Characteristics of deslanoside-induced modulation on jejunal contractility.

AIM: To characterize the dual effects of deslanoside on the contractility of jejunal smooth muscle. METHODS: Eight pairs of different low and high contractile states of isolated jejunal smooth muscle fragment (JSMF) were established. Contractile amplitude of JSMF in different low and high contractile states was selected to determine the effects of deslanoside, and Western blotting analysis was performed to measure the effects of deslanoside on myosin phosphorylation of jejunal smooth muscle. RESULTS: Stimulatory effects on the contractility of JSMF were induced (45.3% ± 4.0% vs 87.0% ± 7.8%, P < 0.01) by deslanoside in 8 low contractile states, and inhibitory effects were induced (180.6% ± 17.8% vs 109.9% ± 10.8%, P < 0.01) on the contractility of JSMF in 8 high contractile states. The effect of deslanoside on the phosphorylation of myosin light chain of JSMF in low (78.1% ± 4.1% vs 96.0% ± 8.1%, P < 0.01) and high contractile state (139.2% ± 8.5% vs 105.5 ± 7.34, P < 0.01) was also bidirectional. Bidirectional regulation (BR) was abolished in the presence of tetrodotoxin. Deslanoside did not affect jejunal contractility pretreated with the Ca(2+) channel blocker verapamil or in a Ca(2+)-free assay condition. The stimulatory effect of deslanoside on JSMF in a low contractile state (low Ca(2+) induced) was abolished by atropine. The inhibitory effect of deslanoside on jejunal contractility in a high contractile state (high Ca(2+) induced) was blocked by phentolamine, propranolol and L-NG-nitro-arginine, respectively. CONCLUSION: Deslanoside-induced BR is Ca(2+) dependent and is related to cholinergic and adrenergic systems when JSMF is in low or high contractile states.

Effects of acute administration of ethanol on experimental arrhythmia.

Many studies have shown that the relationship between alcohol consumption and most cardiovascular diseases is U-shaped, with nondrinkers and heavier drinkers having higher risks than moderate drinkers. However, the association between cardiac arrhythmias and acute alcohol consumption is not well understood. We set up several experimental arrhythmia animal models to examine the effects of acute administration of ethanol on arrhythmia. The results showed 0.4, 0.8 and 1.6 g/kg ethanol consumption obviously delayed the onset time of atrial fibrillation (AF) (P < 0.05 or P < 0.01) and increased the survival rates on acetylcholine-CaCl2-induced AF in mice. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption significantly delayed the onset time of ventricular tachycardia (VT), ventricular fibrillation (VF) and cardiac arrest (CA) (P < 0.01), and 0.4 and 0.8 g/kg ethanol consumption increased the survival rates on CaCl2-induced arrhythmia in rats. Ethanol (0.4 g/kg) essentially increased the cumulative dosage of aconitine required to CA (P < 0.05), and 0.8 g/kg, 1.6 g/kg ethanol reduced the cumulative aconitine dosage to induce VT, VF and CA (P < 0.05 or P < 0.01) on aconitine-induced arrhythmia in rats. Ethanol (0.4, 0.8 and 1.6 g/kg) consumption remarkably increased the cumulative dosage of deslanoside to induce ventricualr premature contraction (P < 0.01) on deslanoside-induced arrhythmia in guinea pigs. Collectively, our results indicate that low concentrations of ethanol had anti-arrhythmic effect on experimental arrhythmia, and high concentrations of ethanol may aggravated the occurrence of experimental arrhythmia.

[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.

Effects of single or combined administration of cedilanid and enalaprilat on visceral damages in early stage of severe scald in rats / 中华烧伤杂志

<p><b>OBJECTIVE</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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).</p><p><b>CONCLUSION</b>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.</p>

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.

Separation of cardiac glycosides by micellar electrokinetic chromatography and microemulsion electrokinetic chromatography.

