Cardiac afferents attenuate the muscle metaboreflex in the rat

The influence of cardiac afferents on the muscle metaboreflex was examined in 16 rats instrumented with a Silastic-tipped catheter in the pericardial space and right atrium, Doppler ultrasonic flow probe and a pneumatic vascular occluder around the terminal aorta, and a Teflon catheter in the thoracic aorta. In protocol I (cardiac efferent and afferent blockade), the muscle metaboreflex was examined under three experimental conditions: 1) control, 2) cardiac autonomic efferent blockade [intrapericardial methylscopolamine (10 micrograms/kg) and propranolol (50 micrograms/kg)], and 3) combined cardiac autonomic efferent and afferent blockade (intrapericardial procainamide, 2%). In protocol II (blood volume expansion), the muscle metaboreflex was examined before and after 15% blood volume expansion. Mild treadmill exercise (9 m/min, 10% grade) increased heart rate (71 +/- 9.4 beats/min), mean arterial pressure (12 +/- 2.0 mmHg), and terminal aortic blood flow velocity (6 +/- 1.0 kHz). During exercise, a reduction of terminal aortic blood flow velocity (10.5 +/- 1.1%) reduced mixed venous PO2 18 +/- 6%. The gain of the muscle metaboreflex in the control condition was 14.6 +/- 2.9 mmHg/kHz. Efferent blockade reduced the gain 51 +/- 7%. However, combined cardiac efferent and afferent blockade increased the gain 207 +/- 64% above the efferent blocked condition and restored the gain to levels above those obtained in the control condition (18.3 +/- 4.6 mmHg/kHz). In addition, 15% blood volume expansion reduced the gain of the muscle metaboreflex regulation of mean arterial pressure and heart rate (44 +/- 9.5% and 41 +/- 12.0%, respectively). Thus cardiac afferents tonically inhibit the pressor response to a reduction in terminal aortic blood flow velocity during exercise.     

Comparative study of the effects of ouabain and digoxin on blood pressure of rats

OBJECTIVE: To compare the effect of ouabain on the blood pressure of rats with that of digoxin to find the evidences of the relationship between endogenous ouabain (EO) and development of hypertension. METHODS: Sprague-Dawley rats, which were divided into 3 groups, were infused with ouabain (23 x 75 micrograms.kg-1/day, i.p.), digoxin (36 x 84 micrograms.kg-1/day, i.p.) and normal saline (NS) once a day respectively. Systolic blood pressure and body weight were recorded weekly. Five weeks later, rats of ouabain group were randomly assigned to three infusion subgroups: Oc group, continued with ouabain infusion; Od group, added digoxin (73 x 68 micrograms.kg-1/day, i.p.) and Os group, stopped administration of ouabain. Another week later, direct blood pressure was recorded in aorta. Systolic and diastolic cardiac function, plasma renin activity and aldosterone levels of all the rats were measured. RESULTS: After a latent period of one week, blood pressure of Ouabain group increased significantly [95.4 +/- 11.8 mmHg (1 mmHg = 0.133 kPa) at the beginning of the experiment vs 122.5 +/- 16.9 mmHg at the end of week 6, P < 0.05] with normal plasma renin activity and higher aldosterone (1.28 +/- 0.45 ng/ml vs 0.69 +/- 0.27 ng/ml, P < 0.05). The blood pressure decreased after either withdrawal of ouabain or addition of digoxin (116.3 +/- 14.4 mmHg vs 100 +/- 10.7 mmHg, P < 0.05; 123.9 +/- 13.9 vs 103.3 +/- 10.5 mmHg, P < 0.05, respectively). No difference of blood pressure was found between the digoxin and NS group. CONCLUSIONS: Our results suggested that EO might be one of the causes of the development of hypertension. Aldosterone might play some role in the mechanism of ouabain-induced hypertension. Digoxin can not induce hypertension. There is a great difference between the effect of ouabain and digoxin on the blood pressure. Moreover, digoxin can reverse the hypertension induced by ouabain.     

Impairment of digoxin clearance by coadministration of quinidine

Seven healthy volunteers received a single 1.0-mg dose of intravenous digoxin in a drug-free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half-life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min.kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long-term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P less than 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.     

