Blockade Of Muscarinic Cholinoceptors Research Articles

Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs.

Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P < .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n = 5) or α- and β-adrenoceptors (n = 5 each) did not abolish the observed responses, NO synthase inhibition (n = 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells.

In anesthetized pigs human chorionic gonadotropin increases myocardial perfusion and function through a β-adrenergic-related pathway and nitric oxide

Human chorionic gonadotropin (hCG) is not only responsible for numerous pregnancy-related processes, but can affect the cardiovascular system as well. So far, however, information about any direct effect elicited by hCG on cardiac function, perfusion, and the mechanisms involved has remained scarce. Therefore, the present study aimed to determine the primary in vivo effect of hCG on cardiac contractility and coronary blood flow and the involvement of autonomic nervous system and nitric oxide (NO). Moreover, in coronary endothelial cells (CEC), the intracellular pathways involved in the effects of hCG on NO release were also examined. In 25 anesthetized pigs, intracoronary 500 mU/ml hCG infusion at constant heart rate and aortic blood pressure increased coronary blood flow, maximum rate of change of left ventricular systolic pressure, segmental shortening, cardiac output, and coronary NO release (P < 0.0001). These hemodynamic responses were graded in a further five pigs. Moreover, while blockade of muscarinic cholinoceptors (n = 5) and of α-adrenoceptors (n = 5) did not abolish the observed responses, β1-adrenoceptors blocker (n = 5) prevented the effects of hCG on cardiac function. In addition, β2-adrenoceptors (n = 5) and NO synthase inhibition (n = 5) abolished the coronary response and the effect of hCG on NO release. In CEC, hCG induced the phosphorylation of endothelial NO synthase through cAMP/PKA signaling and ERK1/2, Akt, p38 MAPK involvement, which were activated as downstream effectors of β2-adrenoceptor stimulation. In conclusion, in anesthetized pigs, hCG primarily increased cardiac function and perfusion through the involvement of β-adrenoceptors and NO release. Moreover, cAMP/PKA-dependent kinases phosphorylation was found to play a role in eliciting the observed NO production in CEC.

Intracoronary gastrin 17 increases cardiac perfusion and function through autonomic nervous system, CCK receptors, and nitric oxide in anesthetized pigs

The release of gastrointestinal hormones has been reported to modulate reflex cardiovascular responses caused by gastric distension, although the role played by gastrin 17 is as yet unknown. The present study was therefore planned to determine the primary in vivo effect of gastrin 17 on coronary blood flow and cardiac function and the involvement of autonomic nervous system, CCK1/2 receptors, and nitric oxide (NO). In 40 anesthetized pigs, gastrin 17 was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure. In 35 of the 40 pigs, the mechanisms of the observed hemodynamic responses were analyzed by repeating gastrin 17 infusion after autonomic nervous system and NO blockade, and after specific CCK receptors agonists/antagonists administration. Intracoronary gastrin 17 administration caused dose-related increases of both coronary blood flow and cardiac function. The intracoronary co-administration of CCK33/pentagastrin and gastrin 17 potentiated the coronary effects observed when the above agents were given alone (P <0.05). The potentiation of the cardiac response was observed only with the co-administration of pentagastrin and gastrin 17 (P <0.05). Moreover, blockade of muscarinic cholinoceptors (intravenous atropine) and of α-adrenoceptors (intravenous phentolamine) did not abolish the hemodynamic responses to gastrin 17. The cardiac and vascular effects of the hormone were prevented by blockade of β-adrenoceptors (intravenous atenolol and butoxamine), CCK1/2 receptors (intracoronary lorglumide and CAM-1028), and NO synthase (intracoronary Nω-nitro-l-arginine methyl ester). In conclusion, gastrin 17 primarily increased coronary blood flow and cardiac function through the involvement of CCK receptors, β-adrenoceptors, and NO release.

CROSSING INTERACTION OF ADRENERGIC, CHOLINERGIC, HISTAMINERGIC AND OPIOIDERGIC SYSTEMS ON WATER INTAKE IN ADULT MALE RATS

