Acute effect of large doses of calcitonin on calcium, magnesium and inorganic phosphate levels in rat serum in correlation to differences in thryroid function.

The acute effect of pharmacological doses of porcine calcitonin were studied on the calcium, inorganic phosphorus and magnesium level in correlation to thyroid function in experimental rats. In every case, and with all three doses, the serum calcium and inorganic phosphorus level fell significantly within 60 minutes after calcitonin administration. The drop in both minerals was most pronounced in the group with experimental hyperthyroidism, in which all different doses had the same effect. In experimental hypothyroidism, the decrease was correlated to the dose. In the case of the serum magnesium level, a statistically significant drop was observed in animals with hyperthyroidism after the two largest doses of calcitonin, while only a mild increase occurred in animals with hypothyroidism after the smallest dose. None of the doses of calcitonin affected the magnesium level in animals with normal thyroid function.     

Adrenergic binding sites and enzyme activities in the heart of hyperthyroid rats.

In present study interactions of some adrenergic drugs with the binding of 3H-norepinephrine (NE) and response of some enzymatic systems in the heart of rats with pharmacological hyperthyroidism have been investigated. Binding of NE to cardiac particles was inhibited by isoproterenol, propranolol and in lower concentrations by another beta-blocking drug trimepranol both in control and hyperthyroid hearts in the same degree. However, after addition of nonradioactive norepinephrine (10(-3) M) the degree of displacement was lower in hyperthyroid than in euthyroid group. Activity of adenylate cyclase was lower in hyperthyroid cardiac particles. This difference remained preserved after stimulation by norepinephrine or NaF. The activities of hormone-sensitive lipase and lipoprotein lipase were increased in preparation of hyperthyroid hearts. The phosphorylase "a" activity was also increased in hyperthyroid cardiac particles. There was no change in cardiac adrenergic binding sites properties in hyperthyroidism with the exception of less displacement of NE by nonlabelled hormone. The results indicate that the increased lipolytic and phosphorylase "a" activities in hyperthyroid hearts are not necessarily linked to elevated activity of adenylate cyclase.     

Dependence of the cytotoxic effect of guanethidine on the degree of sympathetic activity

Young rats aged 15-29 days received a subcutaneous injection of guanethidine sulphate (5 mg/kg body weight) every day. Owing to damage to the postganglionic sympathetic neurones, on about the 60th day of life we observed a significant decrease in the noradrenaline concentration in these animals' hearts compared with the controls. If every guanethidine injection was followed immediately by intensive physical exercise, there was no drop in the heart noradrenaline concentration. Physical exercise of the same intensity performed a few hours before injecting guanethidine did not prevent the drop in the noradrenaline concentration in the heart. The results show that an exercise-induced increase in sympathetic activity, at a time when guanethidine is circulating in the blood and accumulating in the adrenergic neurones, inhibits the cytotoxic effect of guanethidine. Isolated physical exercise performed between the 15th and 29th day of life leads to an increase in the noradrenaline content of the heart of rats aged 60 days.     

Haemodynamic effects of beta-adrenergic blockade in hyperthyroid patients with and without heart failure.

Haemodynamic studies were performed in 10 patients with uncomplicated thyrotoxicosis and seven with thyrotoxic cardiac failure. The cardiac output of those with uncomplicated hyperthyroidism was higher than normal at rest. After 2 mg of intravenous propranolol there was a 13% fall but the level was still higher than normal. In patients with thyrotoxic cardiac failure the resting cardiac output was normal, but it fell after propranolol by 30% to subnormal levels. In both groups there was an increase in right heart pressures and fall in the rate of increase in arterial pressure, which indicated a decrease in myocardial contractility. These results indicate that increased autonomic activity is a compensatory phenomenon in hyperthyroid heart failure and that its abolition by beta-blocking drugs has a deleterious effect on cardiac function. They are therefore contraindicated in patients with thyrotoxic heart failure.     

Pharmacological evidence for catecholamine-independent contractile effects of X-537A on the isolated working rat heart preparation.

