Effect of moricizine hydrochloride in reducing chronic high-frequency ventricular arrhythmia: results of a prospective, controlled trial

The antiarrhythmic efficacy of moracizin HCl (Ethmozine), a new oral phenothiazine derivative, was evaluated in 20 patients with chronic high-frequency ventricular arrhythmia confirmed by multiple ambulatory electrocardiographic recordings. Comparison with 72 +/- 24 hours (+/- standard deviation) of ambulatory recordings on moracizin treatment (average dose 295 +/- 58 mg 3 times daily or 9.8 +/- 1.0 mg/kg/day) was made. Maximal treadmill exercise provocation of arrhythmia and echocardiographic studies to detect effects on left ventricular function were also compared. The group had an average of 378 +/- 97 ventricular premature beats (VPBs) per hour while receiving placebo, with a mean VPB grade of 3.4 +/- 1.1 (modified Lown). When the patients received moracizin HCl, VPB frequency was reduced 53% (p less than 0.01), to a mean VPB grade of 2.2 +/- 1.4 (p less than 0.05). Seventy percent of the patients (14 of 20) showed a reduction in VPB frequency that exceeded the maximal expected variation; in 3 the frequency did not change and in 3 it increased with moracizin HCl. Resting electrocardiographic changes consisted of modest prolongations of PR interval (0.03 second) and QRS duration (0.02 second); however, QT prolongation was not observed. Heart rate and blood pressure at rest and peak exercise, exercise-related arrhythmia, exercise durations and echocardiographic measures of left ventricular function were unchanged by moracizin HCl compared with placebo. Side effects of moracizin++ HCl at these dosages were minimal (diarrhea in 1 patient, dizziness in 1 and diaphoresis in 1), although 2 patients tested at higher dosages had sustained ventricular tachycardia that may have been related to moracizin HCl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of alpha-adrenergic blockage on cellular Ca2+ during endotoxic shock.

The effect of alpha-adrenergic receptor antagonists, phentolamine, and prazosin on cytosolic Ca2+ concentration, [Ca2+]i, was studied in hepatocytes during endotoxic shock. Rats were given intravenous injections of endotoxin (20 mg/kg), phentolamine (3 mg/kg) plus endotoxin (20 mg/kg), or prazosin (5 mg/kg) plus endotoxin (20 mg/kg). They were sacrificed 5 hr later, at which time the endotoxin-injected rats showed signs of shock. Isolated hepatocytes were prepared and employed for the measurement of [Ca2+]i under basal and hormone-stimulated (1 and 10 microM epinephrine) conditions by means of Quin 2 fluorescence technique. The apparent basal level of [Ca2+]i in endotoxic rat hepatocytes (mean +/- SE: 482 +/- 31 nM) was significantly higher (P less than 0.05) than in phentolamine plus endotoxin (242 +/- 73) and prazosin plus endotoxin (240 +/- 43) groups. A significant increase in hepatocyte [Ca2+]i occurred with epinephrine in the phentolamine plus endotoxin and prazosin plus endotoxin groups, but not in the group receiving endotoxin alone. Endotoxic rats showed a mortality rate of 75%, whereas phentolamine plus endotoxin and prazosin plus endotoxin groups showed a mortality rate of 38% and 20% respectively. These data suggest that the protective effect of alpha-adrenergic receptor antagonists during endotoxic shock may be mediated, in part, by attenuating the entrance of Ca2+ into endotoxic liver cells.     

Determination of the optimal dose of captopril in the treatment of severe cardiac failure by hourly hemodynamic monitoring