Several lines of evidence have indicated that many nuclei in the brain including preoptic nucleus, AV3V, subfornical organ, septal area and lateral hypothalamus are the targets of efferents from chemo-sensitive and pressure-sensitive systems. These areas may concern with regulation of fluid homeostasis. In the present study, intracerebroventricular injections were carried out in all experiments. After a 24 h deprivation of water, the volume of consumed water was measured for 1 h. Administration of pilocarpine (0.5-1 ?g/rat), prazocin (2 ?g/rat), histamine (40-80 ?g/rat) and naloxone (0.5-1 ?g/rat) increased, while scopolamine (5-10 ?g/rat), phenylepherine (30 ?g/rat), morphine (2.5 ?g/rat), pyrilamine (25-50 ?g/rat) and ranitidine (10-20 ?g/rat) decreased water intake in isolated rats. The activation of muscarinic cholinoceptors by pilocarpine attenuated the inhibitory effect induced by phenylepherine. Blockade of muscarinic cholinoceptors did not change the phenylepherine-induced response. Pretreatment of rats with prazocin decreased the pilocarpine-induced response. Pharmacological blockade of muscarinic cholinoceptors by scopolamine decreased the prazocin –induced effect on water intake. Blockade of histamine H1 and H2 receptors attenuated the histamine-induced response. Furthermore, pyrilamine, but not ranitidine, increased the inhibitory effect induced by morphine. Pharmacological blockade of H1 and H2 receptors decreased the naloxone-induced effect on water intake. It is concluded that the histaminergic system may have a close interaction with morphine and naloxone regarding drinking behavior. Also, muscarinic cholinoceptors and adrenoceptors may have an interactive effect in this respect.

The effect of dehydroepiandrosterone on coronary blood flow in prepubertal anaesthetized pigs.

Extensive research suspecting an association between plasma levels of dehydroepiandrosterone and the risk of coronary heart disease has not been conclusive. The present study was designed to investigate the effect of dehydroepiandrosterone on the coronary circulation and to determine the mechanisms involved. In prepubertal pigs of both sexes anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary flow caused by intravenous infusion of dehydroepiandrosterone were assessed using an electromagnetic flowmeter. Changes in heart rate and arterial pressure were prevented by atrial pacing and by connecting the arterial system to a pressurized reservoir containing Ringer solution. In 20 pigs, infusion of 1 mg h-1 of dehydroepiandrosterone caused a decrease in coronary flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further eight pigs, a dose-response curve was obtained by graded increases in the infused dose of hormone between 0.03 and 4 mg h-1. The mechanisms of the above response were studied in the 20 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. Blockade of muscarinic cholinoceptors with intravenous atropine (five pigs) and of alpha-adrenoceptors with intravenous phentolamine (five pigs) did not affect the dehydroepiandrosterone-induced coronary vasoconstriction. This response was abolished by blockade of beta-adrenoceptors with intravenous propranolol (five pigs) and of coronary nitric oxide synthase with intracoronary injection of Nomega-nitro-L-arginine methyl ester (five pigs) even after reversing the increase in arterial pressure and coronary vascular resistance caused by the two blocking agents with intravenous infusion of papaverine. The present study showed that intravenous infusion of dehydroepiandrosterone primarily caused coronary vasoconstriction. The mechanisms of this response were shown to involve the inhibition of a vasodilatory beta-adrenergic receptor-mediated effect related to the release of nitric oxide.

The effect of testosterone on regional blood flow in prepubertal anaesthetized pigs.

This work was undertaken to study the effects of testosterone on the coronary, mesenteric, renal and iliac circulations and to determine the mechanisms of action involved. In prepubertal pigs of both sexes anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary, superior mesenteric, left renal and left external iliac blood flow caused by intra-arterial infusion of testosterone were assessed using electromagnetic flowmeters. Changes in heart rate and arterial blood pressure were prevented by atrial pacing and by connecting the arterial system to a pressurized reservoir containing Ringer solution. In 12 pigs, intra-arterial infusion of testosterone for 5 min to achieve a stable intra-arterial concentration of 1 microg l(-1) increased coronary, mesenteric, renal and iliac blood flow without affecting the maximum rate of change of left ventricular systolic pressure (left ventricular dP/dt(max)) and filling pressures of the heart. In a further five pigs, a concentration-response curve was obtained by graded increases in the intra-arterial concentration of the hormone between 0.125 and 8 microg l(-1). The mechanisms of these responses were studied in the 12 pigs by repeating the experiment after haemodynamic variables had returned to the control values before infusions. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the responses caused by intra-arterial infusion of testosterone performed to achieve a stable intra-arterial concentration of 1 microg l(-1). In the same pigs and in the remaining six pigs, the increases in coronary, mesenteric, renal and iliac blood flow caused by intra-arterial infusion of testosterone performed to achieve a stable intra-arterial concentration of 1 microg l(-1) were prevented by intra-arterial injection of N(omega)-nitro-L-arginine methyl ester. The present study shows that intra-arterial infusion of testosterone dilated coronary, mesenteric, renal and iliac circulations. The mechanism of this response involved the release of nitric oxide.

