Plasma noradrenaline response to sustained handgrip in patients with essential hypertension.

The responses of plasma noradrenaline, arterial blood pressure, and heart rate to sustained handgrip at 30% maximal voluntary contraction were studied in untreated patients with essential hypertension and in healthy subjects of comparable age. There were no significant differences between these two groups in the intensity and duration of handgrip. Increases in heart rate and blood pressure induced by the effort were similar in hypertensive patients and normotensive control subjects, whereas the absolute levels of blood pressure were considerably higher in the patients. In the first 1-2 min of exercise the increases in plasma noradrenaline concentration were similar in both groups. Subsequently, plasma noradrenaline concentration tended to plateau in hypertensive patients while in control subjects it continued to increase. The elevation of plasma noradrenaline in the last minute of effort was, therefore, significantly smaller in hypertensive patients than in the control group.     

Effect of thyroidectomy on cardiovascular responses to hypoxia and tyramine infusion in fetal sheep

Fetal sheep were thyroidectomized at 80 days' gestation and reoperated at 118-122 days for insertion of vascular catheters. The effects of hypoxaemia and intravenous tyramine infusion on plasma catecholamine concentrations, blood pressure and heart rate were then determined in experiments at 125-135 days' gestation. Age matched intact fetuses were also studied. Thyroidectomy was associated with increased concentrations of noradrenaline, adrenaline and dopamine in some thoracic and abdominal organs, increased noradrenaline concentrations in the cerebellum, and decreased adrenaline concentrations in the hypothalamus, cervical spinal cord, and superior cervical and inferior mesenteric ganglia. Arterial pressure was significantly lower in the thyroidectomized fetuses (34.0 +/- 0.15 mmHg) than in intact fetuses (44.7 +/- 0.2 mmHg; p less than 0.001). In contrast, plasma noradrenaline concentrations were significantly higher in the thyroidectomized fetuses (2.04 +/- 0.25 ng/ml) compared to the intact fetuses (0.99 +/- 0.08 ng/ml; P less than 0.001). In the intact fetuses there was a significant increase in plasma noradrenaline concentration and blood pressure during hypoxaemia, and bradycardia at the onset of hypoxaemia. In contrast, in the thyroidectomized fetuses hypoxaemia did not cause significant change in plasma catecholamine concentrations, blood pressure or heart rate. Infusion of tyramine produced a 1.9-fold increase of plasma noradrenaline in thyroidectomized fetuses compared to a 9.2-fold increase in the intact fetuses (P less than 0.05). Tyramine infusion caused a similar proportional increase of blood pressure in both thyroidectomized and intact fetuses. Heart rate decreased during the tyramine-induced hypertension in the intact fetus, but increased in the thyroidectomized fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

The effects of noradrenaline, applied by microelectrophoresis on different cells of the rabbit's atrial pacemaker

Noradrenaline has been applied by microelectrophoresis to a small portion of the atrial pacemaker area in the rabbit's heart in order to study the local effects of this chemical transmitter separately from the ones deriving from other parts of the pacemaker area. In a first group of cells, whose action potential and location assimilate them to true pacemaker cells, noradrenaline caused a reduction in cycle length and an increase in the steepness of slow diastolic depolarization. In a second group of cells similar to latent pacemaker cells, noradrenaline caused no change in cycle length, the outstanding effect being an increase in the steepness of the slow diastolic depolarization which afterwards changed into a subthreshold oscillation. A third type of cells showed intermediate characteristics between the two previous groups. These results suggest that: a) the chronotropic effect of noradrenaline on the heart atrial pacemaker seems to be due to changes in the steepness of slow diastolic depolarization which can assume, in some instances, the shape of subthreshold oscillations; the effects on the other parameters in our preparation seem to be either less constant or less significant; b) the different effects which are obtained on various kinds of cells seem to be the result of a different degree of sensitivity to noradrenaline and to the more or less premature activation of mechanisms antagonizing the action of noradrenaline. The results are discussed on the basis of a model of spontaneous atrial pacemaking which has been recently proposed.     

