Interactions between Sympathomimetic Amines and Antidepressant Agents in Man

Intravenous infusions of phenylephrine, noradrenaline, adrenaline, and isoprenaline were given to healthy human volunteers after five to seven days on phenelzine, tranylcypromine, or imipramine, and cardiovascular responses were compared with those observed under control conditions. With monoamine oxidase inhibitors there was a 2-2½ fold potentiation of the pressor effect of phenylephrine, but no clinically significant potentiation of cardiovascular effects of noradrenaline, adrenaline, or isoprenaline. With imipramine there was potentiation of the pressor effects of phenylephrine (2-3 fold), noradrenaline (4-8 fold), and adrenaline (2-4 fold); there were dysrhythmias during adrenaline infusions, but no noticeable or consistent changes in response to isoprenaline.Noradrenaline and adrenaline in amounts contained in local anaesthetics used in dentistry are not likely to be significantly potentiated in otherwise healthy patients receiving monoamine oxidase inhibitors. Hazardous potentiation of their cardiovascular effects might occur in patients receiving tricyclic antidepressants.Our observations do not indicate that the hazards associated with isoprenaline inhalation by bronchial asthmatics would be increased by coincident therapy with a monoamine oxidase inhibitor or tricyclic antidepressant.     

Opposite effects of neuropeptide Y (NPY) and polypeptide YY (PYY) on plasma immunoreactive atrial natriuretic factor (IR-ANF) in rats

Female Sprague-Dawley rats were administered NPY and PYY in doses of 0.1, 2.5 or 5, and 10 micrograms in order to determine whether the natriuretic action is the result of increased ANF secretion. NPY injection increased significantly IR-ANF while PYY decreased IR-ANF in the dose-response manner in normally-hydrated rats as well as in water-loaded rats. Opposite effects on plasma IR-ANF were exerted by NPY and PYY, indicating that an increase of ANF release may be responsible for NPY-induced natriuresis.     

The actions of vasoactive compounds in the foetus and the effect of perfusion through the placenta on their biological activity

In acute experiments on the in utero foetal lamb, angiotensin II was a more potent pressor agent that either noradrenaline or adrenaline, and the response to angiotensin II was not consistently modified by the combined administration of alpha and beta-adrenergic blocking agents. A significant reduction in the pressor response of the foetus to angiotensin II and noradrenaline occurred with infusion of these compounds to the foetus by the umbilical artery when compared with the response obtained with infusions of the same doses of these drugs by the umbilical vein. Moreover, the concentration of angiotensin II (pg. ml-1) present in the foetal circulation was less following umbilical arterial infusions compared with umbilical vein infusions of the same doses. A similar reduction in the pressor activity of adrenaline and the cardio-stimulant effect of isoprenaline occurred when these drugs were infused by the umbilical artery. It is concluded that the foetus, like the adult animal, is more sensitive to angiotensin II than to catecholamines and that the biological activities of noradrenaline, angiotensin II, adrenaline and isoprenaline are reduced by perfusion through the foetal placenta.     

Neuropeptide Y depresses reflex urinary bladder contractions in rats and modifies central activity of opioid agonists

The 36 amino acid peptide neuropeptide Y (NPY) has been found distributed in central structures associated with nociception and the actions of opioid analgesics. We therefore studied its central actions on reflex bladder contractions which we have shown to be inhibited by supraspinal and spinal opioid administrations in urethane anesthetized rats. Neuropeptide Y produced a dose related (0.5-2 micrograms per rat) inhibition of bladder contractions following intracerebroventricular (ICV) and spinal intrathecal (IT) administrations. These effects could not be antagonized by naloxone (2 micrograms, ICV or IT) or by ICI 174,864 [N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH: Aib = alpha-aminoisobutyric acid] (3 micrograms, ICV or IT). NPY (0.5-1 micrograms) reduced the ICV and IT effects of morphine but potentiated the action of the selective delta-receptor ligand [2-D-penicillamine, 5-L-penicillamine] enkephalin (DPLPE). The effect of the mu-selective opioid ligand [D-Ala2, Me-Phe4, Gly(ol)5] enkephalin (DAGO) were unaffected as were the submaximal ICV and IT actions of noradrenaline. It was concluded that NPY-induced inhibition of bladder activity was not due to a direct opioid receptor interaction. However since NPY consistently changed the activity of opioids (morphine and DPLPE), this suggested a possible physiological role in the regulation of opioid receptors, central neural excitability and thereby visceral activity.     