The optimal dose of Captopril was evaluated by hourly haemodynamic monitoring in 10 patients with chronic congestive cardiac failure (Stage IV of the NYHA Classification) after administration of 25 mg, 50 mg, and 100 mg of Captopril. A similar improvement was observed in all the parameters considered with all three dosages. At its peak effect (90 minutes) 25 mg of Captopril caused a fall in pulmonary capillary, and mean pulmonary artery pressures, and a fall in systemic resistance of 40%, 20% and 30% respectively; with 50 mg of Captopril, the effect was a fall of 36%, 24% and 35% respectively. The cardiac index rose by 17% with 25 mg of Captopril, 28% with 50 mg and 12% with 100 mg of Captopril. Although the fall in pulmonary capillary pressure remained significant up to the 6th hour, the improvement in cardiac index was not significant after the 3rd hour. After 8 days' treatment, plasma renin activity increased from 7.01 +/- 4.68 to 23.6 +/- 18.3 ng/ml/hour (p less than 0.02) and serum aldosterone fell from 1.175 +/- 386 p. moles/l to 497 +/- 277 p. moles/l (p less than 0.001). There was no correlation between basal plasma renin activity and pre- or post-therapeutic systemic resistances. The clinical and haemodynamic improvement was sustained after 2 months' treatment in 5 of these patients without side effects. Increasing the dosage of Captopril does not reinforce or prolong its action; moderate doses (25 mg) are as effective as high doses (100 mg). Captopril, which acts by inhibiting the renin- angiotensin-aldosterone system is the current treatment of choice in severe refractory cardiac failure.     

Adrenergic mechanisms involved in the control of pituitary-adrenal activity in the rat: a beta-adrenergic stimulatory mechanism

Epinephrine or isoproterenol was infused into a lateral tail vein of female Wistar rats under Nembutal anesthesia. After 20 min of diffusion, trunk blood was collected for the determination of plasma corticosterone (B) and ACTH immunoreactivity (ACTHi). Infusion of l-epinephrine resulted in a dose-related increase in plasma ACTHi and B. Maximal levels were similar to those observed during ether stress. The pituitary-adrenal system appeared more sensitive than the cardiovascular system to epinephrine, since the ED50 values of epinephrine for its effects on ACTHi and heart rate were 165 and 840 ng/kg . min, respectively. The effect of epinephrine on pituitary-adrenal activity could be mimicked by the beta-adrenergic agonist l-isoproterenol and could be blocked by the beta-adrenergic antagonist l-propranolol, whereas d-propranolol was ineffective. The response of the pituitary-adrenal system to epinephrine was not caused by effects on peripheral parameters such as the distribution or clearance of ACTH or B but was mediated by an increase in ACTH release. The pituitary-adrenal response to epinephrine and isoproterenol was not related to changes in heart rate, blood pressure, or vasopressin secretion. Infusion of epinephrine at a dose that induced a maximal increase in plasma ACTHi and B (1000 ng/kg . min) resulted in a circulating epinephrine concentration of 11 pmol/ml, which is within the physiological range. From these data we conclude that 1) circulating epinephrine can stimulate pituitary-adrenocortical activity, 2) this action is mediated by a beta-adrenergic receptor mechanism, and 3) such a mechanism may be involved in the response of the pituitary-adrenal axis during certain forms of stress.     

Insulin action and fibrinolysis influenced by vitamin E in obese Type 2 diabetes mellitus.

Increased oxidative stress, hypofibrinolysis and insulin resistance are present in obese Type 2 diabetic patients. It is supposed that treatment with antioxidant alpha-tocopherol (vitamin E) could not only decrease free radical production, but also ameliorate insulin action. We evaluated the effect of 3 months administration of vitamin E (600 mg daily) on insulin action examined by hyperinsulinemic clamp in 11 obese Type 2 diabetic patients. Oxidative stress and fibrinolysis were also determined. The administration of vitamin E caused a decrease of glucose disposal rate (26.6 +/- 9.5 vs 21.3 +/- 7.5 micromol/kg/min, P < 0.02) and of metabolic clearance rate of glucose (3.7 +/- 1.6 vs 2.9 +/- 0.8 ml/kg/min. P < 0.02). A decrease of insulin receptor number was observed on erythrocytes after vitamin E (284 +/- 84 vs 171 +/- 59 pmol/l, P < 0.01). Significantly higher plasma malondialdehyde (MDA) concentration documented an increased oxidative stress in diabetic patients as compared with healthy persons (3.13 +/- 0.68 vs 1.89 +/- 0.18 micromol/l, P<0.001). An inverse relationship was found between MDA concentration and insulin sensitivity expressed by glucose disposal rate (r = -0.73). Vitamin E further worsened the hypofibrinolysis documented by a decrease of tissue plasminogen activator (P < 0.01) without changes in its inhibitor PAI-1. In conclusion. our results demonstrate that higher doses of vitamin E may further deteriorate insulin action and fibrinolysis in obese Type 2 diabetic patients.     