The modulatory effects of noradrenaline on vagal control of heart rate in the dogfish,Squalus acanthias

The possible interactions between inhibitory vagal control of the heart and circulating levels of catecholamines in dogfish (Squalus acanthias) were studied using an in situ preparation of the heart, which retained intact its innervation from centrally cut vagus nerves. The response to peripheral vagal stimulation typically consisted of an initial cardiac arrest, followed by an escape beat, leading to renewed beating at a mean heart rate lower than the prestimulation rate (partial recovery). Cessation of vagal stimulation led to a transient increase in heart rate, above the prestimulation rate. This whole response was completely abolished by 10(-4) M atropine (a muscarinic cholinergic antagonist). The degree of vagal inhibition was evaluated in terms of both the initial, maximal cardiac interval and the mean heart rate during partial recovery, both expressed as a percentage of the prestimulation heart rate. The mean prestimulation heart rate of this preparation (36+/-4 beats min(-1)) was not affected by noradrenaline but was significantly reduced by 10(-4) M nadolol (a beta-adrenergic receptor antagonist), suggesting the existence of a resting adrenergic tone arising from endogenous catecholamines. The degree of vagal inhibition of heart rate varied with the rate of stimulation and was increased by the presence of 10(-8) M noradrenaline (the normal in vivo level in routinely active fish), while 10(-7) M noradrenaline (the in vivo level measured in disturbed or deeply hypoxic fish) reduced the cardiac response to vagal stimulation. In the presence of 10(-7) M noradrenaline, 10(-4) M nadolol further reduced the vagal response, while 10(-4) M nadolol + 10(-4) M phentolamine had no effect, indicating a complex interaction between adrenoreceptors, possibly involving presynaptic modulation of vagal inhibition.     

Changes in Sympathetic Nerve Terminals in the Heart of Cold-Exposed Rats

Abstract: Changes in sympathetic nerve terminals of the heart after varying periods of exposure of rats to 4°C were investigated. Two indices were used for changes in the number of noradrenaline storage vesicles, i.e., vesicular dopamine β-hydroxylase (DBH) activity and noradrenaline storage capacity. The latter was obtained after uptake of [³H]noradrenaline; endogenous content, uptake of exogenous noradrenaline, and degree of saturation of the vesicles were calculated using the specific activity of the [³H]noradrenaline. As a measure of tyrosine hydroxylase activity, whole ventricular noradrenaline, dopamine, and dihydroxyphenylacetic acid content were used. After 4 h of cold exposure there was an increase in vesicular endogenous noradrenaline content, uptake, storage capacity, and DBH activity as well as a large increase in whole ventricular dopamine. After 6 h in the cold, vesicular endogenous noradrenaline content, storage capacity, and DBH activity were decreased. The results suggest that during cold exposure there is an initial increase followed by a decrease in the number of functional vesicles in the nerve terminal, which could explain the fluctuations in the rate of noradrenaline release.     

Alpha 1-adrenoceptor activity in arterial smooth muscle following congestive heart failure

The interactions between yohimbine (selective alpha 2-antagonist) with noradrenaline (mixed agonist) and phenylephrine (selective alpha 1-agonist) were studied in the canine dorsal pedal artery in an attempt to characterize the peripheral vascular response to adrenergic agents before and after the development of congestive heart failure in the dog. The contractile responses of the dorsal pedal artery to potassium chloride were also examined. Both noradrenaline and phenylephrine contracted the dorsal pedal artery in a concentration-dependent manner before and at peak heart failure, the responses to the agonists being enhanced at heart failure. The responses of the artery to potassium were not modified by congestive heart failure. Yohimbine caused concentration-dependent antagonism of noradrenaline, without altering the magnitude of the maximum response, providing pA2 values ranging from 8.26 to 7.06 against low and high concentrations of noradrenaline, respectively, before heart failure development. Following heart failure, the pA2 values for yohimbine against noradrenaline remained unchanged, but slopes from the Arunlakshana-Schild plots were significantly different from unity, implying a noncompetitive antagonism. The pA2 values of yohimbine against phenylephrine were at least 10 orders of magnitude lower than those against noradrenaline. After congestive heart failure, yohimbine was even less effective against high concentrations of phenylephrine. These findings suggest that enhanced vasoconstriction during heart failure results, in part, from increased alpha 1-adrenoceptor mechanisms in peripheral arterial smooth muscle.     