Daily variations of platelet aggregation in relation to blood and plasma serotonin in diabetes

INTRODUCTION: An increase in digitalis-like substances has been reported in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We hypothesized that the role of saline and unilateral nephrectomy in DOCA hypertension may be due to stimulation of endogenous digitalis-like substances. METHODS: We investigated the effects of digoxin and DOCA alone and in combination in intact rats drinking water. Forty male Sprague-Dawley rats were used (body weight 223-298 g). RESULTS: Neither digoxin (40 micrograms/kg per day, by gavage, for 35 days, n = 10) nor DOCA (30 mg/kg twice a week, subcutaneously, for 5 weeks, n = 10) caused a consistent increase in blood pressure in intact rats drinking water. In contrast, combined digoxin and DOCA administration (n = 10) increased systolic blood pressure from day 18 of treatment onwards, to a maximum at day 34 compared with sham-treated rats (n = 10). There were no consistent changes in water intake, urine volume, urinary sodium or potassium excretion, or plasma sodium or potassium concentration with digoxin treatment. DOCA increased water intake and urine volume, and caused an initial decrease in urinary sodium excretion, but no change in urinary potassium excretion or plasma sodium concentration. Plasma potassium excretion was lower in DOCA- than sham-treated rats. CONCLUSION: Combined digoxin and DOCA administration in intact rats drinking water increased blood pressure significantly compared with either drug alone, raising the possibility that the mechanism by which nephrectomy and salt loading contribute to DOCA hypertension in the rat might be through stimulation of endogenous digitalis-like substances.     

Effects of carperitide (alpha-human atrial natriuretic peptide) on acute congestive heart failure in dogs

Effects of carperitide (alpha-human atrial natriuretic peptide) on hemodynamics and renal function in dogs with congestive heart failure (CHF) produced by volume expansion and ligation of the left anterior descending coronary artery were compared with those of various anti-heart failure agents (cardiotonic, vasodilator and diuretic). Carperitide (0.1-1 microgram/kg/min) dose-dependently decreased the elevated left ventricular end-diastolic pressure (LVEDP). No significant changes in cardiac contractility (LV dP/dtmax) and heart rate (HR) were noted, although cardiac output (CO) tended to reduce during the infusion of carperitide. Nitroglycerin (NG; 3 micrograms/kg/min) and furosemide (1 mg/kg) also decreased LVEDP, but the potency was less than that of carperitide. Sodium nitroprusside (SNP; 10 micrograms/kg/min) and dobutamine (10 micrograms/kg/min) caused a reduction in LVEDP and increased CO with an increase in HR. Hydralazine (H; 100 micrograms/kg/min) increased CO without reduction in LVEDP and induced a pronounced increase in HR. Double product (systolic blood pressure x HR), an index of myocardial oxygen consumption, was significantly reduced by carperitide, but significantly increased by DB and H. Carperitide, unlike NG, SNP, H and DB, increased urine volume and urinary electrolyte excretion. These results suggest that carperitide will be an useful therapeutic agent for the treatment of CHF.     

Immunoassay of digoxin in hair

Digoxin analysis in blood is an essential tool for therapeutic drug monitoring in cardiology because compliance with the treatment is a critical issue for the patient. Unfortunately, in postmortem cases blood digoxin concentration is of poor quality because there is a possible drug redistribution in the corpse and because of digoxin-like factors present in some people's blood. On the other hand, no biological fluid can be obtained at the autopsy. The aim of the present study was to evaluate the ability of an immunological method to determine digoxin in hair, in order to confirm that hair analysis can provide information on digoxin use before death. We studied 35 elderly patients who had been taking digoxin (60-250 micrograms/day) for 1-5 years. Two decontamination procedures were tested: washing by dichloromethane or by water and methanol. Three extraction procedures were compared: crushing in a ball mill and chloroform/acetone: crushing and methanol; enzymatic digestion. Immunoassays were performed by a microparticulate enzyme immunoassay. Serum digoxin levels were also assayed when sampling hair. The best results were obtained after decontamination with water and methanol followed by enzymatic digestion. Hair digoxin concentrations range from 3.6 to 11.4 pg/mg. Those very low concentrations are probably due to low and narrow range serum digoxin levels (0.3-1.4 ng/ml). No correlation was found between hair and blood digoxin. A forensic case is presented with 5 pg/mg digoxin in hair.     

