Adrenergic Neurone Blocking Research Articles

Pharmacodynamic effects of dehydroemetine.

Abstract The pharmacodynamics of dehydroemetine were studied in isolated preparations and in whole animals. Dehydroemetine had no effect on the guinea-pig isolated ileum but non-specifically antagonized the spasmogenic effect of histamine, acetylcholine and nicotine on this tissue. Dehydroemetine in small concentrations inhibited relaxations of the guinea-pig and rabbit ileum produced by stimulating the sympathetic nerve without inhibiting the effect of noradrenaline. Twitches of the guinea-pig ileum elicited by transmural stimulation were blocked by dehydroemetine while higher doses of the drug also inhibited the indirectly elicited contractions of the isolated rat diaphragm. In vivo, neuromuscular blocking action could not be demonstrated for dehydroemetine while toxic doses were required to demonstrate the presence of an adrenergic neuron blocking action. Dehydroemetine had no anaesthetic action when applied locally to the rabbit cornea. Concentrations of the drug which caused local anaesthesia when injected intradermally into guinea-pigs also caused skin necrosis. It is concluded that dehydroemetine lacks any specific adrenergic neuron blocking action or neuromuscular blocking action or local anaesthetic action. It is suggested that the effects demonstrated are due to non-specific action at the nerve endings.

A comparison of aralkylamines and aralkylguanidines as antagonists of adrenergic neurone blockade.

Abstract Structure-activity relationships have been studied for aralkylamines and aralkylguanidines which restore the responses of the nictitating membranes to nerve stimulation in anaesthetised cats given sympathetic blocking drugs. This reversing action was largely specific for adrenergic neurone blockade; blockade of sympathetic ganglia or of α-adrenergic receptors was unaffected. (+)-Amphetamine was the most active amine and N-benzyl-N-methylguanidine was the most active guanidine. In mice, ptosis resulting from adrenergic neurone blockade was much more readily prevented or abolished by the aralkylamines and aralkylguanidines than was ptosis caused by other types of sympathetic blocking agent. The most potent antagonist of ptosis was N-(2-phenylcyclopropyl)guanidine which was about ten times as active as amphetamine. The relative antagonistic potencies of 2 amines and 8 guanidines were virtually identical for all types of adrenergic neurone blocking drug, regardless of whether or not they cause noradrenaline depletion. The prevention of guanethidine-induced ptosis was always accompanied by some reduction in the extent of heart-noradrenaline depletion, but the minimum dose of antagonist required to prevent ptosis completely was always lower than that required to eliminate depletion.

Increased release of xylocholine (TM10) from guinea-pig vas deferens treated with amphetamine sulphate.

Abstract Although both NN-diethyl- and NN-dimethyl-, N-methyl-[14C]-2-(2,6-xylyloxy) ethylammonium iodide (14C-1DE10 iodide and 14C-TM10 iodide; xylocholine) are taken up by guinea-pig vas deferens to a similar extent in vitro, only TM10 reduced the response of the vas deferens to electrical stimulation. Prior incubation of vas deferens with 14C-1DE10 iodide or with 14C-TM10 iodide followed by measurement of the amount of each of these compounds eliminated from the tissue by repeated washing with Krebs solution, shows both compounds to be strongly retained by the tissue. Incorporation of 10−5 g/ml amphetamine sulphate in the wash fluid failed to modify the release of 14C-1DE10 iodide but produced a short-lived increase in the amount of 14C-TM10 iodide eliminated which reached a maximum approximately 10 min after administration of amphetamine. The additional 14C-TM10 iodide eliminated by amphetamine was about 5% of the total tissue 14C-TM10 iodide content; the possible role of this fraction is discussed in relation to the adrenergic neuronblocking action of 14C-TM10 iodide.

Proton Acts as a Neurotransmitter for Nicotine-Induced Adrenergic and Calcitonin Gene-Related Peptide-Containing Nerve-Mediated Vasodilation in the Rat Mesenteric Artery