The ionophore X-537A increased heart rate and contractility of the isolated, working rat heart preparation. The increased heart rate appeared to be caused solely by release of catecholamines as the response was completely eliminated by reserpine pretreatment or addition of propranolol to the perfusate. The inotropic response, however, had an apparent catecholamine-independent component as neither propranolol, nor propranol in combination with phentolamine, completely eliminated the inotropic response to X-537A. On the other hand, reserpine pretreatment did abolish the inotropic effect of the ionophore but this action appeared to be a nonspecific one as the responses to norepinephrine and to CaCl2 were substantially diminished.     

Effect of phenoxybenzamine, propranolol and guanethidine after repeated administration on nutritional blood flow in rats]

In anesthetized rats, after i.p. treatment during 4 days: phenoxybenzamine and guanethidine were hypotensive and increased nutritional blood flow in squeletal muscles; propranolol had a poor hypotensive effect and decreased nutritional circulation in heart, skin and intestine.     

Increase of the peroxidase activity of mouse submaxillary gland by reserpine

The peroxidase activity of mouse submaxillary gland was found to be elevated by about 128% at 22 hr. after the administration of reserpine (0.5 mg/kg). This effect of reserpine was observed in rat also. Neither pretreatment with 6-hydroxy dopamine (6-OH dopamine) nor surgical sympathetic denervation could abolish the increase of the peroxidase activity elicited by reserpine. Also, treatment with propranolol, dibenamine or atropine sulfate failed to reverse the effect of reserpine. These results suggest that neither catecholamine nor acetyl choline is involved in this reserpine action.     

Effect of beta-adrenoblockaders on the smooth muscles of the trachea and bronchi

It has been shown in experiments on anesthetized guinea-pigs that (+/-) and (+) propranolol produced a dose-dependent increase in the resistance of the air ways. Meanwhile oxprenolol, trimepranol and atenolol had a poor bronchoconstrictor effect, and labetalol evoked no changes in the tone of the bronchi. On an isolated trachea of the guinea-pig both forms of propranolol, as well as trimepranol and oxprenolol produced contractions, atenolol did not cause any changes in the tone of the smooth muscles, while labetalol made the smooth muscles relax. It has been also demonstrated on an isolated trachea that pretreatment with atropine, diphenhydramine, and diethylamide of lysergic acid did not lead to any noticeable changes in the bronchoconstrictive action of propranolol. At the same time verapamil and Ca2+-free Krebs solution reversed the propranolol effect.     

The effect of melatonin on free radical homeostasis in rat tissues at thyrotoxicosis

Experimental thyrotoxicosis in rats is accompanied by the increase of serum alanine aminotransferase (AlAT), aspartate aminotransferase (AsAT), creatine phosphokinase-MB (CPK-MB) activities and the content of primary products of lipid peroxidation, conjugated dienes, in liver, heart and blood. This suggests impairments in functioning of these organs, which accompany intensification of free radical processes. Melatonin administration resulted in the decrease of AlAT, AsAT, CPK-MB and conjugated dienes; this indicates positive effect of melatonin in this pathology. Thyrotoxicosis is accompanied by the increase of catalase activity in rat liver, heart and serum. Exogenous melatonin decreased specific activity of serum and heart catalase by 22 and 43%, respectively, compared with rats subjected to hyperthyroidism. However, there was insignificant increase in specific activity of liver catalase (by ～15%). Melatonin administration caused a decrease of α-tocopherol content increased in rat tissues under conditions of hyperthyroidism. Thus, exogenous melatonin is capable to reduce intensity of lipid peroxidation in hyperthyroidism and to act as an adaptogen, regulating free radical homeostasis in response to action of pathogenic factors on organism that is associated by concomitant reduction of mobilization of components of the antioxidant system.     

