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PubMed1975

Role of alpha-adrenergic receptor mechanism in closure of the internal urethral orifice during ejaculation.

The effects of autonomic drugs on closure of the internal urethral orifice during ejaculation were investigated in dogs. The closure of the internal urethral orifice was induced by the electric stimulation of the lateral fibers of the lower mesenteric plexus. The closing state of the orifice was measured with a latex balloon inserted into the orifice. The autonomic drugs were given into the aorta just above its bifurcation. From the results obtained in this study it was concluded that the closure of the internal urethral orifice during ejaculation is predominantly under the influence of the adrenergic nervous system, particularly through an alpha-adrenergic receptor mechanism.

Adrenergic alpha-Agonists↗
PubMed1970

Pharmacologic identification of the lower esophageal sphincter.

The distal 2/3 of the opossum esophagus contains only smooth muscle. Manometry shows that the most distal 1-2 cm is the lower esophageal sphincter. We used a variety of agonists to seek differences between circular muscle from the sphincteric segment and more rostral levels. Isometric contractions of strips from the distal 6 cm were recorded in vitro in response to acetylcholine, carbachol, methacholine, nicotine. DMPP, norepinephrine, norepinephrine with propranolol, barium, atropine, and potassium. Significant differences in threshold concentration occurred for all drugs except barium, atropine, and potassium, the more distal strips being more sensitive. The gradient of threshold was much steeper for norepinephrine than for the other drugs. Maximal responses did not differ among levels for the choline esters or ganglionic stimulants, but showed proximal diminution for norepinephrine. These differences in threshold concentration could represent differences in distribution density of drug receptor sites, differences in affinity of receptors for the agonists, differences in rates of uptake of agonists, or differences in rates of enzymatic hydrolysis; or they may have no common basis. The sphincter is defined, at least in part, in the esophageal wall rather than in the central nervous system. The greater magnitude of the difference in sensitivity to norepinephrine than for the other agents suggests that the adrenergic innervation is important in defining the lower esophageal sphincter.

Acetylcholine↗
PubMed2006

Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH.

Nitric oxide (NO), also known as endothelium-derived relaxing factor, is produced by endothelial nitric oxide synthase (eNOS) in the intima and by neuronal nitric oxide synthase (nNOS) in the adventitia of cerebral vessels. It dilates the arteries in response to shear stress, metabolic demands, pterygopalatine ganglion stimulation and chemoregulation. Subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow. Hemoglobin, gradually released from erythrocytes in the subarachnoid space, destroys nNOS-containing neurons in the conductive arteries. This deprives the arteries of NO, leading to initiation of delayed vasospasm. But such vessel narrowing increases shear stress, which stimulates eNOS. This mechanism normally would lead to increased production of NO and dilation of arteries. However, a transient eNOS dysfunction evoked by an increase in the endogenous competitive NOS inhibitor, asymmetric dimethylarginine (ADMA), prevents this vasodilation. eNOS dysfunction has been recently shown to be evoked by increased levels of ADMA in cerebrospinal fluid (CSF) in response to the presence of bilirubin-oxidized fragments (BOXes). A direct cause of the increased ADMA CSF level is most likely decreased ADMA elimination owing to disappearance of ADMA-hydrolyzing enzyme [dimethylarginine dimethylaminohydrolase II (DDAH II)] immunoreactivity in the arteries in spasm. This eNOS dysfunction sustains vasospasm. CSF ADMA levels are closely associated with the degree and time course of vasospasm; when CSF ADMA levels decrease, vasospasm resolves. Thus, exogenous delivery of NO, inhibiting the L-arginine-methylating enzyme or stimulating DDAH II, may provide new therapeutic modalities to prevent and treat vasospasm. This paper will present results of pre-clinical studies supporting the NO-based hypothesis of delayed cerebral vasospasm development and its prevention by increased NO availability.

Amidohydrolases↗
PubMed2001

Lobeline inhibits the neurochemical and behavioral effects of amphetamine.