Nicotine stimulates presynaptic nicotinic acetylcholine receptors in perivascular adrenergic nerves and releases unknown transmitter(s) that activate transient receptor potential vanilloid-1 (TRPV1) located on calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves, resulting in vasodilation. The present study investigated a potential transmitter transmitting between perivascular adrenergic nerves and CGRPergic nerves. Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs' solution containing methoxamine, and the perfusion pressure and pH levels of the perfusate were measured. Nicotine perfusion for 1 min induced concentration-dependent vasodilation and lowered pH levels, which were abolished by cold-storage denervation of preparations, guanethidine (adrenergic neuron blocker), and mecamylamine (nicotinic alpha(3)beta(4)-acetylcholine receptor antagonist). Capsazepine (TRPV1 antagonist) blunted nicotine-induced vasodilation, but had no effect on the reduction of pH. Injection of hydrochloric acid (HCl) and perfusion of Krebs' solution at low pH (6.0-7.2) induced vasodilation. HCl-induced vasodilation was inhibited by cold-storage denervation, capsazepine, capsaicin (CGRP depletor), and CGRP(8-37) (CGRP receptor antagonist). Perfusion of adrenergic transmitter metabolites (normetanephrine and 3-methoxydopamine), but not of other metabolites, induced vasodilation, which was not inhibited by capsaicin treatment. Immunohistochemical staining of mesenteric arteries showed dense innervation of CGRP- and TRPV1-immunopositive nerves, with both immunostainings appearing in the same neuron. Mesenteric arteries were densely innervated by neuropeptide Y-immunopositive nerves, which coalesced with CGRP-immunopositive nerves. Scanning and immunoscanning electron microscopic images showed coalescence sites of different perivascular fibers before they intruded into smooth muscles. These results indicate that nicotine initially stimulates adrenergic nerves via nicotinic alpha(3)beta(4)-receptors to release protons and thereby induces CGRPergic nerve-mediated vasodilation via TRPV1.

Investigation of the role of adrenergic and non‐nitrergic, non‐adrenergic neurotransmission in the sheep isolated internal anal sphincter

Nitric oxide is widely established as an important neurotransmitter in the control of anal sphincter tone; although, a number of other transmitters have also been tentatively implicated. Whilst alpha-adrenoceptor antagonists reduce anal sphincter pressure in man, the role of noradrenaline as a possible transmitter is poorly characterised. We have investigated the contribution of these transmitters to neurogenic relaxations, and evaluated the possible role of a non-nitrergic, non-adrenergic transmitter. The magnitude and duration of neurogenic responses were examined by measuring responses to electrical field stimulation (EFS) in segments of sheep internal anal sphincter following the development of spontaneous myogenic tone. Neurogenic relaxations induced by EFS were significantly reduced in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) suggesting major involvement of nitric oxide as a neurotransmitter. The duration of neurogenic relaxations was inversely related to the frequency of EFS, with contractile responses often manifest at higher frequencies. The duration of relaxations at high frequencies of EFS was increased by bretylium (adrenergic neurone blocker) and prazosin (alpha(1)-adrenoceptor antagonist). At higher frequencies of EFS, 60% of preparations also produced a residual non-nitrergic, non-adrenergic, apamin-sensitive relaxation which was unaffected by vasoactive intestinal polypeptide (VIP) and inhibitors of purinergic responses [suramin, pyridoxal-phosphate-6-azophenyl 2',4' disulfonic acid (PPADS) and alpha,beta-methylene adenosine triphosphate (ATP)]. However, MRS2179 (P2Y(1) receptor antagonist) showed a modest inhibitory effect. We conclude that endogenous noradrenaline acts via postjunctional alpha(1)-adrenoceptors to antagonize neurogenic relaxations that are largely mediated by nitric oxide. Our results indicate the involvement of a non-nitrergic, non-adrenergic, apamin-sensitive transmitter which is inhibited by MRS2179, suggesting a possible role for purines.

Pharmacological characterization of cellular mechanisms of the renal vasodilatory effect of nicotine in rats

Nicotine causes vasodilation in the renal vasculature through as yet unidentified mechanism. This study investigated the role of endothelial and non-endothelial factors in the vasodilatory action of nicotine in the rat isolated kidney. Nicotine vasodilation in phenylephrine-preconstricted perfused kidneys was evaluated in the absence and presence of drugs that interfere with nitric oxide synthase (NOS), K + channels, cholinergic or adrenergic activity. Nicotine infusion (5 × 10 − 5 , 1 × 10 − 4 , and 5 × 10 − 4 M) produced concentration-dependent decreases in the renal perfusion pressure, which continued for 20 min with a peak depressor effect observed at approximately 3 min. Nicotine vasodilation was associated with increases in norepinephrine and NO metabolites (nitrite/nitrate, NOx) levels in the renal effluent. Chemical denudation of the endothelium with 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propane-sulfonate (CHAPS), or inhibition of NOS (N G-nitro-L-arginine, L-NNA), or guanylate cyclase (methylene blue) almost abolished the renal vasodilatory action of nicotine. Nicotine vasodilation was also significantly attenuated after selective blockade of ATP-sensitive (K ATP, glibenclamide) or inward rectifier (K ir, BaCl 2) K + channels but remained unaltered after blockade of large-conductance calcium-activated (BK Ca, tetraethylammonium, TEA) or voltage-dependent (K v, 4-aminopyridine) K + channels. Hexamethonium (ganglionic blocker), propranolol (β-adrenceptor blocker), guanethidine (adrenergic neuron blocker), atropine (muscarinic antagonist) or the use of kidneys preconstricted with 80 mM KCl reduced the vasodepressor action of nicotine. Finally, exposure to diclophenac or neostigmine had no effect on nicotine vasodilation. Together, these findings implicate endothelial NOS and K ATP and K ir channels in the renal vasodepressor effect of nicotine. Further, the sympathetic-dependent NO-mediated neurogenic vasodilation apparently contributes, at least partly, to nicotine vasodilation.