Cardiovascular, metabolic and endocrine effects of chemical sympathectomy and of adrenal demedullation in fetal sheep

A procedure in fetal sheep for causing peripheral sympathectomy by regular intravascular guanethidine sulphate administration and for causing adrenal demedullation by intragland injection of acid formalin is reported. Demedullation substantially removed adrenaline from the fetal circulation, but has a small effect only on noradrenaline. Plasma noradrenaline levels were depressed by 50% when demedullated fetuses were also subject to peripheral sympathectomy by guanethidine sulphate treatment. This provides some evidence that the paraganglia in the sheep fetus contributes to resting plasma catecholamines. Furthermore the ability of adrenal demedullation to increase markedly this pool of extra-adrenal chromaffin tissue indicates that in the fetus adrenal activity regulates the growth of these para-aortic bodies. In response to sympathectomy plasma vasopressin concentrations rose substantially, whilst adrenal demedullation caused a small rise. Demedullation and sympathectomy depressed fetal plasma glucose and elevated plasma cortisol. In both sympathectomised and adrenal demedullated fetuses resting heart rate and blood pressure was not depressed. However in those with a depleted peripheral nervous system periods of cardiovascular instability were apparent after 2-3 days of treatment with guanethidine sulphate. Hence there were regular episodes where fetal blood pressure and heart rate fell sharply followed 60-90s later by very large increases in blood pressure sustained for up to 10 min and associated with substantial production of plasma vasopressin and catecholamines. These results show that fine cardiovascular control in the fetus requires an intact sympathetic system as the endocrine system is too slow responding to effectively maintain reflex vascular control.     

Atrial natriuretic factor alters autonomic interactions in the control of heart rate in conscious rats

Regulation of heart rate was studied in rats receiving either i.v. saline at 64 microL/min or synthetic 28-residue rat atrial natriuretic peptide (ANF) at a dose sufficient to decrease mean arterial blood pressure by 10%. Autonomic influences were deduced from steady-state heart rate responses of each group to propranolol, atropine, or propranolol and atropine combined. A multiplicative model of heart rate control was used to derive quantitatively from the data the modulation of intrinsic heart rate by sympathetic and parasympathetic mechanisms. Animals receiving ANF showed a lower heart rate than control animals. This relative bradycardia was abolished by atropine. Blocking of sympathetic effects with propranolol had no effect on basal heart rate in either group, and atropinization led to significant increases in heart rate in both groups of rats. Mathematical analysis of the results showed that the bradycardia produced by ANF was due predominantly to a reduced intrinsic heart rate and to enhanced vagal inhibition of postganglionic sympathetic activity. Parasympathetic contribution to heart rate in the absence of sympathetic activity was negligible in control rats and small during ANF. We conclude that the major influences of ANF on heart rate control are a decrease of intrinsic heart rate and enhanced parasympathetic inhibition of postganglionic presynaptic sympathetic activity.     

Hemodynamic effects of procainamide and quinidine and the influence of beta-blockade before and after experimental myocardial infarction.

The use of antiarrhythmie drugs in combination has been limited because of possible side effects secondary to myocardial depression in the acute myocardial infarction patient. Therefore, we investigated in intact dogs (group I) the hemodynamic interaction of propranolol plus procainamide (subgroup A) or quinidine (subgroup B) and in dogs after experimental myocardial infarction produced by coronary artery ligation (group II). Infusion of procainamide (30 mg/kg over 5 min) in animals of group IA produced a significant (P less than 0.05) decrease of 30% in mean aortic pressure, a decrease of 40% in left ventricular dp/dt and 29% in cardiac output. When procainamide was reinfuse after propranolol (1 mg/kg), its hemodynamic effects were not significantly different from those observed before propranolol in both groups IA and IIA. Infusion of quinidine (10 mg/kg over 5 min) in animals of group IB (intact dogs) also produced significant decreases of 24% in mean aortic pressure and 38% in dp/dt while cardiac output was unchanged. However, these hemodynamic changes were seen only after beta-blockade and were significantly different from those obtained before propranolol, where heart rate increased by 14%, dp/dt by 30%, and cardiac output by 35%. These changes occurred despite a similar reduction in mean aortic pressure. This drug combination produced similar response in animals after coronary artery ligation (group IIB). In conclusion, we feel that the administration of propranolol does not prevent the depressive circulatory effects of procainamide. The combined use of quinidine and propranolol also has a negative circulatory effect although not as marked as the effects observed after procainamide with propranolol.     