Lobeline interacts with the dopamine transporter and vesicular monoamine transporter, presynaptic proteins involved in dopamine storage and release. This study used rodent models to assess lobeline-induced inhibition of the neurochemical and behavioral effects of amphetamine. Rat striatal slices were preloaded with [(3)H]dopamine and superfused with lobeline for 30 min, and then with d-amphetamine (0.03-3.00 microM) plus lobeline for 60 min. As predicted, lobeline (1-3 microM) intrinsically increased (3)H overflow but did not inhibit d-amphetamine-evoked (3)H overflow. Consequently, the effect of lobeline on d-amphetamine-evoked endogenous dopamine and dihydroxyphenylacetic acid overflow was assessed. Lobeline (0.1-1 microM) inhibited d-amphetamine (1 microM)-evoked dopamine overflow but did not inhibit electrically evoked (3)H overflow, indicating a selective inhibition of this effect of d-amphetamine. To determine whether the in vitro results translated into in vivo inhibition, the effect of lobeline (0.3-10.0 mg/kg) pretreatment on d-amphetamine (0.1-1.0 mg/kg)-induced hyperactivity in rats and on d-methamphetamine (0.1-3.0 mg/kg)-induced hyperactivity in mice was determined. Doses of lobeline that produced no effect alone attenuated the stimulant-induced hyperactivity. Lobeline also attenuated the discriminative stimulus properties of d-methamphetamine in rats. Acute, intermittent, or continuous in vivo administration of lobeline (1-30 mg/kg) did not deplete striatal dopamine content. Thus, lobeline inhibits amphetamine-induced neurochemical and behavioral effects, and is not toxic to dopamine neurons. These results support the hypothesis that lobeline redistributes dopamine pools within the presynaptic terminal, reducing pools available for amphetamine-induced release. Collectively, the results support a role for lobeline as a potential pharmacotherapy for psychostimulant abuse.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

Desensitization of the adrenergic neurons of the isolated rabbit ear artery to nicotinic agonists.

At 37 degrees C the vasoconstrictor response of the isolated, perfused rabbit ear artery to an infusion of nicotine or acetylcholine (ACh) was transient--rising rapidly to a peak and then fading completely within a minute or two. After complete fade of the response during continued infusion of either nicotine or ACh (in the presence of atropine), the vasoconstrictor responses to stimulation of periarterial adrenergic neurons or to infused norepinephrine (NE) were not diminished. The fade of response was attributed to desensitization of nicotinic receptors at the adrenergic nerve terminals on which nicotine and ACh act to release NE. On washout of either nicotinic agonist after development of desensitization, recovery of sensitivity was essentially complete within several minutes, provided that neither excessively high concentrations nor excessively long periods of infusion had been used. The rate of desensitization to nicotine of ACh increased with concentration of the agonist. On infusion of high concentrations (200 mug/ml) of either, the time required for full desensitization was estimated to be less than 5 seconds. Cross-desensitization was demonstrated for nicotine, ACh and tetramethylammonium. Considerable desensitization occurred even on infusion of nicotine (1 mug/ml) slightly below that required to give a threshold vasoconstrictor response. Moreover, full desensitization without any preceding vasoconstrictor response could be obtained if the concentration of infused nicotine was gradually increased from an initial subthreshold to a final very high suprathreshold level over a 20- to 30-minute period. Both the rate and degree of desensitization to nicotine decreased as the temperature was decreased from 37 degrees to 27 degrees C. The present results are consistent with the concept that the nicotinic receptor (or receptor mechanism) at the adrenergic nerve terminal, after being activated as a result of combination with the agonist, can undergo a transformation to an inactive or desensitized state. It is proposed that under conditions where desensitization to the agonist develops in the absence of any vasoconstrictor response, the fraction of receptors in the activated state at any instant in time during the development is too small to trigger the release of NE.

Acetylcholine↗
PubMed1975

[Effect of dopamine on perfusion pressure in rat peripheral blood vessels].

Rat mesenteric and hind limb arteries were perfused with the rat's own blood under constant perfusion rate, in situ. The effect of dopamine (DA) administered intraarterially was investigated and compared with effects of norepinephrine (NE), tyramine (Tyr), and phenylephrine (PHE). The magnitude of the vasoconstrictive maximum response of both vasculatures to NE and PHE was larger than those to DA and Tyr, and those to DA were larger than those to Tyr in hind limb, but those to Tyr were more potent than those to DA in the mesenteric artery. The vasoconstriction evoked by celiac ganglionic stimulation was much the same to that evoked by NE and PHE. Under cocaine infusion, the rise in perfusion pressure of both vasculatures evoked by NE and PHE. Under cocaine infusion, the rise in perfusion pressure of both vasculatures evoked by NE was slight, but the duration was markedly potentiated. However, the effect of Tyr was suppressed and that of DA was not changed. In rats on alpha-methyl-rho-tyrosine, the responses of both vasculatures to Tyr were reduced and those to NE and DA were not changed. In the reserpinized rat, the effect of NE was not changed and that of Tyr was reduced, while that of D was more evident in both vasculatures. After phenoxybenzamine treatment, vasoconstrictive effect of DA was reversed in mesenteric and reduced in hind limb artery. Vasodilating effect of DA after phenoxybenzamine, was not changed by treatment with propranolol, atropine, and diphenhydramine but was reduced with reserpine and abolished with haloperidol. These results suggest that the vasoconstrictive effect of DA depends partly on indirect sympathomimetic action, and after phenoxybenzamine, DA acts by vasodilating the DA receptor. Potentiation with reserpine may depend on a post-synaptic mechanism and increase in dopamine-beta-hydroxylase activity.