EANM procedure guidelines for 131I-meta-iodobenzylguanidine (131I-mIBG) therapy

Meta-iodobenzylguanidine, or Iobenguane, is an aralkylguanidine resulting from the combination of the benzyl group of bretylium and the guanidine group of guanethidine (an adrenergic neurone blocker). It is a noradrenaline (norepinephrine) analogue and so-called "false" neurotransmitter. This radiopharmaceutical, labeled with 131I, could be used as a radiotherapeutic metabolic agent in neuroectodermal tumours, that are derived from the primitive neural crest which develops to form the sympathetic nervous system. The neuroendocrine system is derived from a family of cells originating in the neural crest, characterized by an ability to incorporate amine precursors with subsequent decarboxylation. The purpose of this guideline is to assist nuclear medicine practitioners to evaluate patients who might be candidates for 131I-meta-iodobenzylguanidine to treat neuro-ectodermal tumours, to provide information for performing this treatment and to understand and evaluate the consequences of therapy.

Cholinergic innervation of the guinea-pig isolated vas deferens.

Recently, a cholinergic neurogenic component of contraction has been characterised in the aganglionic mouse vas deferens. In this paper, a cholinergic component of contraction in the guinea-pig vas deferens is characterised pharmacologically. A residual, tetrodotoxin-sensitive (TTX, 0.3 microM), neurogenic contraction was revealed after prolonged exposure (5 h) to the adrenergic neurone blocker bretylium (20 microM) or in the presence of prazosin (100 nM) and alpha,beta-methylene ATP (1 microM), a purinergic agonist which desensitizes P2X receptors. The bretylium-resistant component was potentiated by the acetylcholinesterase (AChE) inhibitor neostigmine (10 microM) and inhibited by the muscarinic-receptor (mAChR) antagonist cyclopentolate (1 microM). Nicotine (30 microM) enhanced the bretylium-resistant component. Neostigmine increased the second component of contraction in the presence of prazosin and alpha,beta-methylene ATP, whilst yohimbine (1 microM), an alpha(2) adrenergic receptor antagonist, enhanced both the first and second components of the electrically evoked contraction. These enhanced contractions were blocked by cyclopentolate in both cases. Nicotine enhanced the cholinergic component of contraction revealed by neostigmine but failed to have any detectable effects in the presence of cyclopentolate. Neostigmine alone increased the slow component of contraction which was reversed by cyclopentolate to control levels. The M(3) receptor-antagonist 4-DAMP (10 nM) markedly inhibited the cholinergic component of contraction to a level comparable with cyclopentolate. Laser microscopy has shown that neostigmine also increased the frequency of spontaneous Ca(2+) transients remaining in smooth muscle cells after perfusion with prazosin and alpha,beta-methylene ATP, an effect blocked by 4-DAMP. These experimental data show that there is a functional cholinergic innervation in the guinea-pig vas deferens whose action is limited by acetylcholinesterase, blocked by cyclopentolate and mediated through M3 receptors. Moreover, by blocking the cholinesterase, the increased amount of ACh generates spontaneous Ca(2+) transients in smooth muscle cells.