Differential cardiovascular effects of central clonidine and B-HT 920 in conscious rats

The effect of intracerebroventricular (i.c.v.) injection of the alpha 2-adrenoceptor agonists clonidine and B-HT 920 on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of noradrenaline and adrenaline was examined in conscious unrestrained rats. The injection of 1.0 microgram clonidine significantly decreased MAP and slightly decreased HR. Plasma noradrenaline and adrenaline levels were slightly but not significantly decreased after the injection of 1 microgram clonidine. In contrast, the injection of 0.1-10.0 micrograms B-HT 920 increased MAP and decreased HR. Plasma noradrenaline and adrenaline levels were slightly increased after the injection of the 1- and 10-micrograms doses. The i.c.v. injection of the alpha 2-antagonist rauwolscine slightly but not significantly increased MAP and plasma noradrenaline and adrenaline levels. The responses to i.c.v. injection of clonidine and B-HT 920 were not changed by prior administration of rauwolscine. Neither the pressor response to B-HT 920 nor the depressor response to clonidine was abolished by rauwolscine, suggesting that neither response was mediated by alpha 2-adrenoceptors.     

Stress-induced changes of circulating neuropeptide Y in the rat: comparison with catecholamines

Circulating concentrations of neuropeptide Y-like immunoreactivity (NPY), noradrenaline (NA) and adrenaline (AD) were measured in conscious, chronically catheterized rats submitted to various stress protocols. Basal plasma levels of NPY, NA and AD (194 +/- 52 fmol/ml, 0.90 +/- 0.11 pmol/ml and 0.52 +/- 0.07 pmol/ml) were increased by handling (+132%, +76% and +629%, respectively) and rose further during electric shock treatment. Adrenalectomy resulted in the complete disappearance of circulating adrenaline but did not alter either control or stress values of noradrenaline. In comparison circulating levels of NPY were reduced, but not significantly in adrenalectomized animals. Insulin stress induced a large increase in plasma AD levels and cold stress induced an increase in plasma NA levels, without any parallel change in NPY concentrations. These results demonstrate that NPY, which is colocalized with catecholamines in the peripheral nervous systems, is also released during stress responses and that its release parallels more closely changes in circulating NA than AD. Furthermore, stress-induced changes in circulating NPY-like immunoreactivity do not originate from the adrenal gland but mainly from the peripheral nervous system, and the release of NPY is dependent upon the nature of the stimulus.     

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.     

Postjunctional Origin of the indirect-like sympathomimetic effect of metanephrine and normetanephrine on blood pressure

The effects of metanephrine and normetanephrine have been compared with those from equiactive doses of the origin compounds, adrenaline and noradrenaline, on the pressor responses in rat, in order to determine whether their effects are owed, at least partially, to a releasing presynaptic action of the catecholamines in normal animals as well as those pretreated with reserpine, guanethidine and 6-OH-dopamine. Their effects have likewise been studied in isolated perfused renal arteries both in normal and reserpinized rats. None of the adrenolytic agent used were able either to reduce the duration of the hypertensive response or to accelerate tachyphylaxis. Identical results were obtained in renal artery preparations. It is thus concluded that the catecholamines stored in presynaptic endings are not involved in the observed phenomena and it is suggested that they might depend on the high doses required to produce effects equiactive to those of the origin substances.     

Substitution of calorigenic effects of noradrenaline and adrenaline and differences in their inhibition by propranolol.

The calorigenic effect of infused adrenaline and noradrenaline was measured in cold-acclimated rats. The slopes of the dose-response curves for the two catecholamines and the maxima of the curves were the same. The adrenaline dose-response curve showed a shift to the right, towards higher infusion doses, compared with the noradrenaline curve. Thermogenesis due to the two catecholamines was not additive throughout the whole range of doses used. In interaction with noradrenaline, propranolol caused a parallel shift of the dose-response curve to the right, whereas in interaction with adrenaline it depressed the maximum. The concept that the two catecholamines act via different regulation sites on a common thermogenetic effector is discussed.     