Beneficial effect of perindopril, an angiotensin-converting enzyme inhibitor, on left ventricular performance and noradrenaline myocardial content during cardiac failure development in the rat

The left coronary artery in rats was ligated for a period of 15 days to induce hypertrophy of the non-infarcted myocardium. Left ventricular performances were evaluated in the working heart model. In addition, cardiac hypertrophic indices and noradrenaline content were measured. Variables were determined in the absence or presence of the angiotensin-converting enzyme inhibitor, perindopril. A 35 and 60% decrease in the coronary and cardiac output, respectively, and a 57% decrease in the noradrenaline content of the non-infarcted left ventricular free wall were seen. Furthermore, a 15% increase in the heart/body weight ratio was observed in the infarcted group. After chronic treatment of the animals with perindopril (2 mg.kg-1 body weight, per os), coronary and cardiac output were impaired to a lesser extent: 8 and 35% respectively, with only a 15% decrease in the noradrenaline content of the non-infarcted left ventricular free wall. Furthermore, the increase in heart/body weight ratio was significantly less than in the nontreated infarct group (7%). We conclude that the beneficial effects of converting enzyme inhibition, during the development of myocardial infarction, on left ventricular performances are associated with a decrease in the hypertrophic indices and a normalization of sympathetic activity.     

Sympathetic hyperreactivity in offspring of essential hypertensive patients

A multistage exercise test was carried out in normotensive subjects with normotensive parents (controls; n = 12), and 32 offspring of essential hypertensive patients that were normotensive (NTO; n = 20) or borderline hypertensive (BHO; n = 12) The groups were comparable as to age, weight and working capacity. Changes in sympathetic nervous activity were determined by measurements of plasma noradrenaline. The initial rise in noradrenaline levels during the exercise test was proportional to the increase in work load until the noradrenaline concentration rose sharply to levels more than 1000 pg/ml above baseline levels. The work load immediately prior to the steep rise in plasma noradrenaline (sympathetic threshold level: STL) is considered to represent the point from which anaerobic energy-yielding processes play an increasingly greater role as the work load increases. The initial increase in plasma noradrenaline until STL was significantly higher in both the NTO (p less than 0.02) and BHO (p less than 0.005) compared to the control group. The absolute noradrenaline level at STL and the increase in noradrenaline from baseline to STL were significantly higher in the BHO group (p less than 0.02, p less than 0.005). No significant differences between the groups were found when comparing noradrenaline levels at rest or at absolute or relative work loads. The systolic blood pressure response during the exercise test was significantly more pronounced in the BHO group (p less than 0.05) compared to the controls and the NTO group.     

Relationship of the activity of cardiac cholinergic mechanisms to the state of the sympathetic innervation and its noradrenaline content in hypoxia]

Preliminary sympathectomia depletes acetylcholine (ACh) in the heart of rabbits under hypoxia. In these conditions the inhibitory action of ACh on the rat isolated heart is reduced under the noradrenaline content fall, while under increase it is potentiated. Under hypoxia noradrenaline increases concentration of potassium in the myocardium, thus stimulating ACh formation and activity. It is suggested that under deep hypoxia suppression of the sympathetic mechanisms causes functional isolation of the heart from nervous effects.     

