Intravenous Infusion Of Norepinephrine Research Articles

The influence of phenoxybenzamine and isopropylmethoxamine (BW 61-43) on some cardiovascular, metabolic, and histopathologic effects of norepinephrine infusions in dogs

The effects of intravenous norepinephrine infusion (0.5 mg/kg in two hours) in conscious dogs can be classified according to the influence of pretreatment with phenoxybenzamine (2 or 5 mg/kg intravenously one hour before norepinephrine) or isopropylmethoxamine (BW 61-43) (8 mg/kg intravenously 20 to 30 minutes before infusion). Effects blocked or reduced by phenoxybenzamine, but not by BW 61-43, include the rise in arterial pressure, electrocardiographic changes, accumulation of pericardial fluid rich in lactic dehydrogenase, the rise in hematocrit, presence of inclusion bodies in liver cells, and necrosis of the adrenal cortex. Effects blocked by BW 61-43, but not by phenoxybenzamine, include the rises in plasma FFA and glucose and the accumulation of triglycerides in liver. Both phenoxybenzamine and BW 61-43 block, at least partially, the accumulation of triglycerides in heart. Neither phenoxybenzamine nor BW 61-43 prevents the norepinephrine-induced depletion of glycogen in liver.

THE EFFECTS OF BRETYLIUM AND GUANETHIDINE ON THE PRESSOR RESPONSES TO NORADRENALINE AND ANGIOTENSIN.

In normal human subjects the intravenous administration of bretylium and guanethidine rapidly increased the pressor response to intravenous infusions of noradrenaline, while the response to angiotensin was little or not affected. This result suggests that potentiation of noradrenaline by bretylium and guanethidine is not simply due to block of homeostatic reflexes, but is due to sensitization of arteriolar smooth muscle. But we, like others, have failed to demonstrate such an effect in man when measuring changes in blood flow during intra-arterial infusions of noradrenaline.

CARDIAC NORADRENALINE STORES

The effects of single doses of reserpine or of guanethidine in increasing the heart rate of the dog heart-lung preparation have been studied. Compared with reserpine, guanethidine increased heart rate more and more rapidly, and the increase lasted longer. When the effects of reserpine had subsided, guanethidine now caused a similar rate of change and maximum increase in heart rate, but recovery was quicker. Guanethidine given alone caused less release of noradrenaline in the right atrium than did reserpine alone, but both drugs together caused greater release than did either alone. Thus liberation of noradrenaline in the right atrium was unrelated to the effectiveness of either drug to increase heart rate. Guanethidine and reserpine did not increase the heart rate of heart-lung preparations from dogs which had received reserpine for 2 days and which contained no noradrenaline. Guanethidine had similar actions on the heart rate of preparations either given a slow intravenous infusion of noradrenaline or a single dose of reserpine. Treatment of a normal heart-lung preparation with noradrenaline increased the atrial noradrenaline content, but subsequent addition of reserpine or of guanethidine changed heart rate in the same manner as for preparations not given noradrenaline. Treatment with reserpine increased the heart's sensitivity to noradrenaline without changing initial heart rate. These results are discussed in relation to the idea that there may be more than one noradrenaline compartment in the heart.

Mechanism of the initial adrenergic effects of bretylium and guanethidine.

Treatment with phenoxybenzamine and dichloroisoprenaline prevented the rise of blood pressure, contraction of the nictitating membrane and increase in cardiac contractile force produced by intravenous injections of bretylium and guanethidine in anaesthetized or spinal cats. Treatment with cocaine, imipramine or reserpine reduced the sensitivity to bretylium and guanethidine of the spinal cat. In the spinal cat treated with reserpine, sensitivity to the drugs could be restored by an infusion of noradrenaline. Chlorpromazine also blocked the pressor and nictitating membrane responses to bretylium and guanethidine. The drug effects were unaltered 1 hr after bilateral adrenalectomy. During the intravenous infusion of noradrenaline into spinal cats the pressor responses to bretylium and guanethidine were increased, whilst those to adrenaline and to noradrenaline were decreased. Guanethidine (3 to 5 mg/kg) injected intravenously into the cat caused a sudden relaxation of the rat isolated stomach-strip bathed in blood. In seven similar experiments bretylium (3 to 5 mg/kg) relaxed the strip only once; in the other six experiments there was either no effect (four experiments) or an increase in the tone of the strip (two experiments). It is concluded that the initial adrenergic effects of bretylium and guanethidine are mediated, at least in part, through a release of catechol amines from stores in the effector organ.