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)     

Hypothalamic alpha-adrenergic blockade modifies drinking and blood pressure responses to central angiotensin II in conscious rats

These experiments investigated in the awake rat the involvement of noradrenergic projections to the rostral hypothalamus in the drinking and pressor responses elicited by intracerebroventricular (i.c.v.) injections of 25 ng of angiotensin II. Phentolamine mesylate in doses of 2.5-125 micrograms injected into the rostral hypothalamus produced a dose-dependent depression of both the drinking and pressor responses elicited by i.c.v. administration of angiotensin II. A paradoxical increase in heart rate was associated with a decrease in pressor responses with increasing doses of phentolamine. This response was due to tissue injections, since pretreatment by injecting 12.5 micrograms of phentolamine into the ventricle did not block either the cardiovascular or drinking responses to i.c.v. injections of angiotensin II. Yohimbine (0.33-3.3 micrograms), DL-propranolol (25 micrograms), and atenolol (25 micrograms) did not, but prazosin (0.7 microgram) did significantly alter the pressor responses. Although yohimbine also was without effect on drinking, prazosin reduced the drinking responses. These results suggest that alpha 1-adrenergic receptors in the rostral hypothalamus are involved in the control of both the drinking and pressor responses elicited by i.c.v. injections of angiotensin II. In the case of propranolol and atenolol, beta-adrenergic receptors altered only the drinking response in a nonspecific manner by eliciting competing behaviors. Whether they are involved in modifying the drinking response only remains to be demonstrated.     

Adrenomedullary secretory response to midbrain stimulation in rat: effects of depletion of brain catecholamines or serotonin

Electrical stimulation of the periaqueductal gray substance (PAG) of the rostral midbrain of the rat produced biphasic or monophasic pressor responses depending on the duration of the stimulus train. Marked increases in plasma noradrenaline (NA) and adrenaline (A) levels accompanied the pressor responses, indicating the participation of the adrenal medulla. Depletion of central catecholamines (CA) by intraventricular administration of 6-hydroxydopamine (6-OHDA) did not affect the primary vasomotor component but markedly depleted adrenal CA levels and attenuated the adrenomedullary component of the response to brain stimulation. The intraperitoneal administration of p-chlorophenylalanine (pCPA) not only depleted brain serotonin (5-HT) levels but also reduced brain CA levels significantly. The adrenaline (A) levels were reduced in the adrenal glands of these rats and the adrenal secretory response to brain stimulation was attenuated. In contrast, the selective destruction of central 5-HT neurons by intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) in rats pretreated with desmethylimipramine (DMI) did not influence either the pressor nor the plasma CA responses to brain stimulation. Furthermore, the adrenal glands of these rats were normal. The results suggest that: (i) the central catecholaminergic neurons play an important role in the regulation of the adrenal glands but are not essential for the activation of the sympathetic vasoconstrictor fiber system: (ii) the pressor and plasma CA responses to PAG stimulation are not dependent on the central serotonergic system.     

Pressor effect of centrally administered neuropeptide Y in rats: role of sympathetic nervous system and vasopressin

The haemodynamic effects of intracerebroventricular (i.c.v.) administration of neuropeptide Y (NPY) in urethane-anaesthetized rats were studied. In Sprague-Dawley rats, NPY increased both blood pressure and heart rate in a dose-dependent manner. This response was unaffected by removal of the adrenal medullae or pretreatment with a specific vasopressin antagonist (180 ng/kg i.v.), but was abolished by phenoxybenzamine (1mg/kg i.v.). After pretreatment with propranolol (1mg/kg i.v.), the tachycardia was inhibited and the pressor response was of shorter duration than in controls. In 6-hydroxydopamine treated rats (two doses of 250 micrograms i.c.v., three days apart), NPY still elicited a pressor response and tachycardia, which were significantly higher than controls 15 minutes after the injection. Plasma levels of vasopressin were not altered by i.c.v. administration of NPY. However, in Brattleboro rats the peptide had no haemodynamic effects. Our results suggest that activation of sympathetic nervous system but not release of vasopressin or adrenal catecholamines into the bloodstream mediates the cardiovascular response to NPY. Central vasopressin pathways however may be involved.     