The interest of micellar electrokinetic chromatography (MEKC) and microemulsion electrokinetic chromatography (MEEKC) for the resolution of four cardiac glycosides is demonstrated. First, the influence of some parameters on the resolution of the solutes in MEKC such as the concentration of the surfactant, pH, addition of organic modifiers and urea is discussed. Then, results are compared with those obtained in MEEKC using different microemulsion compositions. Results indicate that MEEKC possesses several advantages over MEKC for the separation of relatively hydrophobic compounds such as digitalic compounds. First, microemulsions allow a better manipulation of the migration time window and of the retention of the solutes. Moreover, efficiency is improved with shorter analysis time.

21'-Di-dehydro-deacetyllanatoside C, a biotransformation product of deacetyllanatoside C from senescent shoot cultures of Digitalis lanata.

Feeding deacetyllanatoside C to senescent shoot cultures of Digitalis lanata resulted in the formation of a new product, which was isolated by semi-preparative HPLC. The molecular structure was elucidated by means of HPLC-mass spectrometry and NMR as 21'-di-dehydro-deacetyllanatoside C.

Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure.

We investigated alterations in autonomic control of heart rate in conscious dogs with left ventricular (LV) dysfunction in the presence and absence of heart failure (HF) due to rapid pacing. In dogs with LV dysfunction but no HF, indexes of parasympathetic control decreased significantly after only 4 days of pacing. In dogs with fully developed HF, both vagal and sympathetic contributions were small. Vagomimetic doses of atropine increased both R-R interval (419 +/- 25 to 466 +/- 34 ms, P < 0.05) and standard deviation (SD) of the R-R interval (13 +/- 2 to 34 +/- 9 ms, P < 0.05). The digitalis glycoside deslanoside (Cedilanid-D) alone prolonged R-R interval (420 +/- 33 to 492 +/- 44 ms, P < 0.01) and tended to increase SD (14 +/- 4 to 28 +/- 8 ms, P = 0.08). After Cedilanid-D, low-dose atropine resulted in no significant further change in R-R interval or SD. These data indicate that changes in vagal control of heart rate become apparent at a very early developmental stage of LV dysfunction, and we speculate that this may provide important prognostic information in patients who are at risk for developing progressive myocardial dysfunction and HF.

Effect of digitalis on norepinephrine kinetics in congestive heart failure.

OBJECTIVE: The aim of this study was to test the hypothesis that digitalis glycosides would reduce sympathetic activity as reflected by forearm venous norepinephrine kinetics in patients with congestive heart failure. BACKGROUND: Digitalis glycosides have been reported to decrease sympathetic nervous system activity with baroreceptor sensitization in experimental animals. Such effects could be of therapeutic importance in congestive heart failure. METHODS: Double-blind randomized assessment was made of the effects of low dose intravenous deslanoside (Cedilanid-D, 0.002 mg/kg body weight) and vehicle on heart rate, arterial pressure, forearm blood flow, plasma norepinephrine, norepinephrine clearance and norepinephrine spillover in nine patients with stable congestive heart failure, New York Heart Association functional class II or III. Open label assessment of the responses to 0.6 mg of deslanoside was made in an overlapping group of seven patients. All measurements were made 30 and 60 min after intravenous injection of drug or vehicle and after 15 min of 30 degrees head-down tilt as a test of the sympathetic response to baroreceptor loading. RESULTS: Heart rate, arterial pressure and forearm blood flow were unchanged by low dose deslanoside. Heart rate decreased slightly with the 0.6 mg dose with the patients in the supine position. Norepinephrine spillover and clearance decreased with time on each study day in the supine position, but no effect was attributable to digitalis. Plasma norepinephrine and norepinephrine clearance and spillover all remained unchanged during head-down tilt on each study day. CONCLUSIONS: Nonpressor doses of deslanoside do not suppress sympathetic activity as reflected by venous norepinephrine and norepinephrine spillover in patients with congestive heart failure. Further, deslanoside did not normalize the sympathetic response to mild baroreceptor loading produced by head-down tilt. These data do not support sympathoinhibition through baroreceptor sensitization as a likely effect of digitalis in congestive heart failure.