Animals↗
PubMed1990

Role of alpha-1 and alpha-2 adrenoceptors in the sympathetic control of the proximal urethra.

In the pithed rat, postjunctional alpha-1 and alpha-2 adrenoceptors mediate increases in proximal urethral perfusion pressure (UPP). The present study examined the role of alpha-1 and alpha-2 adrenoceptors in sympathetic control of the isolated in situ proximal urethra of the rat. An endogenous alpha adrenergic constriction was demonstrated in the proximal urethra by eliciting dose-related and phentolamine-sensitive increases in UPP after the systemic administration of tyramine. Transient dose-related and hexamethonium-sensitive increases in UPP were also elicited by ganglionic stimulation with 1,1-dimethyl-4-phenylpiperazinium (DMPP). Based on the relative sensitivity of the DMPP response to standard autonomic blockers, it was determined that constriction is the predominant autonomic response in the proximal urethra and this response is mediated by alpha adrenoceptor mechanisms. Prazosin, a selective alpha-1 adrenoceptor antagonist, substantially reduced (72%) the steady-state increases in UPP elicited by discrete low frequency electrical stimulation of the spinal hypogastric outflow. In contrast, selective alpha-2 adrenoceptor blockade with rauwolscine significantly increased (28%) the UPP response to hypogastric stimulation. Prazosin also abolished the increase in urethral tone elicited by tyramine, whereas rauwolscine had no effect on the tyramine. A different response profile was observed for prazosin and rauwolscine when the steady-state increase in UPP was evoked by simultaneously stimulating the midthoracic and hypogastric spinal outflow. Under these conditions of sympathoadrenal activation, UPP was reduced by both prazosin and rauwolscine (63 and 50%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Vasoconstriction of the isolated rabbit ear artery caused by nicotinic agonists acting on adrenergic neurons.

In the perfused isolated central ear artery of the rabbit, nicotine, acetylcholine (ACh), tetramethylammonium (TMA) and carbachol (CCh) at high concentrations (greater than 1 mug/ml) produced transient vasoconstriction. The order of potency was: nicotine greater than ACh greater than TMA greater than CCh. Over the concentration range used, all of the agonists except ACh gave bell-shaped log concentration-response curves. Methacholine did not cause vasoconstriction. The response to ACh, TMA or CCh, but not to nicotine, was potentiated by atropine (0.1-1.0 mug/ml). Tetraethylammonium, hexamethonium, mecamylamine and d-tubocurarine blocked the response to the nicotinic agonists and to nerve stimulation. Ear arteries from reserpine-treated rabbits gave no, or very little, constrictor response to the nicotinic agonists or to nerve stimulation. These findings support the conclusion that the vasoconstriction produced by the nicotinic agonists is mediated by norepinephrine released from adrenergic nerve terminals as a result of the action of the agents on neuronal nicotinic receptors located at or near the terminals. The potentiation by atropine of the constrictor response to ACh, TMA and CCh is attributed to the blockade by atropine of neuronal muscarinic receptors on which these agonists act to inhibit the release of norepinephrine.

Acetylcholine↗
PubMed1986

Pharmacological characterization of rat jejunal contractility after chronic ablation of the myenteric plexus.

The authors have pharmacologically characterized longitudinal muscle contractility of the isolated rat jejunum chronically devoid of myenteric neurons. The myenteric plexus of a 3- to 4-cm segment of rat jejunum was ablated by serosal application of the cationic surfactant benzalkonium chloride (BAC). Fifteen days after treatment, both BAC-treated and untreated control jejunal segments were removed from each animal for pharmacological studies. BAC-treated tissues did not respond to the ganglionic stimulants nicotine, 1,1-dimethyl-4-phenylpiperazinium iodide and McN-A-343 or to the acetylcholinesterase inhibitor physostigmine. Short-pulse duration transmural electrical stimulation (0.1 msec) caused a frequency-dependent, tetrodotoxin-sensitive contraction in control but not BAC-treated tissues. Long-pulse duration transmural electrical stimulation (5.0 msec) contracted both control and BAC-treated jejunum. These contractions were partially reduced but not completely blocked by tetrodotoxin. To assess smooth muscle function, the mechanical responses to the muscarinic receptor agonist carbachol were examined. Carbachol contracted both control and BAC-treated tissues with maximal responses and ED50 values that were not significantly different. In addition, the maximal tension development produced by 10(-2) M barium chloride in similar lengths of control and BAC-treated jejunal segments was not significantly different. These studies demonstrate that chronic ablation of the myenteric plexus by serosal application of BAC essentially eliminates neuronally mediated responses without a concomitant alteration in longitudinal muscle contractility. Because nerve-mediated longitudinal muscle responses are lost despite the presence of an intact submucosal plexus in the BAC-treated jejunum, our data suggest that the motor neurons innervating the rat jejunal longitudinal muscle are located in the myenteric plexus.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1989