Leukotoxin, 9, 10-epoxy-12-octadecenoate, causes cardiac failure in dogs

An epoxy derivative of linoleate, 9, 10-epoxy-12-octadecenoate, was demonstrated to be biosynthesized by leukocytes, thus nominated as leukotoxin. Its chemical structure was determined by gas-chromatography/mass spectrometry and nuclear magnetic resonance measurements. When it was injected intravenously, 15 mg/kg, canine heart showed signs of a typical cardiac failure; viz. Aortic flow started to drop immediately after the injection, and fell to 22% of the original at 40 min after the injection. At that point, systolic aortic pressure dropped to 35%, diastolic aortic pressure to 23%, and electronically differentiated maximal rate of left ventricular pressure rise (LV dp/dt) to 29%. All of experimental dogs died 40 to 50 min after the injection. On the contrary, administration of linoleic acid (15 mg/kg) did not affect these hemodynamical parameters. Therefore, leukotoxin seems to be an important factor to the genesis of heart failure.     

Effect of catecholamine depletion on oxidative energy metabolism in rat liver, brain and heart mitochondria; use of reserpine

Regulation of mitochondrial functions in vivo by catecholamines was examined indirectly by depleting the catecholamines stores by reserpine treatments of the experimental animals. Reserpine treatment resulted in decreased respiratory activity in liver and brain mitochondria with the two NAD+-linked substrates: glutamate and pyruvate + malate with succinate ATP synthesis rate decreased in liver mitochondria only. With ascorbate + TMPD system, the ADP/O ratio and ADP phosphorylation rate decreased in brain mitochondria. For the heart mitochondria, state 3 respiration rates decreased for all substrates. In the liver mitochondria basal ATPase activity decreased by 51%, but in the presence of Mg2+ and/or DNP increased significantly. In the brain and heart mitochondria ATPase activities were unchanged. The energy of activation in high temperature range increased liver mitochondrial ATPase while in brain mitochondria reserpine treatment resulted in abolishment in phase transition. Total phospholipid (TPL) content of the brain mitochondria increased by 22%. For the heart mitochondria TPL content decreased by 19% and CHL content decreased by 34%. Tissue specific differential effects were observed for the mitochondrial phospholipid composition. Liver mitochondrial membranes were more fluidized in the reserpine-treated group. The epinephrine and norepinephrine contents in the adrenals decreased by 68 and 77% after reserpine treatment.     

Reserpine pretreatment prevents increases in extracellular striatal dopamine following L-DOPA administration in rats with nigrostriatal denervation

The influence of L-DOPA and reserpine on extracellular dopamine (DA) levels in the striatum of intact and dopaminergic denervated rats was studied using the brain microdialysis technique. In intact rats, reserpine (5 mg/kg s.c.) reduced extracellular DA levels to 4% of basal values. L-DOPA (50 mg/kg i.p.) had no effect on extracellular DA levels in reserpine-pretreated rats. In rats with 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic system, basal levels of extracellular DA were low but markedly increased by L-DOPA (50 mg/kg i.p.). In 6-hydroxydopamine-lesioned rats, pretreatment with reserpine (5 mg/kg s.c.) diminished L-DOPA (50 mg/kg i.p.)-induced increases in extracellular DA levels to 16% of those obtained in denervated animals not pretreated with reserpine (p<0.01). These results suggest that in the intact striatum, extracellular DA stems mainly from vesicular storage sites and that in the striatum with dopaminergic denervation, a large part of the L-DOPA-derived extracellular DA is also derived from a vesicular pool that is released by an exocytosis mechanism.     

The nature of the hypermetabolism and tachycardia in cold adaptation and experimental hyperthyroidism

The cross circulation method has been used to study contribution of humoral and nonhumoral components to the origin of hypermetabolism (increased level of basal metabolism) and tachycardia under adaptation to cold and experimental hyperthyroidism. Consumption of oxygen, heart rate and rectal temperature have been studied in periods prior to and during the cross circulation. It is shown that under experimental hyperthyroidism contribution of humoral and nonhumoral factors to the origin of hypermetabolism equals 22 and 78%, while that to genesis of tachycardia--44 and 56%, respectively. Under cold adaptation an increase of the basal metabolism level depends on humoral agents by 77% and on changes of the stationary character only by 23%. The nature of adaptation tachycardia is mainly, of the humoral origin (65%).     