A possible mechanism for cadmium-induced hypertension in rats

The mechanism of cadmium-induced hypertension was explored by measuring noradrenaline metabolism. Cadmium $\text{in vitro}$ was shown to inhibit both monoamine oxidase and catechol-O-methyltransferase, the two enzymes which inactivate the neurotransmitters noradrenaline and adrenaline. However, rats which were injected or fed (via the drinking water) with cadmium showed that, among the tissues surveyed, these two enzymes were inhibited significantly only in the aorta. $\text{In vitro}$, cadmium was found to inhibit noradrenaline binding to membranes from the heart, lung, and kidney, while stimulating binding to aortic membranes, which suggests that the effects may be specific. These results suggest that, in the aorta, cadmium may inhibit the two catabolic enzymes of noradrenaline, while at the same time stimulating noradrenaline-binding. Thus the effects of noradrenaline on vascular smooth muscle would be increased as well as prolonged.     

Noradrenaline dynamics in prolonged ischemia after ischemic preconditioning

AIM OF THE STUDY: To determine the effects of two-staged ischemic preconditioning on myocardial noradrenaline in prolonged ischemia and reperfusion. METHODS: Thirty-two male Wistar rats anesthetised with urethane randomly divided into 2 groups: group 1 (ischemic preconditioning group, n = 16), and group 2 (control, n = 16). Myocardial interstitial noradrenaline levels were measured using a microdialysis technique. Ischemic preconditioning was elicited by two episodes: 5 min of ischemia and 10 min of reperfusion. The intermittent occlusions were followed by prolonged occlusion (60 min) and reperfusion (60 min). RESULTS: An increase in interstitial noradrenaline was observed in 10 min of prolonged ischemia in group 2, and in 20 min in group 1. After 20 min of myocardial ischemia there was a significant difference between groups (p < 0.05) in interstitial noradrenaline levels. In control group, it was 60% higher. In reperfusion, noradrenaline levels decreased markedly in group 1. CONCLUSION: We suggest that ischemic preconditioning by two episodes: 5-min ischemia and 10-min reperfusion prevents excessive noradrenaline interstitial accumulation, perhaps, through protection of physiological uptake I carrier.     

Effect of the early postnatal administration of cortisol on development of the nervous control of cardiac function in albino rats

When infant rats were treated with cortisol, in daily s.c. doses of 20 mg X kg-1, between the ages of 2 and 15 days, the noradrenaline content of their heart and spleen, between the ages of 23 and 65 days, was lower than in the controls. The decrease in the noradrenaline content did not diminish with advancing age; on the contrary, it was the most pronounced at 65 days. Cortisol treatment did not affect the noradrenaline content of skeletal muscles. The functional significance of the decrease in the noradrenaline content was studied in nervous control of the sinoatrial node of the heart. In agreement with the drop in noradrenaline concentration, transmural stimulation of the sinoatrial node region of isolated atria led to a mild, but statistically significant reduction of the function of sympathetic nerve endings, whereas parasympathetic innervation of the node showed no signs of impairment. This peripheral functional deficiency of sympathetic innervation of the node is not seen in the intact organism, where it is masked by central nervous mechanisms. Rats given cortisol postnatally had a significantly higher heart rate at 23, 33 and 44 days, because, in the presence of normal sympathetic influence, the tone of the parasympathetic nerves was reduced. The heart rate was highest at 23 days; with advancing age the difference diminished and at 65 days it was statistically nonsignificant.     