Role of d-tubocurarine in suppression of cardiovascular responses following endotracheal intubation.

The role of d-tubocurarine in blocking the hypertensive tachycardiac response following laryngoscopy and endotracheal intubation was evaluated in 45 female patients aged 20-40 yr. The patients belonging to grade I (of American Society of Anaesthesiologists) and undergoing elective surgical procedures under general anaesthesia were allocated in 3 equal groups. Patients in the 3 groups received 1.5 mg/kg succinylcholine, 0.6 mg/kg d-tubocurarine and 0.12 mg/kg pancuronium bromide, respectively for intubation. There were no dysrhythmias in any of the groups following endotracheal intubation. There was significant (P less than 0.01) fall in blood pressure following induction prior to intubation in all the three groups. Maximum fall was noted in group II (23.53 +/- 7.21 mmHg in mean arterial pressure). Following endotracheal intubation, blood pressure and heart rate increased significantly (P less than 0.01) in all 3 groups. Maximum increase was observed in group I (26.4 +/- 4.95 mmHg in mean arterial pressure and 19.07 +/- 6.54 beats/min in heart rate). Blood pressure and heart rate increases in groups II and III were comparable. Our findings indicate that hypotension produced by d-tubocurarine through ganglion blockade is not effective in attenuating the cardiovascular responses following endotracheal intubation. It is also possible that increased cardiovascular response following endotracheal intubation may not be due to sympathetic ganglion stimulation.

Adult↗
PubMed1989

Pharmacological characterization of neural mechanisms regulating mucosal ion transport in mouse jejunum.

Neural regulation of electrolyte transport in mouse jejunum was investigated in vitro using: 1) a full-thickness intestinal segment (intact preparation) and 2) a mucosal preparation, consisting of only mucosa, basement membrane and muscularis mucosa. In Ussing chambers, intact tissues exhibited high- and low-frequency oscillations of basal transmural potential difference (PD) and short-circuit current (Isc), whereas mucosal tissues exhibited only low-frequency oscillation of these parameters. High-frequency oscillations of PD and Isc were found to originate from muscle activity. Under basal conditions, intact tissues exhibited net Na+ absorption and net Cl- secretion, whereas mucosal tissues displayed greater net Na+ absorption and net Cl- absorption. When applied to the serosal medium of intact tissues, tetrodotoxin, a neurotoxin, and chlorisondamine, a ganglionic blocking agent, caused a concentration-dependent reduction of basal PD and Isc, whereas atropine produced no significant effect; these agents were without effect in mucosal tissues. Furthermore, in intact tissues, tetrodotoxin caused significant increases in net Na+ absorption and net residual flux, attaining values that were comparable to those seen in mucosal tissues. Carbachol, a muscarinic agonist, and 1,1-dimethyl-4-phenylpiperizinium, a ganglionic stimulant, elicited concentration-dependent, transient increases of basal PD and Isc when applied to the serosal medium of intact tissues; in mucosal preparations, carbachol elicited greater changes of basal PD and Isc, whereas 1,1-dimethyl-4-phenylpiperizinium produced no significant effect. In intact tissues, Isc responses elicited by carbachol were antagonized by atropine, but not tetrodotoxin or chlorisondamine; Isc responses induced by 1,1-dimethyl-4-phenylpiperizinium, however, were blocked by tetrodotoxin or chlorisondamine, but not atropine. These results support the existence of a multisynaptic, and tonically active neural pathway which serves to limit intestinal Na+ transport at some point below the maximal absorptive capacity of the mucosa. Furthermore, cholinergic muscarinic and nicotinic receptors are present in distinct neural pathways that influence intestinal electrolyte transport in the small intestine of the mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1987

[General pharmacological studies on isepamicin sulfate (HAPA-B)].