2-Deoxyglucose as a tool for analyzing the humoral component of the cardiovascular reaction to stress

Blood pressure (BP), heart rate (HR), adrenaline (A) and noradrenaline (NA) effects of 2-desoxyglucose (500 mg/kg i.v.) were studied in conscious chronically instrumented wistar rats. A and NA contents in the blood were estimated by HPLC with electrochemical detection. In 15-40 minutes after 2-DG administration it was 13-16-fold increase in A content, 1.7-1.9-fold increase in NA content. At the same time BP fell by 5 mm Hg and HR fell by 100 beats/min. Atropine blocked bradycardia but had no effect on BP. It is concluded that high levels of endogenous A during stress are not responsible for cardiovascular responses usually observed.     

Pressor effects of systemic administration of methionine and leucine enkephalin in the conscious rat

Experiments were designed using conscious Sprague-Dawley rats to determine the blood pressure (BP) and heart rate (HR) responses to intravenous doses of (1) the adrenal catecholamines noradrenaline (NA) and adrenaline (A), (2) adrenal pentapeptides methionine enkephalin (ME) and leucine enkephalin (LE), (3) combination (i.v.) injections of both ME or LE with NA or A that modulate the hemodynamic responses when the adrenal catecholamines were given alone, and (4) the possible receptor mechanisms mediating the resultant BP and HR response to i.v. pentapeptide administration. NA (0.48 and 2.4 nmol) and A (0.3 and 1.5 nmol) given i.v. evoked potent, dose-related pressor responses associated with reflex bradycardia. ME and LE (1.6 - 48 nmol) elicited transient (10-20 s) increases in mean arterial pressure (MAP), which was associated either with no change in mean heart rate (MHR), such as ME, or with slight bradycardia (i.e., LE). Combining ME or LE (16 nmol) with NA (2.4 nmol) or A (0.3 or 1.5 nmol) did not change MAP and MHR from when these respective doses of NA or A were given alone. However, 16 nmol of ME or LE with a low dose of NA (0.48 nmol) increased the pressor response compared with NA (0.48 nmol) given alone. Other experiments whereby specific receptor blockers (naloxone, diprenorphine, atropine, propranolol, phentolamine or guanethidine) were given i.v. 5 min before subsequent i.v. administration of LE or ME (16 nmol) indicated that only phentolamine or guanethidine could completely suppress the pressor responses of LE and ME. Naloxone and diprenorphine pretreatment attenuated the pressor response of LE but did not affect the BP response to ME.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adaptation of the circulatory system to frequently repeated submaximal workloads in the light of left ventricular contraction analysis

In two groups of healthy men aged 20-22 years the left ventricular systolic time intervals were evaluated by the method of Weissler et al. during frequently repeated workloads and restitution. Each exercise was carried out on a Zimmerman cycle ergometer during 10 minutes, and was repeated five times at 50-minutes intervals from 8.00 o'clock a.m. Group I (15 subjects) performed the exercise at a stable workload which produced during the first exercise heart rate acceleration to 170/min, but gave a successive further rise in the heart rate during consecutive exercises. Group II (11 subjects) performed all exercises to a stable rise in heart rate to 170/min with decreasing workloads. It was found that successive exercises caused in both groups a similar decrease of the left ventricular ejection time index (LVETI), pre-ejection period (PEP), isovolumetric contraction time (ICT), and decrease of the PEP/LVET index (p less than 0.05). Each successive exercise began with higher values of LVETI, PEP, ICT and PEP/LVET than the first one. No significant differences were found in the values of left ventricular systolic time intervals in both groups (p greater than 0.05). The duration of restitution of normal values of the left ventricular systolic time intervals after successive exercises was not changing but the tolerance of these exercises measured by heart rate increase and work performed decreased successively.