Are contraction and relaxation coupled in patients with and without congestive heart failure?

BACKGROUND: Although changes in contractility are often accompanied by changes in relaxation, a mathematical model of ventricular coupling has not been described. A model we examined suggests a hyperbolic relation between measurements of contraction and relaxation. We thus tested the hypothesis that relatively load-independent measurements of contractility (end-systolic elastance [Ees]) and relaxation (the slope of the tau-to-end-systolic pressure relation [R]) were coupled. METHODS AND RESULTS: To establish the validity of the model, an assessment of Ees and R was made in 30 subjects who underwent sequential digital ventriculography and micromanometer pressure measurements during atrial pacing (93 +/- 10 min-1) before and after graded doses of nitroprusside. To establish if a cyclic AMP (cAMP)-mediated intervention alters coupling, seven of the 30 subjects were studied before and after 3 months of beta-blockade. To determine if a non-cAMP-mediated intervention alters coupling, 12 other patients were studied before and after deslanoside. Nonlinear regression analysis for the initial 30 patients suggested a hyperbolic relation: (Ees) (R) = 1.05 (r = 0.79, p less than 0.001) with an inflection point near Ees = 1.02 mm Hg/ml. Thus, with normal or near-normal contractility, relaxation is normal and not load dependent (R is close to 0). With systolic dysfunction, relaxation becomes very afterload dependent and so must be normalized for load. After long-term beta-blockade in patients with severe left ventricular dysfunction, small improvements in contractility (elastance) occurred with larger changes in relaxation, but the curve describing the relation was not displaced. Acute administration of deslanoside resulted in a large increase in elastance and a smaller change in relaxation but did not alter coupling. However, the magnitude of the change in R was dependent on the predrug R value. CONCLUSIONS: These data suggest contraction and relaxation may be physiologically coupled with relaxation relatively preserved in early heart failure and more rapid deterioration in relaxation as elastance falls under 1.02 mm Hg/ml. Both beta-blockers (which may act through cAMP) and digitalis (which is cAMP independent) improve contraction and relaxation, but both mechanisms appear to maintain coupling. The hyperbolic relation between contraction and relaxation may have important implications regarding therapeutic response and selection of patients for clinical trials in heart failure.

The effect of calcitonin gene-related peptide on arrhythmia caused by adenosine diphosphate and desacetyldigilanide-C in rats.

We investigated the effect of calcitonin gene-related peptide on the arrhythmia induced by two drugs in rats. The results of our experiments have proved that calcitonin gene-related peptide could reduce the degree of atrioventricular block, protect against the attacks of sinus standstill and ventricular fibrillation produced by adenosine diphosphate, and improve restoration of sinus rhythm. Calcitonin gene-related peptide was able to eliminate sinus standstill and ventricular fibrillation resulting from administration of desacetyldigilanide-C. These results demonstrate that calcitonin gene-related peptide has strong antiarrhythmic effects in experimental animals.

Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans.

BACKGROUND: Digitalis glycosides augment cardiopulmonary baroreceptor mechanisms in animals. This could result from inotropic actions or from direct sensitization of cardiac mechanoreceptors. METHODS AND RESULTS: To determine if digitalis has similar actions in humans and to evaluate the mechanisms involved, we measured muscle sympathetic nerve activity (MSNA; microneurography) during unloading of cardiopulmonary baroreceptors with incremental lower body negative pressure (LBNP; 0 to -15 mm Hg) and during the cold pressor test in 22 normal subjects (age 22 +/- 1 year, mean +/- SEM). Arterial and central venous pressures, heart rate, and MSNA were measured during LBNP before and after intravenous digitalis (Cedilanid 0.02 ng/kg, n = 8), dobutamine (2.8 +/- 0.5 micrograms/kg/min, n = 8), or placebo (n = 6). Digitalis and dobutamine produced similar increases in baseline mean arterial pressure and decreases in central venous pressure and MSNA. LBNP produced similar decreases in central venous pressure in all groups before and after drug administration. The MSNA responses to LBNP were markedly potentiated by digitalis but not by dobutamine or placebo. CONCLUSIONS: Digitalis did not alter responses to the cold pressor test. Thus, digitalis selectively potentiated cardiopulmonary baroreflex regulation of sympathetic neural responses in normal humans, whereas dobutamine (another positive inotropic agent) did not produce this effect. We conclude that digitalis augments cardiopulmonary baroreflex control of sympathetic activity, probably by direct baroreceptor sensitization.