The Effect of Progesterone on Coronary Blood Flow in Anaesthetized Pigs

The present study was designed to investigate the effect of progesterone on the coronary circulation and to determine the mechanisms involved. In pigs anaesthetized with sodium pentobarbitone, changes in left circumflex or anterior descending coronary blood flow caused by intravenous infusion of progesterone at constant heart rate and arterial blood pressure were assessed using an electromagnetic flowmeter. In 14 pigs, infusion of 1 mg h(-1) of progesterone caused an increase in coronary blood flow without affecting left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In a further four pigs, this vasodilatory coronary effect was enhanced by graded increases in the dose of the hormone of between 1, 2 and 3 mg h(-1). The mechanisms of the above response were studied in the 14 pigs by repeating the experiment after haemodynamic variables had returned to the control values observed before infusion. In six pigs, blockade of muscarinic cholinoceptors and adrenoceptors with atropine, propranolol and phentolamine did not affect the coronary vasodilatation caused by progesterone. In the remaining eight pigs, this response was abolished by intracoronary injection of N(omega)-nitro-L-arginine methyl ester (L-NAME) even when performed after reversing the increase in arterial blood pressure and coronary vascular resistance caused by L-NAME with continuous intravenous infusion of papaverine. The present study showed that intravenous infusion of progesterone primarily caused coronary vasodilatation. The mechanism of this response was shown to involve the endothelial release of nitric oxide.

The effect of 17beta-oestradiol on regional blood flow in anaesthetized pigs.

1. The present study was designed to investigate the effects of 17beta-oestradiol on the mesenteric, renal, iliac and coronary circulations and to determine the mechanisms involved. 2. In pigs anaesthetized with sodium pentobarbitone, changes in blood flow in the superior mesenteric, left renal, left external iliac and left circumflex coronary arteries caused by intravenous infusion of 17beta-oestradiol at constant heart rate and arterial pressure were assessed using electromagnetic flowmeters. 3. In eight pigs, infusion of 2 microg h-1 of the hormone caused an increase in renal, iliac and coronary blood flow without affecting mesenteric blood flow, left ventricular dP/dtmax (rate of change of left ventricular systolic pressure) and filling pressures of the heart. In four pigs, these vasodilator effects were enhanced by graded increases in the dose of the hormone between 1, 2 and 3 microg h-1; the highest dose also caused an increase in mesenteric blood flow. 4. In five pigs, blockade of muscarinic cholinoceptors and adrenoceptors with the intravenous administration of atropine, propranolol and phentolamine did not affect the vasodilator responses caused by infusion of 2 microg h-1 of 17beta-oestradiol. 5. The increases in renal, iliac and coronary blood flow caused by infusion of 2 microg h-1 of 17beta-oestradiol were prevented, respectively, by the injection of Nomega-nitro-L-arginine methyl ester (L-NAME) into the renal artery (five pigs), the iliac artery (five pigs) or the coronary artery (five pigs). In five pigs, all responses were prevented by injection of L-NAME into all three arteries. In two pigs, injection of L-NAME into the mesenteric, renal, iliac and coronary arteries abolished the vasodilator responses to the infusion of 3 microg h-1 of 17beta-oestradiol. 6. The present study shows that intravenous infusion of 2 microg h-1 of 17beta-oestradiol primarily dilated renal, iliac and coronary circulations and that a higher dose of the hormone also caused vasodilatation in the mesenteric vascular bed. The mechanism of these responses was shown to be nitric oxide dependent.

Hypo- and Hypersalivation Induced by Psychoactive Drugs

Psychoactive drugs can have profound effects on salivation: apart from affecting the amount of saliva secreted (i.e. causing either hypo- or hypersalivation), they may also modify the composition of the saliva. Hyposalivation leads to the subjective experience of ‘dry mouth’ (xerostomia) which, in addition to causing subjective discomfort, may be associated with dental caries and oral infections. On the other hand, hypersalivation leads to ‘drooling’ (sialorrhoea), which can be a source of social embarrassment and can be associated with parotitis, choking and even aspiration pneumonia. Both xerostomia and sialorrhoea can impair patient compliance. Antidepressants [tricyclic antidepressants, noradrenaline (norepinephrine) reuptake inhibitors], lithium, antipsychotics of the phenothiazine class and (α2-adrenoceptor agonists (e.g. clonidine and lofexidine) are commonly associated with hyposalivation and xerostomia, whereas both classical and novel antipsychotics can cause sialorrhoea. However, only clozapine-induced sialorrhoea, occurring in about 30% of patients treated with the drug, is of any major clinical significance The salivary glands receive a dual sympathetic (noradrenergic) and parasympathetic (cholinergic) innervation, and psychoactive drugs may affect either the gland cells themselves or their neural control. The effects of psychoactive drugs on the autonomic control of salivation is mediated via their multiple actions at neuroreceptors and synaptic mechanisms. Blockade of muscarinic cholinoceptors and α1-adrenoceptors, inhibition of noradrenaline uptake and stimulation of (α2-adrenoceptors may lead to hyposalivation, whereas stimulation of muscarinic cholinoceptors and dopamine D2 receptors, blockade of (α2-adrenoceptors and depletion of noradrenaline from central stores may result in hypersalivation It is important that the clinician is familiar with the effect of each class of drug on salivation, so that he/she can mitigate these by the judicious choice of drug and dosage schedule, and, if necessary, by providing symptomatic treatment for these distressing, and occasionally dangerous, adverse effects