The effects of nialamide on adrenergic functions.

Nialamide potentiated the pressor effects of noradrenaline in the pithed cat. In cats treated with reserpine and then pithed, it prevented the restoration of the pressor effects of tyramine by slow intravenous infusions of noradrenaline. Nialamide produced a gradual decline in the pressor effects of repeated injections of tyramine whilst the effects of tyramine on the nictitating membrane were potentiated. The development of tachyphylaxis to tyramine in the isolated guinea-pig heart was associated with a 40% reduction in the myocardial concentration of noradrenaline. The onset of tachyphylaxis to tyramine was more rapid when nialamide was either included in the perfusion fluid or administered in vivo. Prior treatment with nialamide increased threefold the myocardial concentration of noradrenaline; however, the development of tachyphylaxis to tyramine was associated with a proportionate fall in the myocardial concentration of noradrenaline. In five out of nine experiments the acute administration of nialamide increased the output of noradrenaline per stimulus from the isolated cross-perfused spleen of the cat when the stimulus frequency was 30 shocks/sec, but not when the frequency was 10 shocks/sec. When nialamide (20 mg/kg) was given subcutaneously to cats 20 hr before their spleens were isolated and perfused, there was a rapid fall-off in the contractions of the spleen in response to periods of nerve stimulation. The outputs of noradrenaline per stimulus were decreased at both frequencies of stimulation. Nialamide decreased the concentrations of noradrenaline in the myocardium and spleen of the cat. The hypothesis is proposed that nialamide diminishes the availability of transmitter, as a consequence of a decreased re-entry of noradrenaline into a storage site present in nerve endings, and that such a decrease in the availability of noradrenaline in hyperactive nerve pathways may account for the antihypertensive effects of monoamine oxidase inhibitors in man.

The effect of eserine on the activity of adrenergic nerves in the rat

Summary The hypertensive response to eserine was blocked in the reserpine treated rat. Intravenous infusion of noradrenaline, dihydroxyphenylalanine and 5-hydroxytryptamine only occasionally restored this effect. Bretylium and choline 2,6-xylyl ether bromide depressed or abolished the hypertensive effect of eserine. Pretreatment with isopropylisoniazid did not antagonize the inhibitory action of reserpine on the hypertensive response to eserine. The electrical activity in the preganglionic cervical sympathetic was found to be increased by eserine. The hypertensive response to eserine in the rat is due to central adrenergic activation. Liberation of noradrenaline (and adrenaline) from the adrenals and from the blood vessels does not play a significant role in producing the hypertensive reaction to eserine in the rat.

Localizing tritiated norepinephrine in sympathetic axons by electron microscopic autoradiography.

Following intravenous infusion of tritiated norepinephrine, rat pineals were prepared for combined autoradiography and electron microscopy. Concentrations of photographic grains were observed only over regions of preterminal autonomic axons containing granulated vesicles, thereby directly demonstrating uptake of norepinephrine into these axons and strongly suggesting that their granulated vesicles contain norepinephrine.

Inhibition of adrenal secretion of epinephrine during infusion of catecholamines.

The effect of intravenous infusion of epinephrine or norepinephrine on the secretion of epinephrine by the adrenal was studied in dogs. The epinephrine content of adrenal venous blood was assayed on the rat uterus, automatically stimulated. The infusion of epinephrine or norepinephrine at a rate which produced an increase in blood pressure inhibited the output of epinephrine by the adrenal. If the rate of infusion of catecholamines was too slow to increase the blood pressure, or if the increase in blood pressure was prevented by a pressure compensator, secretion of epinephrine was not inhibited. A good correlation exists between the per cent decrease in epinephrine secretion and the per cent increase in blood pressure produced by infusion of catecholamines. It appears that the inhibition of epinephrine secretion during infusion of catecholamines is produced reflexly by the induced increase in blood pressure. In two experiments the aortic epinephrine concentration exceeded the adrenal venous epinephrine concentration during infusion of epinephrine, suggesting an uptake of epinephrine by the adrenal gland.