Influence of sympatho-adrenal system on insulin sensitivity using the euglycemic clamp technique.

The aim of the present study was to further investigate the role of the adrenergic system on insulin action using the euglycemic clamp technique. Whole-body glucose metabolism (GM) was calculated as the glucose infusion rate for maintaining euglycemia under insulin infusion and used as an indicator of insulin sensitivity. Euglycemic clamps were performed in adrenodemedullated, epinephrine-treated, phentolamine-treated (alpha-blockade), propranolol-treated (beta-blockade), and epinephrine plus phentolamine and/or propranolol-treated rats. The following results were obtained at an insulin level of approximately 80 mU/l. GM in adrenodemedullated rats (13.97 +/- 0.98 mg/kg/min) was significantly higher than that of the control rats (10.26 +/- 0.50 mg/kg/min, P less than 0.01). GM in epinephrine-treated rats (1.7 mg/kg body weight/h) was 2.12 +/- 0.49 mg/kg/min (P less than 0.001 vs. control). Dose-response curves for phentolamine and propranolol established maximally effective doses (3.0 mg and 12 mg/kg body weight/h, respectively). Using these doses, GM in epinephrine plus phentolamine-treated rats (4.90 +/- 0.39 mg/kg/min) was significantly higher than that of epinephrine alone and GM in epinephrine and propranolol-treated rats (4.49 +/- 0.47 mg/kg/min) was also significantly higher than that of the epinephrine alone. GM in the epinephrine plus both propranolol and phentolamine (5.94 +/- 0.45 mg/kg/min) was significantly higher than that of the epinephrine alone, but not different from either treatment alone and was not additive. Neither phentolamine alone (9.48 +/- 1.45 mg/kg/min), propranolol alone (10.36 +/- 0.55 mg/kg/min) or the combination of blockades (11.14 +/- 0.65 mg/kg/min) had any effect on GM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cariporide potentiates the effects of epinephrine and vasopressin by nonvascular mechanisms during closed-chest resuscitation

BACKGROUND: The efficacy of vasopressor therapy during closed-chest resuscitation is limited and decreases over time. We previously reported that sodium-hydrogen exchanger isoform-1 inhibition during ventricular fibrillation (VF) using cariporide ameliorates ischemic contracture and enhances the efficacy of chest compression. We currently investigated whether cariporide could potentiate pressor responses to epinephrine and vasopressin. METHODS: VF was induced and left untreated for 12 min in two series of 16 rats each. Chest compression was then started and the depth adjusted within the initial 2 min to attain an aortic diastolic pressure between 26 and 28 mm Hg. In one series, rats received boluses of epinephrine (150 microg/kg); in the other series, rats received boluses of vasopressin (0.8 U/kg) to maintain the aortic diastolic pressure > 25 mm Hg. Within each series, rats were randomized to receive a 3 mg/kg bolus of cariporide or 0.9% NaCl immediately before starting chest compression. Defibrillation was attempted at 20 min of VF (8 min of chest compression). RESULTS: Cariporide prompted higher and more sustained coronary perfusion pressures in both the epinephrine group (37 +/- 5 mm Hg vs 29 +/- 7 mm Hg, p < 0.05) and the vasopressin group (36 +/- 5 mm Hg vs 28 +/- 6 mm Hg +/- SD, p < 0.02) even though fewer additional vasopressor doses were required. After resuscitation, cariporide-treated rats had less ventricular ectopic activity, better hemodynamic function, and improved survival scores. In separate experiments, in situ perfusion of the aorta excluded a vascular-mediated effect of cariporide. CONCLUSION: Cariporide enhanced the hemodynamic efficacy of vasopressor agents and improved resuscitation outcomes probably as a result of enhanced forward blood flow without effect on the peripheral vasculature.     