Naloxone's effect on the inotropic and chronotropic responses of isolated, electrically stimulated or spontaneously beating rat atria

Experiments were conducted to determine (i) how naloxone administration alone could modify the inotropic (in electrically stimulated (ES) rat atria) and both the inotropic and chronotropic responses (in spontaneously beating (SB) rat atria) isolated from normotensive and hypotensive (hemorrhaged) rats, and (ii) how naloxone administration would modify the inotropic and chronotropic responses of isolated rat atria previously administered an opiate agonist (morphine), a muscarinic agonist (carbachol), or an alpha- and beta-adrenergic agonist (noradrenaline). Naloxone (51-340 microM) added to ES atria caused a delayed but dose-related decrease in atrial tension (AT), whereas in SB atria, naloxone caused atrial heart rate (AHR) to fall and atrial tension (AT) to increase. Naloxone (68-340 microM), given to SB atria from acutely hypotensive rats, caused a similar increase in atrial tension as seen in the "normotensive" isolated (SB) atria and a similar decrease in atrial heart rate. Morphine sulphate (MS), 37-375 microM, administered to ES atria caused a delayed fall in AT; which was further decreased when naloxone (340 microM) was also added. In the SB atria, morphine caused a dose-related decrease in atrial heart rate whereas atrial tension increased. In SB preparations, atrial heart rate fell even further when naloxone was added to morphine compared with when morphine sulphate was given alone, whereas atrial tension was increased. Noradrenaline (3 or 12 microM) caused a positive, dose-related inotropic response in the ES atria, effects not influenced by the addition of naloxone. In the SB atria, naloxone caused no change in the dose-related increases in atrial tension and heart rate when combined with the lower dose of noradrenaline but decreased AT when combined with 12 microM noradrenaline, compared with when this dose of noradrenaline was given alone. Carbachol (683 nM-1.37 microM) caused a dose-related decrease in atrial tension in ES atria, which was reversed completely by the addition of naloxone. In SB atria, carbachol decreased both atrial tension and heart rate, and with the addition of naloxone (340 microM), a further slight drop in atrial heart rate occurred, but concurrently, a marked rise in atrial tension was observed. The results indicate that naloxone can act with receptors directly within atrial tissue to cause changes in atrial tension and heart rate. The comparable delayed responses of morphine and naloxone suggest their effects are mediated by nonopiate receptors which, in time, cause decreases in calcium influx into the atria.(ABSTRACT TRUNCATED AT 250 WORDS)     

A possible mechanism for cadmium-induced hypertension in rats

The mechanism of cadmium-induced hypertension was explored by measuring noradrenaline metabolism. Cadmium $\text{in vitro}$ was shown to inhibit both monoamine oxidase and catechol-$\text{O}$-methyltransferase, the two enzymes which inactivate the neurotransmitters noradrenaline and adrenaline. However, rats which were injected or fed (via the drinking water) with cadmium showed that, among the tissues surveyed, these two enzymes were inhibited significantly only in the aorta. $\text{In vitro}$, cadmium was found to inhibit noradrenaline binding to membranes from the heart, lung, and kidney, while stimulating binding to aortic membranes, which suggests that the effects may be specific. These results suggest that, in the aorta, cadmium may inhibit the two catabolic enzymes of noradrenaline, while at the same time stimulating noradrenaline-binding. Thus the effects of noradrenaline on vascular smooth muscle would be increased as well as prolonged.     

Effect of repeated exercise on postnatal development of the noradrenaline content of the albino rat heart, spleen and skeletal muscle

The authors studied the effect of repeated elevation of sympathetic activity on the postnatal development of the noradrenaline content of tissues of the albino rat. Between the ages of 15 and 29 days, young rats were forced to swim in water heated to 25 degrees C, 3 X 30 min on weekdays and 1 X 30 min on Saturdays and Sundays. At 30, 45 and 65 days, the noradrenaline content of the tissues was determined spectrofluorometricaLly by the trihydroxyindole method. The noradrenaline content of the heart of trained rats was higher than in the controls in all the given age groups and the size of the absolute difference rose with advancing age. The noradrenaline content of the spleen developed similarly. Repeated exercise did not lead to an increase in the noradrenaline content of skeletal muscle. The results show that the repeated elevation of the activity of sympathetic adrenergic neurones which occurs in young rats during exercise is a long-term factor stimulating the development of sympathetic innervation of the heart and spleen. The development of the neurones innervating skeletal muscle was not stimulated, probably because the activity of these neurones is not increased by stress.     

