 0.05). In group 5 (n = 15), a 100-mg bolus of i.v. lidocaine did not have a significant effect on %D. This study indicates that cardiovascular drugs may have significant effects on the relative duration of diastole either by affecting HR or the duration of systole. This may have clinical implications for patients with coronary artery disease and patients with left ventricular hypertrophy, since in both cases coronary flow in mostly diastolic.

Pharmacokinetics of deslanatoside C-3H administered parenterally to the guinea-pig, rabbit and dog.

The pharmacokinetics of Deslanatoside C-3H, a short-acting polar cardiac glycoside, were investigated in the guinea-pig, rabbit and dog, after parenteral administration. Deslanatoside C was on average 20% plasma protein-bound and had a red blood celle/plasma partition ratio of 1/9. Tissue uptake of Deslanatoside C observed in the guinea-pig seems on average to be higher than in rabbits. Among the various organs and fluids tested, the highest levels were encountered in the urine, bile and kidneys of both the guinea-pig and rabbit. The main excretory route of this glycoside was via the urine, although significant amounts were excreted via the bile in all the three species tested. Cumulative urinary excretion 24 hr after i.v. injection was 50% (75% of which in unchanged form) in the guinea-pig, 46.5% (86% of which in unchanged form) in the rabbit, and 42.9%(84% of which in unchanged form) in the dog. Among the cardiac glycosides, Deslantoside C seems to possess the highest urinary excretion rate, which has in fact also recently been confirmed in human subjects.

[Dromotropic effects of drug combinations. Initial results bearing on a combination of deslanoside and ajmaline]. / Effets dromotropes des associations médicamenteuses. Premiers résultats portant sur l'association deslanoside - ajmaline.

The electrophysiological effects of the cardiotropic drugs have been studied in man by the agency of endocavitary electrocardiography. The effects of drug combinations, which are often prescribed therapeutically, have been studied less often. The authors report the results of a preliminary study of the combination of deslanoside with ajmaline in 26 patients; its effects were compared with those using each drug separately. This combination seems to have true dromotropic effects; although deslanoside alone, in the doses used, does not modify conduction below the bundle of His, it can still act synergistically with ajmaline at this level. A detailed study of the pharmacological effects as a function of the original status of conduction shows that at the level above the bundle His, the dromotropic action is quantitively less on healthy conducting tissue than on abnormal tissue. The effects of ajmaline on the conduction times below the bundle seem to be similar whether or not there is any conduction defect under basal conditions. The difficulties in obtaining and interpreting such measurements in man are discussed in the hope of arriving at a general protocol for studying drug combinations.