Anesthesia for heart transplantation in newborn and suckling infants. Special aspects of the hypoplastic left heart syndrome

Paediatric cardiac transplantation (pHTX) has gained widespread acceptance as a therapy in end-stage myocardial failure and some forms of congenital heart disease, particularly hypoplastic left heart syndrome (HLHS). The major problems to the anaesthesiologist in these patients are induction of anaesthesia in infants with HLHS and treatment of pulmonary hypertension in the early post-bypass period. PATIENTS AND METHODS. Anaesthesia for pHTX was performed in 15 children < 1 year of age (4-237 days); 12 suffered from HLHS, 2 from endocardial fibroelastosis, and 1 from dilatative cardiomyopathy. Induction of anaesthesia in patients with HLHS IS a challenge to the anaesthesiologist, as he has to maintain the delicate balance between pulmonary and systemic blood flow. Anaesthesia was induced with fentanyl (10-15 micrograms/kg) and pancuronium (0.2-0.4 mg/kg) and maintained with fentanyl (total dosage 70-100 micrograms/kg). Modification of ventilatory parameters such as FiO2, PaCO2, and airway pressure (PEEP, I:E ratio) was used to influence systemic and pulmonary blood distribution in the pre-bypass period according to changes in haemodynamics (target: O2 saturation approximately 75%-80%, PaCO2 45-50 mmHg). Treatment of pulmonary hypertension in the weaning and early post-bypass period consisted of respiratory (PaCO2 < 30 mmHg) and metabolic alkalinisation (pH 7.45-7.55, BE > +3 mmol/l), the use of prostaglandin E1 (3-6-12 micrograms/kg.h), and the phosphodiesterase inhibitor enoximone (10-15 micrograms/kg.min). Additional positive inotropic support was achieved with dobutamine (5-10 micrograms/kg.min), adrenaline (0.1-0.5 micrograms/kg.min), and/or orciprenaline (0.1-0.2 micrograms/kg.min) and calcium chloride (25-100 mg/kg). RESULTS. Two children died intraoperatively and 1 on the 1st postoperative day from overwhelming pulmonary vascular resistance and right ventricular failure. Three children died between 3 and 4 weeks postoperatively, 1 from cytomegalovirus infection, 1 from sepsis, and 1 from acute rejection. Nine patients survived and are well up to 5.5 years after transplantation. CONCLUSION. Pulmonary hypertension in the weaning and early post-bypass period is the main anaesthesiological problem of pHTX, particularly in children with HLHS. A polypragmatic approach to this problem consisting of alkalinisation, pulmonary vasodilatation, and inotropic support is presented and seems to be effective. Further improvements in concepts of pHTX are limited by the lack of donor organs. Though the experience with pHTX in neonates and infants is growing slowly, it might be a routine procedure from the anaesthesiological point of view within a few years in some selected centres.     

Responses of older men with and without chronic obstructive pulmonary disease to prolonged ozone exposure

Measurement of cardiac output by Doppler echocardiography were compared to simultaneous measurements by thermodilution in 9 conscious horses. In the Doppler technique, mean blood flow velocities for estimation of cardiac output were recorded from the aorta and pulmonary artery. The flow area of each vessel was calculated from the vessel diameter, measured from a 2-dimensional ultrasound image. Differences in the site and method of measuring the vessel diameter altered the estimation of cardiac output by the Doppler method. Cardiac output was modified by the i.v. infusion of 4 micrograms/kg bwt/min dopamine and 4 micrograms/kg bwt/min dobutamine and by the i.v. administration of 10 micrograms/kg bwt detomidine and 20 micrograms/kg bwt butorphanol. Doppler measurements of cardiac output correlated closely with measurement by thermodilution. Measurements from the aortic outflow correlated more closely with thermodilution, than those from the pulmonary artery (r = 0.89 and r = 0.77, respectively). Doppler measurements when the mean flow velocity was recorded from the aorta and the flow area was measured from the ascending aorta using the leading edge method. There was no significant bias between the 2 techniques when Doppler flow velocities were recorded by this method and the limits of agreement were narrow (+/- 12.26 l/min). The differences between the 2 methods increased with increasing cardiac output. Doppler echocardiography is a safe noninvasive method of measuring cardiac output in horses. The agreement between Doppler echocardiography and thermodilution in this study is similar to that reported in man and is similar to that reported between thermodilution and other techniques in man.     