General pharmacological properties of isepamicin sulfate (HAPA-B), a new aminoglycoside antibiotic, were studied in animals and the results obtained were summarized below. Intramuscular injections of HAPA-B at doses of 500 mg/kg inhibited the writing response induced by acetic acid, and at doses of 1,000 mg/kg, caused muscle relaxation, respiratory depression, suppression of spontaneous motor activity and prolongation of thiopental anesthesia. Anticonvulsive action and the effect on the rectal temperature were not observed. Intravenous Intravenous HAPA-B showed no significant effect on the general behavior and the function of the central nervous system at doses of 100 mg/kg. Intravenous injections of HAPA-B to anesthetized dogs resulted increases in the femoral arterial blood flow at doses of 12.5 mg/kg, decrease in the blood pressure and increase in the respiratory rate at doses of 25 mg/kg, and increase in the carotid arterial blood flow at doses of 50 mg/kg. Apparent changes were not recognized in the heart rate and electrocardiograms. In conscious rabbits, intravenous HAPA-B produced increases in the heart rate without significant changes of the blood pressure and electrocardiograms at doses of 100 mg/kg. Spontaneous beatings of isolated atria were depressed by HAPA-B in concentrations of 3 X 10(-4) to 10(-3) g/ml. The HAPA-B inhibited the gastric secretion at intramuscular doses of 500 mg/kg or intravenous doses of 100 mg/kg, and depressed charcoal transport through small intestine and the spontaneous movement of isolated ileum at intramuscular doses of 1,000 mg/kg and at concentrations of 3 X 10(-4) to 10(-3) g/ml, respectively. No irritative effect was found on the gastric mucous membrane. Intravenous HAPA-B inhibited the response of nictitating membrane to pre and post ganglionic stimulations of cervical sympathetic nerve at doses of 100 mg/kg. In in vitro test, HAPA-B inhibited nonspecifically the constrictive responses of trachea, aorta, stomach, ileum and vas deferens to various agonists in concentrations of 3 X 10(-4) to 10(-3) g/ml. Spontaneous movements of uteri of estrous or pregnant animals were depressed by HAPA-B at intravenous doses of 50 to 100 mg/kg and in in vitro at concentrations of 10(-4) to 3 X 10(-4) g/ml. Antidiuretic effect was also observed at intramuscular doses of 250 mg/kg. HAPA-B increased the length of the whole blood clotting time and raised the plasma glucose level at intramuscular doses of 1,000 mg/kg and inhibited the platelet aggregation induced by ADP in vitro at concentrations of 10(-3) g/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminoglycosides↗
PubMed1978

[Histamine analogues with nicotine-like action. 11th communication: Structure-activity relationships among histamine analogues (author's transl)].

Structure-activity relationships between histamine and nicrotine are described. If alkyl groups are substituted on the primary amino group of the side chain in histamine the histamine-like action decreases stepwise. While N,N-diethylhistamine (I) clearly shows histamine-like activity, 4-(2-pyrrolidinoethyl)-imidazole (II), an analogue having a pyrrolidine ring in place of the diethylamino group, possesses, on the other hand, distinct nicotine-like properties. The ganglionic stimulation was investigated on the isolated ileum of the guinea-pig, as well as on the blood pressure of the narcotized rat. The nicotine-like effects remained as the imidazole ring was replaced with a pyridine or benzene ring. These results make it plausible to assume that the effect of nicotine-like acting substances is due to an angular conformation, corresponding to nicotine.

Animals↗
PubMed1980

Selective effects of clonidine on the canine sinus node.

The direct and indirect chronotropic effects of clonidine (0.001--10 micrograms/ml) were studied by selective perfusion of the sinus node artery of 20 pentobarbital anesthetized dogs. Concentrations of 0.1, 1.0 and 10 migrograms/ml produced dose-related reductions in sinus rate of 3.7 +/- 0.9 (P less than .005), 6.9 +/- 1.8 (P less than .005) and 15.8 +/- 2.3 (P less than .0001) beats/min, respectivel. Sinus acceleration after right stellate ganglion stimulation at 16 and 32 Hz was significantly (P less than .05) inhibited by intranodal clonidine (0.1 microgram/ml). The positive chronotropic effect of norepinephrine (0.1 microgram/ml, sinus node artery) was not significantly affected by prior administration of clonidine. Atropine (1 mg/kg i.v. or 10 micrograms/ml, selectively perfused into the sinus node artery) had no effect on the sinus slowing produced by clonidine. Clonidine had an inconsistent effect on the response to vagal stimulation. Clonidine had an inconsistent effect on the response to vagal stimulation. Clonidine inhibits the heart rate increase after sympathetic nerve stimulation without affecting the heart rate response to norepinephrine infusion. The findings are consistent with previous observations that clonidine can inhibit norephinephrine release and demonstrate that this mechanism of action may occur within the sinus node.

Animals↗