Mechanism of cardiac arrhythmias induced by epinephrine in dogs with hypokalemia

To investigate the mechanism of ventricular arrhythmias induced by epinephrine in dogs with hypokalemia, 30 adult mongrel dogs were separated into a control group (n = 13) and a hypokalemia group (n = 17). In the hypokalemia group, sodium polystyrene sulfonate (5 g/kg body weight) was infused into the colon. In both groups, the serum concentrations of sodium, potassium and calcium were measured every 15 minutes for 60 minutes. The mean (+/- standard deviation) serum potassium level of the hypokalemia group decreased significantly from 3.81 +/- 0.21 to 2.92 +/- 0.36 mEq/liter; there were no significant changes in other electrolytes. After 60 minutes, epinephrine (10 micrograms/kg) was injected intravenously in the hypokalemia and control groups, and the arrhythmia ratio (the number of ventricular ectopic beats divided by the total heart rate) was calculated for 5 minutes. Each group was further classified into subgroups of dogs with an arrhythmia ratio higher or lower than 10%. An arrhythmia ratio over 10% was observed in 7.7% of the control group and 53% of the hypokalemia group. Immediately after 5 minutes of epinephrine injection, myocardial mitochondria and plasma membrane fraction were prepared from each group. Mitochondrial calcium content and phospholipase activity of plasma membrane fraction were determined. Significant increases in both mitochondrial calcium content and phospholipase activity were observed in the dogs with hypokalemia and an arrhythmia ratio greater than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)     

The adrenocorticotropin response to interleukin-1 beta instilled into the rat median eminence depends on the local release of catecholamines

Interleukin-1 beta (IL-1 beta) is a potent ACTH secretagogue which activates the release of hypothalamic CRF but is unable to cross the blood brain barrier. Recently, it was reported that IL-1 beta, instilled directly into the hypothalamic median eminence (ME), rapidly induced ACTH secretion. Thus, due to the lack of a blood brain barrier the ME appears to be a site whereby iv IL-1 beta can access the brain to stimulate CRF and, consequently, ACTH secretion. To evaluate the role of central catecholamines in this process, 250 g male rats were lesioned with 6-hydroxy-dopamine instilled into the lateral ventricle. Ten days later, rats received recombinant h-IL-1 beta (10 or 30 ng) into the ME and blood was sampled via indwelling jugular cannulae. The ACTH response to IL-1 beta, 30 ng, was reduced by approximately 50% in the lesioned rats (P = 0.05), and it was abolished in those receiving IL-1 beta, 10 ng (P less than 0.05). Moreover, in rats given iv IL-1 beta (1 microgram), 6-hydroxy-dopamine significantly reduced the ACTH response by more than 50% (P less than 0.001). To determine the effect of acute epinephrine depletion, 2,3 dichloro-alpha-methylbenzylamine (DCMB, 60 mg/kg BW) and SKF64139 (SKF) (100 mg/kg BW), inhibitors of the enzyme which converts norepinephrine to epinephrine, were administered ip 4 h before intra-ME IL-1 beta (30 ng). DCMB reduced the ACTH response by 80% and SKF reduced it to its own baseline. LY 10853, which acutely depletes both norepinephrine and epinephrine, also reduced the ACTH response by 80%. Because of the reported capacities of DCMB and SKF to block alpha 2 adrenoreceptors in vitro, yohimbine, an alpha 2 receptor antagonist, was studied. Intra-ME yohimbine failed to inhibit the ACTH response to intra-ME IL-1 beta. In contrast, a significant (P less than 0.01) dose-dependent reduction in the ACTH response to intra-ME IL-1 beta (30 ng) was observed in rats pretreated with either a nonselective alpha or beta adrenoreceptor antagonist (phentolamine, 2-40 micrograms or propranolol, 2-20 micrograms, respectively, into the ME). In contrast, intra-ME phentolamine, 20 micrograms, failed to reduce the ACTH response to iv CRF, 1 microgram/kg BW. Thus, the secretion of ACTH stimulated by the action of IL-1 beta at the ME depends, in part, on the local secretion of norepinephrine and epinephrine interacting with both alpha and beta adrenergic receptors.     