The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension

OBJECTIVE: Studies on the effects of digoxin in patients with right ventricular failure and normal left ventricular function have not been performed. We evaluated the short-term effects of digoxin administration in patients with primary pulmonary hypertension on hemodynamics, neurohormones, and baroreceptor responsiveness. DESIGN: This was a prospective study with patients serving as their own controls. SETTING: University Hospital Intensive Care Unit with central monitoring. PATIENTS: Seventeen patients with primary pulmonary hypertension and symptomatic heart failure were enrolled. INTERVENTIONS: Following baseline hemodynamics, neurohormonal samples were drawn and the heart rate response to change in blood pressure following a challenge of phenylephrine and nitroprusside were recorded. One mg of intravenous digoxin was given and the measurements repeated after 2 hours. RESULTS: Following digoxin there was a significant increase in cardiac output (3.49+/-1.2 to 3.81+/-1.2 L/min., p=0.028), a significant fall in norepinephrine (680+/-89 to 580+/-85 pg/ml, p=.013), and a significant increase in atrial natriuretic peptide (311+/-44 to 421+/-9 pg/ml, p=0.01). All of the patients had changes in heart rate and blood pressure following phenylephrine and nitroprusside challenge, but there was no significant difference in the change in heart rate response to change in blood pressure when rechallenged after digoxin treatment. CONCLUSION: Digoxin produces a modest increase in cardiac output in patients with pulmonary hypertension and right ventricular failure, as well as a significant reduction in circulating norepinephrine. No detectable effects of digoxin on baroreceptor responsiveness were apparent. The use of digoxin in pulmonary hypertension is warranted.     

K+ channel-opening action contributes to the preventive effects of nicorandil on U46619-induced vasoconstriction of canine large coronary arteries in vivo

The antispasmogenic effects of nicorandil on epicardial coronary artery vasoconstriction were compared with those of a K+ channel opener, cromakalim, and a nitrovasodilator, nitroglycerin, in open-chest dogs. Intracoronary administration of U46619 (0.5-1.0 micrograms), a stable thromboxane A2 analogue, reduced the external diameter of the left circumflex coronary artery with no marked alternations in systemic hemodynamics. This U46619-induced vasoconstriction of large epicardial coronary arteries was dose-dependently prevented by the intracoronary infusion of nicorandil (1-10 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min). After pretreatment with glibenclamide (3 mg/kg, i.v.), and ATP-sensitive K+ channel blocker, these effects of nicorandil and cromakalim were inhibited significantly, whereas the response to nitroglycerin remained unchanged. Nicorandil (3 micrograms/kg/min), cromakalim (0.03 micrograms/kg/min) and nitroglycerin (1 micrograms/kg/min) increased coronary blood flow. However, the inhibitory effects of each drug on the U46619-induced vasoconstriction were not influenced by the partial occlusion of the left circumflex coronary artery, which kept coronary blood flow constant. This indicates a direct antispasmogenic effect of K+ channel openers, which is independent of that mediated by the response to flow. Furthermore, our results suggest that, by this effect, nicorandil protects large coronary arteries from U46619-induced vasoconstriction.     

Effect of KRN2391 on venous return: comparison with other vasodilators

We compared the cardiohemodynamic effects of KRN2391, a novel coronary vasodilator, with those of nicorandil, nifedipine, cromakalim, and nitroglycerin (NTG) administered intravenously (i.v.) to anesthetized open-chest dogs. KRN2391 (10 and 30 micrograms/kg) decreased mean blood pressure (MBP) and superior vena cava flow (SVCF), and increased inferior vena cava flow (IVCF), total venous return (TVR), pulmonary artery blood flow (PAF), and right atrial pressure (RAP). Administration of KRN2391 (30 micrograms/kg) decreased heart rate (HR). Nicorandil (100 and 300 micrograms/kg) decreased MBP and SVCF, and produced transient increases followed by decreases in IVCF, TVR, PAF, and RAP. HR was decreased by administration of nicorandil (300 micrograms/kg). Nifedipine (1 and 3 micrograms/kg) decreased MBP and increased SVCF, IVCF, TVR, PAF, and RAP. HR was not affected by either dose of nifedipine. Cromakalim (10 micrograms/kg) decreased MBP, SVCF, and increased HR, IVCF, TVR, PAF and RAP. Nitroglycerin (3 micrograms/kg) decreased MBP, SVCF, IVCF, TVR, PAF, and RAP. In dogs that received glibenclamide (5 mg/kg, i.v.), the changes in MBP, SVCF, IVCF, TVR, PAF, and RAP caused by KRN2391 were reduced in comparison with those in dogs that received vehicle for glibenclamide. The decreases in IVCF, TVR, and PAF induced by nicorandil were not affected by glibenclamide, but the decrease in MBP was diminished and the decrease in RAP was augmented. The hemodynamic changes caused by cromakalim were almost inhibited by glibenclamide, whereas those caused by NTG were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)     