Evidence for purinergic neurotransmission in the urinary bladder of pithed rats

The purpose of this study was to investigate the contribution of adenosine-5′-triphosphate (ATP) to segmental (L6-S2) spinal electrical stimulation evoked increases in intra-vesical pressure in pithed rats. Exogenous ATP and substance P produced dose-dependent increases in intra-vesical pressure (ED 10 mmHg (dose required to elicit 10 mmHg increase in intra-vesical pressure)=1.7 mg/kg and 1.1 μg/kg, i.v., respectively). Desensitisation (or antagonism) of P 2x purinoceptors with α, β-methylene ATP ( α, β-meATP; 30 μg/kg per min, i.v.) or pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 10 mg/kg, i.v.) significantly ( p<0.05) antagonized the intra-vesical pressure responses to ATP (>8 and 3.6-fold increase in ED 10 mmHg, respectively) but had no significant effect on intra-vesical pressure responses to substance P. Spinal stimulation evoked frequency-dependent increases in intra-vesical pressure (EF 20 mmHg (frequency required to produce 20 mmHg increase in intra-vesical pressure)=3.4 Hz). Blockade of muscarinic cholinoceptors and adrenoceptors with atropine (3 mg/kg, i.v.), propranolol (3 mg/kg, i.v.) and phentolamine (10 mg/kg, i.v.) produced marginal attenuation of the intra-vesical pressure responses to spinal stimulation indicating a major non-adrenergic non-cholinergic (NANC) component in the overall response. The NANC responses were significantly ( p<0.05) antagonized by α, β-meATP (30 μg/kg per min, i.v.) and PPADS (10 mg/kg, i.v.) (>2.6-fold increase in EF 20 mmHg), consistent with involvement of a purinergic neurotransmitter, presumably ATP. Comparative studies in young (4–6 months) and old (21–23 months) Fischer rats revealed no age-dependent changes in the relative contribution of the cholinergic and purinergic systems, with the latter being the dominant one. These findings suggest that purinergic neurotransmission, presumably mediated by ATP acting via P 2x purinoceptors, represents a major component of excitatory innervation to the urinary bladder in pithed rats.

Calcium and the activation of the alpha 1-adrenoceptors in the guinea-pig taenia caeci.

1. The actions of phenylephrine (0.1-100 mumol l-1) and methoxamine (0.1-100 mumol l-1) were compared with that of adrenaline (0.01-10 mumol l-1) using the single sucrose gap method and mechanical recording in the guinea-pig taenia caeci. Drugs were applied for variable periods of time. 2. The characteristics of the inhibitory effects of alpha-adrenoceptor agonists were the same when exposure time did not exceed 5 min. When the exposure was prolonged, in contrast to the sustained effects of adrenaline (0.1-3 mumol l-1), phenylephrine and methoxamine (1-10 mumol l-1) produced a transient inhibitory action. 3. During the delayed recovery phase of phenylephrine, adrenaline preserved its ability to suppress the spontaneous electrical and mechanical activities of the taenia both when phenylephrine was replaced by adrenaline or when adrenaline was applied in addition to phenylephrine. All the above effects were found in untreated preparations, as well as during blockade of muscarinic cholinoceptors by atropine (1.4 mumol l-1), beta-adrenoceptors by propranolol (3 mumol l-1) and release of endogenous catecholamines by guanethidine (2.5 mumol l-1). 4. In the presence of phorbol 12,13-dibutyrate adrenaline ceased to be effective, while the inhibitory action of phenylephrine was converted to a contraction. 5. In calcium-free conditions in the presence of EGTA (0.4 mmol l-1) the initial hyperpolarization induced by adrenaline and phenylephrine was significantly reduced and with repeated applications of the agonists the inhibitory response disappeared. Similar results were obtained using tissues treated with nifedipine (1 and 10 mumol l-1). When caffeine (30mmolI 1) was present in the calciumfree solution the alpha-agonists studied were unable to produce any membrane potential changes. 6. The present results imply that the inhibitory effect of alpha-adrenoceptor agonists is mediated by the opening of potassium channels, which are activated by calcium derived from an intercellular source supplied from the extracellular space via a nifedipine-sensitive mechanism.