Effects of bunazosin and propranolol on ventricular arrhythmias in dogs with hypokalemia

The arrhythmogenic mechanism in dogs with hypokalemia was investigated in relation to the effects of an alpha 1-blocking agent and a beta-blocking agent. Hypokalemia was induced by inserting an ion-exchange resin into the colon. In the hypokalemia group, nine out of 17 dogs with arrhythmia ratios of over 10% (that is the percentage of the number of ventricular ectopic beats divided by the total number of heart beats during 5 min, after 10 micrograms/kg of epinephrine injection) were observed. In the control group (n = 13), which maintained normal serum K+ levels, only one dog showed an arrhythmia ratio of over 10%. Dogs with lower serum K+ levels showed higher arrhythmia ratios. The Ca2+ content of heart mitochondria, considered to be a reflection of intracellular Ca2+ concentration, was 24.4 +/- 5.7 nmoles/mg protein in the control group 5 min after epinephrine injection, while that of the hypokalemia group was increased to 35.0 +/- 13.4. A good reciprocal correlation between the concentration of serum K+ just before epinephrine injection and mitochondrial Ca2+ content was observed in the hypokalemia group (r = -0.79), while in the control group, no correlation was observed. Clear correlation between mitochondrial Ca2+ content and the arrhythmia ratio was also observed in the propranolol group. Pretreatment with bunazosin, an alpha 1-"blocker," effectively prevented the increase in mitochondrial Ca2+ content, and reduced the arrhythmia ratio. On the other hand, pretreatment with propranolol, a beta-"blocker," did not affect the mitochondrial Ca2+ content and the arrhythmia ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of epinephrine on urea synthesis in vivo in rats.

Three hours after hysterectomy the rate of urea synthesis doubles in rats. At the same time the increase in catecholamines is at a maximum, suggesting that catecholamines might be of regulatory importance. The effect of exogenous epinephrine on the rate of urea synthesis was studied in rats receiving epinephrine at rates of 2 and 20 micrograms/kg/h. The low dose increased plasma concentration of catecholamines two-fold over control values (p less than 0.01), comparable with the increase seen after surgery, and the high dose of epinephrine increased the concentration five-fold. The high dose increased the rate of urea synthesis by 30% (p less than 0.05), whereas the low dose had no effect. Following a high dose of epinephrine, alanine decreased from 358 +/- 29 to 254 +/- 17 mmol/l (p less than 0.05), indicating that the increase in urea synthesis was due to an effect on the liver rather than on extra-hepatic tissues, in that more aminonitrogen was eliminated from plasma than released into it. In conclusion, epinephrine in physiological concentrations cannot by itself account for the increase of urea synthesis seen in vivo after surgery.     

The hemodynamic effects of sympathetic stimulation combined with parasympathetic blockade in man

To define the effects of circulating norepinephrine and epinephrine on cardiac function and to determine whether left ventricular function is influenced by parasympathetic mechanisms during catecholamine stimulation, hemodynamic changes were investigated in healthy young human subjects who were supine and awake during infusion of intravenous norepinephrine alone (125 ng/kg/min) (n = 6), norepinephrine (125 ng/kg/min) plus epinephrine (50 ng/kg/min) (n = 6), and norepinephrine plus epinephrine plus parasympathetic blockade induced by atropine (2 mg intravenously) (n = 5). Ejection fraction and changes in cardiac volumes were measured by radionuclide ventriculography. During the infusion of norepinephrine plus epinephrine, plasma norepinephrine increased from 358 +/- 35 to 1782 +/- 123 pg/ml (mean +/- SE) and plasma epinephrine increased from 31 +/- 5 to 355 +/- 90 pg/ml (both p less than .01 vs baseline). These increases in plasma catecholamines were associated with increases in the heart rate (58 +/- 3 to 67 +/- 2 beats/min, p = NS), systolic blood pressure (113 +/- 3 to 140 +/- 6 mm Hg, p less than .01), ejection fraction (0.64 +/- 0.02 to 0.72 +/- 0.02 ejection fraction units, p less than .01), stroke volume (+41 +/- 5%, p less than .01), and cardiac output (+54 +/- 8%, p less than .01), and a decrease in systemic vascular resistance (-31 +/- 3%, p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antidiabetic potentials of the methanol leaf extract of Oxytenanthera abyssinica