Investigation of serotonin receptors in the isolated penile bulb of rats

The aim of this study was to investigate serotonin (5-HT) receptors in the penile bulb, which have been suggested to play a role in penile erection. Serotonin (10(-7)-3 x 10(-4) M) contracted penile bulbs in a concentration-dependent manner. Ketanserin (5-HT(2A) antagonist, 10(-9)-10(-7) M) and prazosin (alpha(1)-adrenergic receptor blocker, 10(-9)-10(-7) M) suppressed the lower and upper parts of concentration-response curves to 5-HT, respectively. Guanethidine (adrenergic neuron blocker, 5 x 10(-5) M) reduced the responses to 5-HT at only 10(-4) and 3 x 10(-4) M concentrations. NAN-190 (5-HT(1A) antagonist, 10(-8), 10(-7) M) shifted the concentration-response curve to the right with a reduction in the maximum response to 5-HT. While ondansetron (5-HT(3) antagonist, 10(-6)-10(-5) M) and GR55562 (5-HT(1B/1D) antagonist, 10(-6)-10(-5) M) had no effect on the concentration-response curve to 5-HT. The 5-HT(1A) agonist 8-OH-DPAT (10(-7)-3 x 10(-4) M) contracted penile bulbs in a concentration-dependent manner with a lower pD(2) value than that of 5-HT. Sumatriptan (5-HT(1B/1D) agonist, 10(-8)-10(-4) M) did not produce any contractile response in the penile bulbs. Prucalopride, a selective 5-HT(4) agonist (R093877, 10(-7)-3 x 10(-4) M) produced concentration-dependent relaxation in penile bulbs contracted by phenylephrine (10(-5) M). 5-HT(4) agonists cisapride (10(-7)-10(-4) M) and metoclopramide (10(-7)-3 x 10(-4) M) also relaxed the tissue, concentration-dependently. Selective 5-HT(4) antagonists GR125487 (10(-6)-10(-5) M) and GR113808 (10(-6)-10(-5) M) slightly, but not significantly, decreased prucalopride- and cisapride-induced relaxation. Propranolol (beta-adrenergic receptor blocker, 10(-6)-10(-5) M) and L-NOARG (nitric oxide synthase inhibitor, 10(-4) M) had no effect on prucalopride-induced relaxation. These results suggest the existence of alpha(1)-adrenergic, 5-HT(1A) and 5-HT(2A) serotonergic receptors in the penile bulb of rats, which are responsible for 5-HT-induced contraction. Additionally, a serotonergic receptor resembling a 5-HT(4)-type plays a role in the relaxation. The latter receptor is activated by 5-HT(4) agonists, but is not antagonized by 5-HT(4) antagonists.

Adrenergic nerves mediate the venoconstrictor response to PVN stimulation

Veins play an important role in the control of venous return, cardiac output and cardiovascular homeostasis. However, the central nervous system sites and effector systems involved in modulating venous function remain to be fully elucidated. The hypothalamic paraventricular nucleus (PVN) is an important site modulating autonomic outflow to the cardiovascular system. Venous tone can be modulated by sympathetic nerves or by adrenal catecholamines. The present study assessed the relative contribution of these autonomic effector systems to the venoconstrictor response elicited by stimulation of the hypothalamic paraventricular nucleus. Male Sprague–Dawley rats were subjected to sham operation or bilateral adrenal demedullation fitted with PVN guide cannulae and fitted with catheters for recording arterial pressure (AP) and intrathoracic vena caval pressure (VP). A latex balloon was advanced into the right atrium. MCFP was calculated from the AP and VP recorded after 4 s of right atrial occlusion. MCFP = VP + (AP − VP)/60. Mean arterial pressure (MAP), heart rate (HR), VP and MCFP responses to injections of BMI (25 ng/side) into the PVN were recorded from conscious rats to avoid the complicating effects of anesthesia. In sham-operated rats, injection of BMI into the PVN increased MAP by 13 ± 3 mm Hg and HR by 56 ± 6 bpm. MCFP was also increased significantly by 0.98 ± 0.15 mm Hg indicating an increase in venomotor tone. Adrenal medullectomy did not affect the pressor (ΔMAP = 12 ± 2 mm Hg), tachycardic (ΔHR = 48 ± 7 bpm) or venoconstrictor (ΔMCFP = 0.73 ± 0.11 mm Hg) responses. Ganglionic blockade abolished the PVN-induced responses in both groups of rats. In a separate group, pretreatment with the adrenergic neuron blocker, guanethidine (20 mg/kg), also abolished the PVN-mediated venoconstrictor responses. Conversely, selective β2 adrenergic receptor blockade did not affect MCFP responses to BMI. These data indicate that adrenomedullary catecholamines are not necessary for full expression of the venoconstrictor response to PVN stimulation.