A new concept of cotreatment with human growth hormone and menotropins in ovulation induction protocols

Inhibition of Na+/K+ ATPase by cardiac glycosides has been shown to potentiate toxic effects of excitatory amino acids and mitochondrial poisons in neurons in vitro. The present study tested the hypothesis that the systemic administration of the cardiac glycoside, digoxin, potentiates effects of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in vivo. Mice were injected with digoxin (1 mg/kg) or vehicle followed by MPTP (20 mg/kg) or saline 1 h later. After 1 or 8 days, mice were euthanized and dopamine levels in the striatum were measured by high-performance liquid chromatography with electrochemical detection. MPTP caused a significant 35-45% reduction in striatal dopamine levels compared to those in control mice. However, pretreatment with digoxin completely prevented the MPTP-induced dopamine depletion. This result was unexpected and suggests that cardiac glycosides may protect against MPTP neurotoxicity.     

Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism

A standard electrical stimulus applied to the posterior hypothalamus evoked cardiac arrhythmogenic responses in the spontaneously hypertensive rat. Isolated premature ventricular beats or doublets and nonsustained ventricular tachycardic salvos were observed. This effect was associated with a large rise in blood pressure (79 +/- 3 mm Hg). The same stimulus in normotensive Wistar-Kyoto rats produced no significant cardiac arrhythmias, and the rise in blood pressure was smaller (36 +/- 2 mm Hg). We investigated the influence of baclofen, a GABAB receptor agonist, and two N-methyl-D-aspartate receptor antagonists on the arrhythmogenic response to hypothalamic stimulation. Intravenous baclofen (3 mg/kg) had no effect in the normotensive Wistar-Kyoto rats, but in the spontaneously hypertensive rats it enhanced the adjusted mean value of the number of extrasystoles from 0.5 +/- 0.5 to 18 +/- 1 (P < .001). This value was also increased (from 3 +/- 1 to 17 +/- 1, P < .001) by an intracisternal injection of baclofen (1 micrograms/kg). This facilitatory effect of baclofen was prevented by treatment with atenolol (0.5 mg/kg). Two glutamate receptor antagonists, ketamine (7.5 mg/kg IV) and kynurenic acid (200 micrograms/kg intracerebroventricularly), prevented both the arrhythmogenic response to the hypothalamic stimulation and its facilitation by baclofen. The study confirms that hypothalamic stimulation facilitates the development of arrhythmias through a sympathetic drive and that these arrhythmias are easier to induce in spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. Both the central GABAergic and the glutamatergic systems are implicated in the development of these ventricular arrhythmias, since baclofen could disinhibit the glutamatergic central pathway. These results could account for the ability of the spontaneously hypertensive rats to develop ventricular arrhythmias of central origin.     

Increase in myocardial digoxin content associated with circulatory volume overload in the dog

1. Tritiated (12alpha-3H) digoxin (0-05 mg/kg body weight) was administered intravenously to conscious dogs with circulatory volume overload induced by previous creation of aorto-caval fistulae. Dogs were killed after 5 min, 1, or 4 h, and the myocardium sampled. Digoxin was extracted and counted and results compared to those in normal dogs. 2. At each time, myocardial digoxin concentration of all cardiac chambers in test dogs was greater than normal. Plasma digoxin concentration measured 5 min after administration was greater in dogs with fistulae but the subsequent levels were not different. 3. Anaesthetized and open-chest dogs with fistulae studied 5 min after digoxin administration had greater myocardial concentrations than similarly studied normal dogs. Although myocardial concentrations of digoxin were higher in anaesthetized than in conscious dogs the group with fistulae had higher values than did the normal group, as was the case for unanaesthetized dogs. 4. The basis for the effect of fistula is probably multifactorial. Diminised peripheral blood flow and peripheral digoxin delivery and uptake, resulting initially in higher digoxin levels in plasma perfusing the myocardium, may play a role. Increased myocardial mechanical and metabolic activity almost certainly are important. Cardiac hypertrophy, cardiac failure per se and plasma electrolyte changes are probably not. 5. The results are consistent with previously demonstrated reduced digitalis tolerance in the dog with circulatory volume overload.     