Two-stage cultivation of Digitalis lanata cells: semicontinuous production of deacetyllanatoside C in 20-litre airlift bioreactors.

A two-stage cultivation method was employed to develop a semicontinuous biotransformation process for the production of deacetyllanatoside C, a cardenolide of the important digoxin series. Digitoxin was used as the substrate for biotransformation. The process was optimized in 1-l shake flasks and then established on the 20-l scale using two airlift bioreactors, one for cell growth (working volume 12 litres) and another for deacetyllanatoside C production (working volume 18 litres). Growth and production phases were synchronized and the process finally ran semicontinuously in 7-d cycles. Six consecutive production runs were performed yielding a total of 43.8 g deacetyllanatoside C.

Determination of cardiac glycosides in digitoxin tablets and deslanoside injections by micro-HPLC.

A micro high-performance liquid chromatographic (micro-HPLC) procedure for the assay of digitoxin tablets and deslanoside injections has been developed. Micro-HPLC is performed on an ODS micro column, with acetonitrile-methanol-water (10:20:17) for digitoxin tablets and acetonitrile-water (21:70) for deslanoside injections. The effluent is monitored by UV absorption at 220 nm. Quantitation of cardiac glycosides in tablets and injections is carried out by the internal standard method. The composite assay results for digitoxin tablets and deslanoside injections provide average values of 101.2 and 99.9% with standard deviations of 1.2 and 0.93%, respectively. This micro-HPLC method is sensitive, quantitative, and reproducible. It is suitable for use in examining the content uniformity of pharmaceutical preparations.

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.

[A case of psittacosis].

A 67-year-old Japanese housewife, who had been attended the out patient department of medicine, Fukuoka Dental College (FDC) Hospital for paroxysmal atrial fibrillation, was admitted to FDC Hospital because of high fever, exhaustion, anorexia, myalgia and mild stupor. Her ECG finding revealed atrial fibrillation and roentgenologic examination of the chest showed diffuse opacities in the left lung field (S10) without pleural effusion. As she had told her physician that her pet parakeet had been dead recently, she was diagnosed immediately as psittacosis. She was instantly treated with minocycline orally and deslanoside intravenously. Laboratory findings on admission disclosed the following results: Complement-fixing antibodies against Chlamydia psittaci were 1:64, and liver dysfunction (GOT 253, GPT 86, LDH 846) was shown. The white blood cell count was 4,700 associated with shift to the left, C-reactive protein was 6 plus and the erythrocyte sedimentation rate was 109 mm in 1 hour. The course in the hospital was satisfactory and after 38 hospital days she was discharged with complete recovery from the psittacosis. It is emphasized the importance of that the question about the history of contact with psittacine birds or other avian species is essential to diagnose psittacosis.

Comparative studies of doxorubicin and 4'-epidoxorubicin effects on cardiovascular system in rabbits.

4'-epidoxorubicin (4'-epiDXR) was compared with doxorubicin (DXR) for myocardial effects in rabbits. Histologically, both drugs when given for six weeks induced a high incidence of diffused myocardial damage. The myocardial damage was less evident in rabbits treated with 4'-epiDXR than DXR for 3 weeks. Functionally 4'-epiDXR like DXR significantly reduced cardiac index (CI), stroke index (SI) and mean arterial blood pressure (MAP).