AN ENZYMIC METHOD FOR THE ESTIMATION OF GLYCEROL IN BLOOD AND ITS USE TO DETERMINE THE EFFECT OF NORADRENALINE ON THE CONCENTRATION OF GLYCEROL IN BLOOD

A sensitive, specific method is described for the estimation of plasma glycerol. It depends on the reduction of DPN in the presence of a partially purified glycerol dehydrogenase prepared from Aerobader aerogenes. With this method rabbit plasma has been found to contain 8 to 16 μmoles of glycerol per 100 ml. Intravenous infusion of noradrenaline causes an increase in plasma glycerol, which returns to its resting level about half an hour after the end of the infusion.

Role of the liver in calorigenic action of epinephrine and norepinephrine.

Intravenous infusion of epinephrine and norepinephrine into eviscerated cats at rates of 4 µg/kg/min for 5 min results in an increase in oxygen consumption to an average 121% and 123% of control, respectively, with return to control level in the 15-min period after infusion. A similar response is obtained in normal cats during epinephrine infusion, but only in this group is a secondary or delayed rise to an average 110% of control noted in the 15-min period after infusion. It is suggested that the calorigenic action of epinephrine might be separated into an immediate effect occurring during intravenous infusion, independent of the presence of the liver, and a delayed or secondary effect occurring after infusion, requiring the presence of the liver. Both drugs change lung volume and thus introduce artifacts that interfere with measurement of oxygen consumption by conventional methods. This is overcome by use of a thermostat-controlled compensating body chamber which frees the oxygen consumption record from any dependence on lung volume.

Changes in renal function resulting from norepinephrine infusion.

The experiments of this study show that intravenous infusion of norepinephrine has a direct effect on the kidneys of areflex dogs to cause a decrease in renal blood flow, glomerular filtration rate, and urinary output. However, when the infusion rate is below an average of 0.0006 mg/kg/min, the renal blood flow, glomerular filtration rate, and urinary output increase as a result of an increase in arterial pressure which accompanies the infusion of norepinephrine. Above this infusion rate, the direct effect of the norepinephrine on the kidneys is greater than the effect of the rising arterial pressure, thus causing the blood flow, glomerular filtration rate, and urinary output to decrease. The results from this study indicate that changes in renal arterial pressure result in very significant changes in renal blood flow, glomerular filtration rate, and urinary output in spite of the local autoregulation of renal blood flow.

Effect of hexamethonium on the vascular response to noradrenaline in man.

Intra-arterial infusion of hexamethonium into the brachial artery had no potentiating effect on the constrictor response of the vessels of the forearm or hand to noradrenaline given by the same route. The response of the hand vessels to intravenous infusion of noradrenaline was enhanced after intra-arterial hexamethonium, but this was attributed to entry of the blocking agent into the general circulation resulting in blockade of baroreceptor reflexes since the potentiation was seen to an equal degree on both sides. It is concluded that if increased sensitivity to noradrenaline plays a part in the phenomenon of tolerance to hexamethonium this must be a slowly developing effect.

An investigation of the action of tyramine and its interrelationship with the effects of other sympathomimetic amines.

Choline 2,6-xylyl ether potentiated the sympathomimetic effects of tyramine and adrenaline in anaesthetized and spinal cats; the effects of noradrenaline were not significantly affected. The pressor activity of tyramine was also potentiated by the drug in reserpine-treated spinal cats and in pithed rats. The acute intravenous injection of reserpine in pithed rats potentiated pressor responses to tyramine, but depressed those to adrenaline and noradrenaline. During the intravenous infusion of noradrenaline in spinal cats and pithed rats the pressor responses to tyramine were increased, whilst those to adrenaline and noradrenaline were decreased. Infusion of isoprenaline in a spinal cat depressed responses to tyramine and noradrenaline, but potentiated those to adrenaline. A lower rate of infusion of isoprenaline in the same animal subsequently potentiated adrenaline and noradrenaline, but continued to depress tyramine. These results are held to be inconsistent with the view that the sympathomimetic effects of tyramine are produced entirely by the release of catechol amines.

AN ENZYMIC METHOD FOR THE ESTIMATION OF GLYCEROL IN BLOOD AND ITS USE TO DETERMINE THE EFFECT OF NORADRENALINE ON THE CONCENTRATION OF GLYCEROL IN BLOOD

A sensitive, specific method is described for the estimation of plasma glycerol. It depends on the reduction of DPN in the presence of a partially purified glycerol dehydrogenase prepared from Aerobader aerogenes. With this method rabbit plasma has been found to contain 8 to 16 μmoles of glycerol per 100 ml. Intravenous infusion of noradrenaline causes an increase in plasma glycerol, which returns to its resting level about half an hour after the end of the infusion.