Primary anastomosis of the trachea: management and pitfalls

The potentiating activity of SG-86[N-(2-hydroxyethyl)nicotinamide], a denitrated metabolite of nicorandil, on the adenosine-induced vasodepression was compared with that of nicorandil in anesthetized rats. Single bolus i.v. adenosine (3-100 micrograms/kg) produced dose-dependent reductions of blood pressure, accompanied by slight decreases (except for 100 micrograms/kg) in heart rate. The adenosine-induced vasodepression was significantly enhanced during i.v. infusion of either SG-86 (100 micrograms/kg per min) as well as nicorandil (10 micrograms/kg per min). The enhancement of adenosine action by them did not occur in the presence of glibenclamide (20 mg/kg i.v.). Single bolus i.v. injections of SG-86 (0.3-30 mg/kg), except for 30 mg/kg, which caused a glibenclamide-sensitive decrease by about 5-10 mmHg in mean arterial blood pressure, had no effects on blood pressure and heart rate, whereas those of nicorandil (30-300 micrograms/kg) elicited overt reduction of blood pressure, accompanied by decreases in heart rate. The present results revealed that SG-86, like nicorandil, significantly enhanced the vasodepressor response to adenosine, probably in part through KATP channel activation, and that the activity of SG-86 was about 10 times less potent than that of nicorandil.     

Effect of subintimal resection on initial outcome and restenosis for native coronary lesions and saphenous vein graft disease treated by directional coronary atherectomy. A report from the CAVEAT I and II investigators. Coronary Angioplasty Versus Excisional Atherectomy Trial

An analytical method is presented for liquid chromatographic (LC) determination of mebendazole (MBZ), hydroxymebendazole (MBZ-OH), and aminomebendazole (MBZ-NH2) in eel muscle tissue. Muscle tissue is extracted with ethyl acetate at pH 7.5. After addition of n-hexane, the extract is cleaned up and concentrated on an aminopropyl solid-phase extraction column. The test solutions are analyzed isocratically on a ChromSpher B LC column with acetonitrile-phosphate buffer, pH 6.2, as mobile phase. Limits of detection and quantitation were 0.7 and 1.1 micrograms/kg, respectively, for MBZ-OH; 1.4 and 2.3 micrograms/kg, respectively, for MBZ; and 1.5 and 2.1 micrograms/kg, respectively, for MBZ-NH2- Interand intraday coefficients of variation were 3.5 and 3.4%, respectively, for MBZ-OH; 2.5 and 3.1%, respectively, for MBZ; and 5.8 and 4.8%, respectively, for MBZ-NH2. Mean recoveries were 90% for MBZ, 74% for MBZ-NH2, and 92% for MBZ-OH. A linear range of applicability of at least 10-1000 micrograms/kg was found for each analyte. Incurred MBZ-NH2 (181.3 micrograms/kg) was identified in eel muscle tissue apart from MBZ (23.7 micrograms/kg) after 48 h exposure in a treatment bath containing MBZ at 1 mg/L.     

Cardioprotective effect of enalapril in renovascular and angiotensin II hypertension

The influence of chronic treatment with enalapril or losartan (10 or 30 mg/kg/24h, respectively) on cardiac mass was evaluated in one-kidney, one clip (1K-1C) hypertensive rats submitted to sodium restriction 3 weeks after clipping and in rats infused for 10 days with angiotensin II (ANGII: 200 ng/kg/min). In 1K-1C hypertension, cardiac mass and arterial pressure were reduced to a similar extent by enalapril and losartan. In ANGII hypertension, enalapril and losartan blunted the increase in cardiac mass whereas losartan but not enalapril prevented the development of hypertension. The cardioprotective effect of enalapril was attenuated by concomitant blockade of bradykinin receptors (Hoe140: 300 micrograms/kg/24h) in both models. The beneficial influence of enalapril on cardiac mass appears to be independent of its effect on blood pressure and ANGII generation and seems partly mediated by endogenous bradykinin in these high ANGII models of hypertension.     