Oxytenathera abyssinica is used for the treatment of diabetes mellitus in folklore medicine in Nigeria. In this study, we evaluated its antidiabetic activity in alloxan-induced diabetic mice. Diabetes was induced in the mice by a single intraperitoneal injection of alloxan monohydrate and the fasting blood glucose (FBG) levels measured with blood from the tail snip at 0, 1, 3 and 6 h. The activity was compared with reference drug, glibenclamide (2 mg/kg) and negative control. Oral glucose tolerance test (OGTT) was evaluated by loading glucose to rats at the dose of 2,000 mg/kg and checking their FBG at 0, 60 and 180 min. Antioxidant activity was evaluated using ferric reducing antioxidant power (FRAP) and 1, 1- diphenyl-2- hydrazyl (DPPH) photometric assay. The extract and the reference drug caused a significant (P?<?0.02–P?<?0.002) time and dose dependent decrease in the FBG levels of the mice when compared to the negative control; the extract (500 mg/kg) reduced FBG by 38.0 % at the 6th hr as against 45.6 % by glibenclamide. In OGTT the extract caused a time dependent decrease in the blood glucose level up to 33.3 % at 180 min at the dose of 300 mg/kg. The extract also caused a concentration dependent increase in antioxidant activity having 91 % increase and 1.95 total antioxidant activities at a concentration of 400 μg/ml. Extract of Oxythenanthera abyssinica showed significant antidiabetic activity.     

Comparative effect of graded doses of epinephrine on regional brain blood flow during CPR in a swine model

Cerebral blood flow (CBF) with conventional closed-chest cardiopulmonary resuscitation (CCPR) has been measured at only 2% to 11% of prearrest values. The purpose of our study was to determine whether the peripheral administration of higher doses of epinephrine than currently recommended during CCPR following a prolonged cardiac arrest improves CBF compared to CCPR using a standard dose of epinephrine. Fifteen swine were randomized to receive CCPR plus 0.02 mg/kg, 0.2 mg/kg, or 2.0 mg/kg epinephrine through a peripheral IV line following a ten-minute cardiopulmonary arrest and three minutes of CCPR. Regional CBF measurements were made by radionuclide microsphere technique during normal sinus rhythm (NSR), CCPR, and following epinephrine administration. The adjusted regional blood flows (in mL/min/100 g) following epinephrine administration for the 0.02-, 0.2-, and 2.0-mg/kg groups were, respectively, left cerebral cortex (3.3, 13.1, 11.8); right cerebral cortex (3.9, 13.8, 12.2); cerebellum (9.2, 32.0, 33.1); midbrain/pons (9.9, 32.1, 32.3); medulla (10.6, 61.5, 54.2); and cervical spinal cord (12.2, 53.8, 35.8). In this swine model, 0.2 mg/kg and 2.0 mg/kg epinephrine significantly increased regional CBF over that seen with standard doses. Because neuronal survival is dependent on flow rates of 10 to 15 mL/min/100 g, this preliminary evidence suggests that these higher doses of epinephrine may help improve neurological outcome in CCPR.     

p-Chloro-diphenyl diselenide, an organoselenium compound, with antidepressant-like and memory enhancer actions in aging male rats

The aim of this study was to evaluate the protective effects of p-chloro-diphenyl diselenide (p-ClPhSe)(2) on depressant-like action and cognitive impairment caused by aging in male rats. For this purpose, old rats were orally treated with (p-ClPhSe)(2) (10 or 25 mg/kg) for seven days. Then, rats were tested in experimental models of ambulation, memory and depression. In addition, Na(+) K(+) ATPase activity and reactive species (RS) levels were measured in rat cortex and hippocampus. Our findings demonstrated that treatment of old rats with (p-ClPhSe)(2) (10 and 25 mg/kg) reversed spatial memory deficit in the object location test and depressant-like action in the forced swimming test (FST) caused by aging. Reduction in exploratory behavior (rearings) in the open-field test caused by aging was not altered by (p-ClPhSe)(2) administration. Moreover, the increase of RS levels and inhibition of Na(+) K(+) ATPase activity in cortex and hippocampus resulting from aging were restored by the highest dose of (p-ClPhSe)(2). To assess the mechanisms involved in the antidepressant-like effect of (p-ClPhSe)(2), old rats received WAY100635 (0.1 mg/kg, subcutaneous, a selective 5-HT(1A)R antagonist), ritanserin (1 mg/kg, intraperitoneal, a 5-HT(2A/2C)R antagonist) or ondansetron (1 mg/kg, intraperitoneal, a 5-HT(3)R antagonist) 15 min before (p-ClPhSe)(2) (25 mg/kg) treatment. After 30 min, the FST was performed. Results showed that in addition to the antioxidant action, the modulation of 5-HT(1A) and 5-HT(3) receptors may be at least partly involved in the antidepressant-like action elicited by (p-ClPhSe)(2) in old rats. These findings highlight the beneficial potential of (p-ClPhSe)(2) in aged male rats.     