Comparison of the effects of neuropeptide Y and adrenergic transmitters on LH release and food intake in male rats

In view of the recent demonstrations that Neuropeptide Y (NPY) and adrenergic transmitters coexist in neurons of the rat brain, we have compared the effects of intraventricular (Ivt) injections of NPY and catecholamines on LH release and food intake in intact male rats. Of the three catecholamines, dopamine (DA), norepinephrine (NE) and epinephrine (E), only E (5.3 micrograms or 15.9 micrograms/rat) significantly stimulated LH release, although NE and E (5.3 micrograms/rat) were equally effective in eliciting food intake in satiated rats. Ivt administration of 10 micrograms NPY significantly stimulated LH release, whereas either lower (0.5 or 2 micrograms/rat) or higher (25 micrograms/rat) doses were ineffective. In contrast, NPY at doses of 0.5 - 10 micrograms/rat increased cumulative food intake in a dose-related fashion. These findings present preliminary evidence of the physiological correlates of the neuronal coexistence of adrenergic transmitters and NPY in the brain and raise the possibility that NPY may normally act either independently, in concert with or via adrenergic systems to evoke LH release and feeding responses in the rat.     

Feeding inhibition by urocortin in the rat hypothalamic paraventricular nucleus

Ventricular administration of urocortin (UCN) inhibits feeding, but specific site(s) of UCN action are unknown. In the current studies we examined the effect of UCN in the hypothalamic paraventricular nucleus (PVN) on feeding. We tested UCN administered into the PVN in several paradigms: deprivation-induced, nocturnal, and neuropeptide Y (NPY)-induced feeding. We compared the effect of equimolar doses of UCN and corticotrophin releasing hormone (CRH) on NPY-induced and nocturnal feeding, determined whether UCN in the PVN produced a conditioned taste aversion (CTA) and induced changes in c-Fos immunoreactivity (c-Fos-ir) after UCN and NPY administration in the PVN. UCN in the PVN significantly decreased NPY and nocturnal and deprivation-induced feeding at doses of 1, 10, and 100 pmol, respectively. UCN anorectic effects lasted longer than those attributed to CRH. Ten and thirty picomoles UCN did not induce a CTA, whereas 100 pmol UCN produced a CTA. UCN (100 pmol) in the PVN neither increased c-Fos-ir in any brain region assayed nor altered c-Fos-ir patterns resulting from PVN NPY administration. These data suggest the hypothalamic PVN as a site of UCN action.     

The cardiovascular actions of centrally administered neuropeptide Y

The cardiovascular actions of intracerebroventricular (i.c.v.) administration of neuropeptide Y (NPY) were examined in conscious, unrestrained rats. A prolonged decrease in heart rate (HR) and a fall in mean arterial pressure (MAP) were obtained following i.c.v. administration of NPY (1 and 10 micrograms). Passive immunization with an antiserum directed against NPY confirmed that the slowing of HR following i.c.v. administration of NPY was mediated via a central nervous mechanism and not from leakage of NPY out of the brain. Administration of NPY into different brain parenchymal regions identified a putative site of action in the rostral region of the solitary tract. The mechanism of the decrease in HR caused by centrally administered NPY was investigated by i.c.v. administration of NPY to animals that were pretreated with agents that altered autonomic tone. Administration of NPY to atropine-treated animals produced a reversal of the atropine-induced tachycardia, suggesting that the NPY-induced decrease in HR was not due to augmented vagal tone. However, administration of NPY to animals pretreated with propranolol did not significantly lower HR below that obtained with propranolol alone. These data suggest that i.c.v. administration of NPY may cause a decrease in cardiac sympathetic outflow. The effects of centrally administered NPY on baroreflex function were studied. The changes in HR caused by NPY did not significantly alter baroreflex set-point or gain. These studies provide evidence that NPY acted within a brainstem region to decrease sympathetic nervous outflow, resulting in a decrease in HR and MAP.     

Interactions between neuropeptide Y and alpha 2-adrenoceptors in selective rat brain regions.