Dexamethasone-induced hypertension in the rat: effects of L-arginine

1. The effects of L-arginine treatment on dexamethasone-induced hypertension were examined in the Sprague-Dawley rat. Seventy rats were randomly divided into the following eight groups: sham, dexamethasone (5 and 10 micrograms/day, L-arginine (100 and 500 mg/kg per day), L-arginine (100 or 500 mg/kg per day) + dexamethasone (10 micrograms/day), L-arginine (520-797 mg/kg per day in food) + dexamethasone (5 micrograms/day). Systolic blood pressure (SBP), bodyweight and plasma nitrate/nitrite concentration were measured. 2. Dexamethasone (5 and 10 micrograms/day) increased SBP in both sham and L-arginine-treated rats. Dexamethasone at 10 micrograms/day decreased bodyweight, but did not alter plasma nitrate/nitrite concentrations. 3. L-Arginine (500 mg/kg per day, i.p.) increased plasma nitrate/nitrite concentrations in 10 micrograms/day dexamethasone-treated rats. L-Arginine did not alter blood pressure in either sham or dexamethasone-treated rats. 4. Dexamethasone-induced hypertension differs from adrenocorticotropic hormone (ACTH)-induced hypertension in the rat in that it is not modified by L-arginine. Thus, ACTH-induced hypertension cannot be explained simply in terms of glucocorticoid activity.     

The effect of hypoxia on the regional distribution of cardiac output in the dog

Twenty-one dogs were studied under conditions of normal oxygenation and hypoxia with the microsphere distribution method to determine the effect of arterial oxygen saturation on the regional distribution of cardiac output. The dogs were anesthetized and artifically ventilated. Cannulas were placed in the left ventricle to administer microspheres and in a peripheral artery to determine cardiac output. Each dog received two microsphere injections: (1) while normally oxygenated (room air), and (2) under hypoxia (10% oxygen-90% nitrogen in 10 dogs and 5% oxygen-95% nitrogen in 11 dogs). Absolute cardiac output increased from 87 +/- 15 ml/min per kg to 101 +/- 14 ml/min per kg during mild hypoxia (10% oxygen) (P less than 0.05), and from 73 +/- 17 ml/min per kg to 120 +/- 24 ml/min per kg during severe hypoxia (5% oxygen) (P less than 0.01). Absolute blood flows increased to all organs except skin and muscle during hypoxia, although there were decreases in the fractional distribution of cardiac output to the splanchnic bed and kidney. Striking changes were found in coronary, hepatic, and cerebral circulation, and the organ with, greatest response to hypoxia was the heart, with increased coronary flow of 37% and 285% during exposure to 10% and 5% oxygen, respectively. Hence, low oxygen levels in blood cause redistribution of cardiac output and arterial content plays an important role in blood flow regulation.     

Effects of recombinant human interleukin 6 (rhIL-6) in marmosets (Callithrix jacchus). 1. General toxicity and hematological changes

The physiological and toxicological properties of recombinant human interleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jacchus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 micrograms rhIL-6/kg per day for three weeks and (b) 25, 100 or 500 micrograms rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific signs of toxicity. The main findings were: (1) A two- to threefold increase in platelet counts at 2-4 weeks, which decreased following further continuous rhIL-6 administration; (2) increase in total white blood cells between 1 and 4 weeks of administration, including an absolute increase in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total red blood cells, which peaked at 4 weeks, sustained elevation of red cell distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemoglobin at 4 weeks. This effect persisted for 9 weeks in the 100 micrograms/kg and 500 micrograms/kg groups; (4) decrease in plasma AST activity and increase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) RhIL-6 after s.c. administration was detectable in the plasma, peak levels (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were measured after a single dose of 100 or 1000 micrograms/kg; (7) antibodies against rhIL-6 developed within 2 weeks, increased during administration and neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tolerated in marmosets and had a profound and sustained effect on thrombopoiesis. Due to the formation of neutralizing antibodies, the chronic biological effect of rhIL-6 is lost in marmosets and studies beyond 4 weeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alterations on lymphocyte receptors will be reported in two following publications.