Effects of insulin, glucose and ACTH on corticosterone production by fetal adrenal cells from diabetic rats

Experiments were carried out on Sprague-Dawley rats to determine whether changes in fetal corticosterone levels during maternal diabetes were caused by the accompanying fetal hyperinsulinaemia or fetal hyperglycaemia. Diabetes was induced by injecting streptozotocin (30-45 mg/kg, i.v.) on day 2 of gestation. Fetal adrenals were removed on day 20 of gestation and cultured. Streptozotocin caused moderate (blood glucose 14-22.5 mmol/l) to severe (blood glucose greater than 25 mmol/l) diabetes. Both moderate and severe diabetes caused a decrease in fetal body weights. Relative to non-diabetic controls, maternal and fetal plasma concentrations of corticosterone were higher in the severely and lower in the moderately diabetic rats. Corticosterone production by fetal adrenal cells from control and moderately diabetic rats was comparable, but cells from the severely diabetic animals produced significantly greater amounts of corticosterone than did control cells. Neither glucose (28 mmol/l) nor insulin (1 nmol/l) exerted significant effects on [3H]thymidine uptake or corticosterone production by fetal adrenal cells from non-diabetic, moderately diabetic or severely diabetic rats. Human ACTH (0.02-20 nmol/l) caused a concentration-dependent increase in corticosterone output of comparable magnitude by cells from all three groups of animals. These data suggest that fetal growth abnormalities during diabetic pregnancy are not directly related to changes in glucocorticoid levels and that changes in glucocorticoid levels are not caused by any direct action of fetal hyperinsulinaemia or hyperglycaemia on adrenal cells.     

Effects of cardiotoxic doses of adrenergic amines on myocardial cyclic AMP.

The role of beta-adrenergic activation in the cardiotoxicity of adrenergic amines was assessed by measuring rat myocardial cyclic AMP at various times after subcutaneous injection of necrosis-inducing amounts of isoproterenol, phenylephrine or epinephrine in the presence and in the absence of the phosphodiesterase inhibitor aminophylline. The β-adrenergic agonist isoproterenol (5.25 mg/kg) increased myocardial cyclic AMP at 1 h to 147% of control and in the presence of aminophylline (75 mg/kg) to 261% of control as compared to 146% for aminophylline alone. Propranolol (6.25 mg/kg) blocked isoproterenol-induced increases in cyclic AMP. Neither the α-adrenergic agonist phenylephrine (15 mg/kg) nor epinephrine (4 mg/kg), which has both α- and β-adrenergic properties, increased myocardial cyclic AMP above control levels even in the presence of aminophylline. With α-adrenergic blockade by tolazoline (15 mg/kg) or phenoxybenzamine (2 mg/kg), combined administration of epinephrine and aminophylline caused an increase of the myocardial cyclic AMP content to 163% and 173%, respectively, of that of control rats. These results suggest that in the intact rat, cyclic AMP-mediated myocardial stimulation is an important factor in the cardiotoxicity of isoproterenol but not of phenylephrine, while the beta-adrenergic component of epinephrine cardiotoxicity is unmasked only in the presence of α-adrenergic blockade.     

Homeostatic regulation of bronchomotor tone by sympathetic activation during bronchoconstriction in normal and asthmatic humans