Neuropeptide Y significantly reduced the potassium-stimulated release of [3H]norepinephrine [( 3H]NE) from slices of rat hippocampus, hypothalamus and frontal cortex but not from slices of parieto-occipital cortex. The NPY-induced inhibition of [3H]NE release from frontal cortical slices was concentration dependent, reaching statistical significance at 10 nM. The alpha 2-adrenoceptor partial agonist, clonidine, also reduced the potassium-stimulated release of [3H]NE. The combination of NPY and clonidine in hippocampal slices produced a greater reduction of stimulated [3H]NE release than either of the two compounds alone, suggesting a potentiation of their activity, whereas in frontal cortical slices, the effect was additive. When NPY and clonidine were added to frontal cortical slices, they independently produced a significant concentration-dependent reduction in forskolin-stimulated cAMP accumulation. However, NPY and clonidine combined did not produce a further reduction in forskolin-induced cAMP accumulation than either compound when used alone. These results suggest that the ability of NPY to potentiate alpha 2-adrenoceptor-induced inhibition of [3H]NE release in discrete brain regions does not depend on the reductions in cAMP.     

Effect of oestradiol on catecholamine-stimulated lipolysis

The authors studied the effect of a single in vivo dose of oestradiol (OE) on adrenergic lipolysis in the epididymal adipose tissue of adult and juvenile male rats, and the effect of OE on plasma free fatty acids (FFA), cholesterol and beta-lipoprotein levels at various intervals after its administration. It was found that OE injected 24 h beforehand in vivo (s.c.), in doses of 100 and 200 micrograms X kg-1 body weight, significantly potentiated the lipid-mobilizing action of the catecholamines noradrenaline (NOR) and isoprenaline (ISO) in adult rats (the action of ISO was potentiated more intensively); in addition, the adipose tissue became more sensitive to the action of NOR, but not of ISO. Raising the dose of OE to 400 micrograms X kg-1 did not enhance the potentiation of the lipolytic action of the catecholamines any further; on the contrary, the lipid mobilizing effect of the catecholamines was potentiated less than after half this dose. Following the s.c. injection of an oily OE solution, the lipolytic effect was potentiated after more than 7 h; the potentiation was strongest after 12 h, but only as far as the maximum attainable degree of lipolysis was concerned. Potentiation of adrenergic lipolysis was found only in adult male rats. In male rats weighing 130-150 g the lipolytic effect of catecholamines (in mumol/g adipose tissue) was significantly greater than in adult animals and the pre-administration of OE did not potentiate adrenergic lipolysis any further. Determination of plasma FFA, cholesterol and beta-lipoprotein levels 1, 2, 4 and 6 hours after the s.c. injection of OE showed only nonsignificant changes (an increase in FFA and a decrease in cholesterol). The authors consider it important to distinguish between the effect of OE on catecholamine-stimulated lipolysis in depot adipose tissue and its effect on lipid metabolism. In their opinion, the dose-dependent effect of OE on muscular and metabolic adrenergic reactions could be one of the factors co-reversible for certain side reactions to steroid contraceptives.     

Effect of Heparin on Serum Free-fatty-acids,Plasma Catecholamines,and the Incidence of Arrhythmias following Acute Myocardial Infarction

The effect of intravenous heparin in a therapeutic dosage on cardiac arrhythmias in patients with indubitable acute myocardial infarction was investigated. The value of serum free-fatty-acids (F.F.A.s) and plasma catecholamines in the prediction of patients vulnerable to serious arrhythmias was also studied.Heparin produced a significant rise in F.F.A., maximal within 10 minutes of injection, but did not increase the incidence of cardiac arrhythmias.No relationship was found between the incidence of arrhythmias and the initial levels of F.F.A. or adrenaline. No correlation was obtained between F.F.A. and plasma catecholamine levels. Heparin did not have a consistent effect on plasma catecholamines. Initial control plasma noradrenaline concentrations, however, were found to be significantly correlated with the incidence of subsequent arrhythmias. It is suggested that the level of plasma noradrenaline may be a valuable predictive guide to those patients likely to develop significant arrhythmias after acute myocardial infarction.     

Radioprotective action of catecholamines on a Chinese hamster fibroblast culture

The radioprotective ability of adrenaline, noradrenaline and isoproterenol in various concentrations has been studied in experiments on cultured Chinese hamster fibroblasts in vitro. Radioprotective effect of isoproterenol is pronounced at 10(-8)M concentration; adrenaline and especially noradrenaline are effective at higher concentrations. The antagonist of beta-adrenergic receptors propranolol blocks the radioprotective effect of catecholamines on cells. The beta-adrenergic mechanism of catecholamines radioprotective action on the mammals cells is under discussion.