Alteration of schizophrenic states with hypertensive agents

The favourable action of blood transfusions on acute schizophrenics suggests a possible importance of the (cerebral) circulation in the pathogenesis of certain forms of schizophrenia. Reminding this possibility we investigated the effect of hypertensive substances on the psychosis in 23 schizophrenics (repeated intravenous infusions of norepinephrine and hypertensine). As a control 7 schizophrenic subjects received infusions of derivatives of dioxyphenylalanine which are not hypertensive.

Effect of noradrenaline, bretylium and cocaine on the blood pressure response to tyramine in the rat.

Tyramine is mainly a pressor agent in the rat under urethane, although the hypertensive effect of tyramine in some experiments is followed by a prolonged increase or depression of blood pressure. Bretylium, in doses up to 10 mg/kg, prolonged the response to tyramine, whereas larger doses depressed or blocked its effect. When the hypertensive effect of tyramine was blocked by bretylium, both noradrenaline and dihydroxyphenylalanine, when slowly infused, were found to restore it. The well-known block by cocaine of the hypertensive response to tyramine could also be reversed by intravenous infusion of noradrenaline and dihydroxyphenylalanine. It is concluded that the infusion of noradrenaline and dihydroxyphenylalanine makes available noradrenaline in the postganglionic adrenergic nerves which is necessary for the action of tyramine.

Effect of cocaine and related drugs on the uptake of noradrenaline by heart and spleen.

Noradrenaline uptake by heart and spleen after intravenous infusion of noradrenaline was measured in the pithed rat. Cocaine, given before the infusion, inhibited the noradrenaline uptake in relation (a) to the dose administered and (b) to the amount of noradrenaline infused. There was an association between increase in the pressor response to a test dose of noradrenaline and inhibition of the uptake by the heart. Drugs related chemically to cocaine, such as alpha-cocaine, amethocaine, and atropine, did not alter the noradrenaline uptake or potentiate the blood pressure response to noradrenaline. The noradrenaline uptake by the heart was unchanged after dibenamine, but blocked by the dichloro-analogue of isoprenaline. It was concluded that cocaine specifically prevented the uptake of noradrenaline by tissues, thus increasing the amount of noradrenaline available for combination with adrenergic receptors. The dichloro-analogue of isoprenaline appeared to block both uptake by the heart and the combination with receptors.

Cardiac adrenergic blockade with DCI in the intact unanesthetized animal.

Using techniques developed in this laboratory for continuous recording of essential parameters of left ventricular function, the cardiovascular responses of intact unanesthetized animals to intravenous infusions of isoproterenol, epinephrine and norepinephrine, and to exercise and hypothalamic stimulation, have been compared with responses to the same drugs and procedures after adrenergic blockade, first with the dichloro analogue of isoproterenol (DCI), and then with both DCI and phenoxybenzamine. At dosage level of 5 mg/kg, DCI effectively blocked the response to isoproterenol, but had less effect on the response to epinephrine and norepinephrine, and no effect on the response to exercise or central stimulation. The effects of DCI, per se, were dosage-dependent.

Effect of norepinephrine on plasma free fatty acids level in man.

Plasma free fatty acid (FFA) and glucose levels were measured in 44 young male subjects who received intravenous infusions of norepinephrine. Dose levels and rates of infusion were independently varied. A significant dose-response relationship was noted for FFA. The time at which the peak response occurred depended on the duration of infusion. A postinfusion fall in FFA level was observed, which suggests that exogenous infusion of norepinephrine may inhibit endogenous lipid-mobilizing mechanisms. Submitted on October 11, 1960

Autonomic response patterns during intravenous infusion of epinephrine and nor-epinephrine.

A.LTI HOUGH extensive work has been reported on the differential effects of epinephrine and nor-epinephrine upon functions mediated by the autonomic nervous system (ANS) ,»•' *• • •• few variables have been measured simultaneously and most studies have used direct injection rather than controlled infusion. Drug reactions are thereby confounded with reactions to the needle. This study reports the effects of these drugs upon a number of simultaneously recorded ANS variables and isolates reactions to needle insertion, to saline at different rates of infusion, and to the drugs at different infusion rates and concentrations. It is one of a series of studies on autonomic response patterns to various stimuli, and is of particular interest in view of recent attempts to relate circulating levels of epinephrine and nor-epinephrine to emotional states such as fear and anger.-->-