It has been assumed previously that the sympathetic nervous system (SNS) serves to antagonize bronchoconstrictor stimuli. To assess the homeostatic regulatory effect elicited by exogenously induced bronchoconstriction, we studied the effect of inhaled methacholine on the SNS response in 12 normal and 9 asthmatic humans. Exogenous SNS response was assessed as change in plasma epinephrine and norepinephrine concentrations from basal levels during inhalation challenge. A 74 +/- 3% decrease in specific airway conductance (SGaw) (p less than 0.001) was induced in normal subjects and a 78 +/- 7% decrease in asthmatics by methacholine challenge (p less than 0.001). Neither plasma epinephrine nor norepinephrine increased significantly from basal concentrations in normal or asthmatic subjects after maximal challenge (p greater than 0.33). To determine if physiologically achievable epinephrine concentrations potentially could modulate bronchoconstriction, the effect of intravenously infused epinephrine was measured in 11 of these subjects. After the highest dose of methacholine, a 15-min intravenous infusion of epinephrine (0.06 micrograms/kg/min) caused an 85 +/- 7% increase in SGaw in normal subjects (p less than 0.02). In asthmatics, a 319 +/- 68% increase in SGaw (p less than 0.002) was observed with similar changes in plasma epinephrine. Plasma epinephrine concentrations after infusion were comparable to those obtained in 4 normal and 1 asthmatic subject undergoing 60-degree, head-up tilt 1 h after volume depletion with intravenously administered furosemide. We conclude that physiologic concentrations of epinephrine can modulate moderately severe bronchoconstriction. However, the SNS does not regulate bronchomotor tone during mild to moderate bronchoconstriction.     

Repeated administration of vasopressin but not epinephrine maintains coronary perfusion pressure after early and late administration during prolonged cardiopulmonary resuscitation in pigs

BACKGROUND: It is unknown whether repeated dosages of vasopressin or epinephrine given early or late during basic life support cardiopulmonary resuscitation (CPR) may be able to increase coronary perfusion pressure above a threshold between 20 and 30 mm Hg that renders defibrillation successful. METHODS AND RESULTS: After 4 minutes of cardiac arrest, followed by 3 minutes of basic life support CPR, 12 animals were randomly assigned to receive, every 5 minutes, either vasopressin (early vasopressin: 0.4, 0.4, and 0.8 U/kg, respectively; n=6) or epinephrine (early epinephrine: 45, 45, and 200 microg/kg, respectively; n=6). Another 12 animals were randomly allocated after 4 minutes of cardiac arrest, followed by 8 minutes of basic life support CPR, to receive, every 5 minutes, either vasopressin (late vasopressin: 0.4 and 0.8 U/kg, respectively; n=6), or epinephrine (late epinephrine: 45 and 200 microg/kg, respectively; n=6). Defibrillation was attempted after 22 minutes of cardiac arrest. Mean+/-SEM coronary perfusion pressure was significantly higher 90 seconds after early vasopressin compared with early epinephrine (50+/-4 versus 34+/-3 mm Hg, P<0.02; 42+/-5 versus 15+/-3 mm Hg, P<0.0008; and 37+/-5 versus 11+/-3 mm Hg, P<0. 002, respectively). Mean+/-SEM coronary perfusion pressure was significantly higher 90 seconds after late vasopressin compared with late epinephrine (40+/-3 versus 22+/-4 mm Hg, P<0.004, and 32+/-4 versus 15+/-4 mm Hg, P<0.01, respectively). All vasopressin animals survived 60 minutes, whereas no epinephrine pig had return of spontaneous circulation (P<0.05). CONCLUSIONS: Repeated administration of vasopressin but only the first epinephrine dose given early and late during basic life support CPR maintained coronary perfusion pressure above the threshold that is needed for successful defibrillation.     

Effects of epinephrine on urea synthesis in vivo in rats

Abstract: Three hours after hysterectomy the rate of urea synthesis doubles in rats. At the same time the increase in catecholamines is at a maximum, suggesting that catecholamines might be of regulatory importance. The effect of exogenous epinephrine on the rate of urea synthesis was studied in rats receiving epinephrine at rates of 2 and 20 μg/kg/h. The low dose increased plasma concentration of catecholamines two-fold over control values (p>0.01), comparable with the increase seen after surgery, and the high dose of epinephrine increased the concentration fivefold. The high dose increased the rate of urea synthesis by 30% (p>0.05), whereas the low dose had no effect. Following a high dose of epinephrine, alanine decreased from 358 ± 29 to 254 ± 17 mmol/1 (p>0.05), indicating that the increase in urea synthesis was due to an effect on the liver rather than on extra-hepatic tissues, in that more aminonitrogen was eliminated from plasma than released into it. In conclusion, epinephrine in physiological concentrations cannot by itself account for the increase of urea synthesis seen in vivo after surgery.