Is the damaging action of catecholamines on the myocardium realized via hyperstimulation of the beta receptors?

Experiments on an isolated rat heart were made to compare the damaging action on the myocardium of catecholamines (noradrenaline, adrenaline and isoproterenol) differing in the affinity for beta-receptors. The damage to myocardial cells was evaluated from the release into the perfusate of intracellular enzymes (creatine phosphokinase and lactate dehydrogenase) and the number of contracture damaged myocytes. Noradrenaline exerted the most powerful damaging action on the myocardium at a concentration of 10(-6) M. Perfusion of the heart with isoproterenol at concentrations of 10(-6) M and 10(-5) M did not lead to the affection of cardiomyocytes. It was isoproterenol concentration exceeding noradrenaline concentration 100 times that produced an increase in the rate of the release of the enzymes to the perfusate and a rise of the number of contractures in the myocardium, with the above increase being less than that provoked by adrenaline and noradrenaline (10(-6) M). It is concluded that the mechanism of the cardiotoxic effect of catecholamines cannot be reduced only to their effect on myocardial beta-receptors.     

Reduction of tissue noradrenaline content in the isolated perfused rat heart during ischemia: importance of monoamine oxidation.

The effect of ischemia on myocardial noradrenaline concentration and endogenous noradrenaline output was studied in the isolated perfused rat heart. Following a 15-min stabilization period, regional ischemia was produced by coronary artery ligation. After 60 min of ischemia, noradrenaline concentrations were significantly reduced in the interventricular septum and left ventricle but not in the right ventricle. The reduction in tissue noradrenaline concentration was not prevented when the 60-min ischemia was replaced by a 10-min ischemia followed by a 50-min perfusion. No modification in noradrenaline output was observed during a 60-min ischemia. In contrast, reperfusion was accompanied by a washout of noradrenaline in the coronary effluent, corresponding to only 2% of the amount lost by the tissue. The effect of monoamine oxidase inhibition during the whole ischemic period was studied by perfusing the preparation with pargyline starting 10 min before the artery ligation. Although the administration of pargyline did not alter the noradrenaline output, it did prevent a reduction in myocardial noradrenaline concentration. It was concluded that monoamine oxidase may contribute to the elimination of the noradrenaline lost by the cardiac tissue during ischemia.     

Activity of various enzymes of energy metabolism of the myocardium after neurogenic injury]

A 3-hour electrostimulation of the aortic arch in rabbits was followed by the exhastion of the tissue noradrenaline stores in the myocardium accompanied by increase in the activity of the glycolysis enzymes and of the enzyme limiting the process of the pentosophosphate route-G-6-PDH. The use of noradrenaline precursor - 1-DOPA restored the noradrenaline level in the myocardium completely after a 48-hour stimulation. Simultaneously there were noted no changes in the activity of the enzymes under study caused by the stimulation of the aortic arch. The data obtained confirmed the important role of the sympathetic nervous system and of its mediator - noradrenaline in the mechanism of the tissue metabolism regulation, whose derangement played a significant role in the development of dystrophic lesions of the heart tissue.     

Chemical sympathectomy and diurnal fluctuations of noradrenaline calorigenic action in the rat

In the rat, in which a diurnal fluctuation of the sensitivity to noradrenaline was previously found, the effect of injected 6-hydroxydopamine (6-OHDA) was investigated. The heat production and catecholamines contents in the interscapular brown adipose tissue, heart and adrenals were measured. Chemical sympathectomy induces a disappearance of diurnal fluctuation in the sensitivity to injected noradrenaline. In these animals a lower capacity for heat production was found. However, a significant calorigenic effect of injected noradrenaline in 6-OHDA-treated animals was still present. In sympathectomized animals a depletion of noradrenaline from interscapular brown adipose tissue and the heart was observed. Besides, a change in adrenaline/noradrenaline ratio was found in the adrenals.