Cholinergic innervation of the mouse isolated vas deferens

Recently, a population of nerves has been described in the aganglionic mouse vas deferens, in which electrically evoked contractions were insensitive to high concentrations of the adrenergic neurone blocker, bretylium. In this paper, the pharmacology of this nerve-evoked contraction has been examined in more detail. Bretylium (20 microM) revealed, after 5 h exposure, a new residual neurogenic contraction (20 stimuli at 10 Hz) that was tetrodotoxin-sensitive. The muscarinic antagonist, cyclopentolate (0.1 and 1 microM), reduced this residual component and the inhibition was reversed by the acetylcholinesterase inhibitor, neostigmine (1 and 10 microM). Nicotine (30 microM) enhanced the residual component revealed by bretylium, suggesting that there are prejunctional nicotinic receptors (nAchRs) influencing acetylcholine (Ach) release. In the presence of prazosin (0.1 microM), a selective alpha(1)-adrenoceptor antagonist, and alpha,beta-methylene ATP (1 microM), a purinergic agonist that desensitise P2X receptors, neostigmine increased the hump component of contraction and yohimbine (0.3 microM), an alpha(2)-adrenoceptor antagonist, enhanced both components of the electrically evoked stimulation. The contraction was blocked by cyclopentolate (1 microM). In the absence of bretylium, neostigmine alone increased the hump component of contraction in a frequency-dependent manner. This increase was reversed by atropine (1 microM) and cyclopentolate (1 microM) to control levels. However, in control experiments, atropine or cyclopentolate did not detectably influence the delayed neurogenic contraction. Ach (10 microM) induced a contraction in the mouse vas deferens, either when applied alone or in the presence of neostigmine.Thus, it has been demonstrated unequivocally that the mouse vas deferens is innervated by functional cholinergic nerves, whose action is terminated by cholinesterase. Furthermore, Ach release can be enhanced by activation of prejunctional nAchRs presumably located on the cholinergic nerve terminals.

Effects of Acute Administration of and Tachyphylaxis to α,β‐Methylene ATP in the Guinea‐Pig Small Intestine

The aim of the present study was to assess the acute motility effects and desensitizing activity of the stable ATP analogue and P(2X) purinoceptor agonist alpha,beta-methylene ATP (alpha,beta-meATP) and the effect of alpha,beta-meATP desensitization on nerve-mediated cholinergic responses in the guinea-pig ileum in vitro. It was confirmed that alpha,beta-meATP (1-30 microM) causes neurally-mediated, cholinergic (tetrodotoxin- and atropine-sensitive) longitudinal contractions. These responses were not influenced by the ganglionic blocking drug hexamethonium (50 microM), or a combination of the adrenergic neurone blocking drug guanethidine (3 microM), the opioid receptor antagonist naloxone (0.5 microM) and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 100 microM), but were strongly reduced or abolished by the P2 purinoceptor antagonist PPADS (30 microM) or by tachyphylaxis evoked by 10 microM alpha,beta-meATP. The contractile effect of alpha,beta-meATP (3 microM) was moderately inhibited by 10 microM and strongly suppressed by 30 microM of NF 279, an antagonist predominantly affecting P2X1 purinoceptors, but left uninfluenced by the P2X(5,7) receptor antagonist Brilliant blue G. No relaxant effect of alpha,beta-meATP was detected in the concentration range of 1-30 microM. Tachyphylaxis to alpha,beta-meATP (1-10 microM) caused a moderate inhibition of the cholinergic (atropine-sensitive) contractile response of the ileum to electrical field stimulation (5 Hz for 5 sec.). This reduction was unaltered in the presence of guanethidine, naloxone and L-NOARG. Responses to nicotine (1 or 2 microM) were not reduced by alpha,beta-meATP tachyphylaxis. It is suggested that alpha,beta-meATP-sensitive P(2X) purinoceptors are involved in the prejunctional modulation of cholinergic neurotransmission between the myenteric plexus and longitudinal smooth muscle in the guinea-pig small intestine.

Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats.

1. This study characterises some of the mechanisms and mediators involved in the orofacial nociception triggered by injection of formalin into the upper lip of the rat, by assessing the influence of various treatments on behavioural nociceptive responses (duration of facial rubbing) elicited either by a low subthreshold (i.e. non-nociceptive; 0.63%) or a higher concentration of the algogen (2.5%). 2. The kininase II inhibitor captopril (5 mg kg(-1), s.c.) and prostaglandin(PG) E(2) (100 ng lip(-1)) potentiated both phases of the response to 0.63% formalin, whereas tumour necrosis factor (TNF alpha; 5 pg lip(-1)), interleukin(IL)-1 beta (0.5 pg lip(-1)), IL-6 (2 ng lip(-1)) and IL-8 (200 pg lip(-1)), or the indirectly acting sympathomimetic drug tyramine (200 microg lip(-1)), each augmented only the second phase of nociception. 3. Conversely, both phases of nociception induced by 2.5% formalin were inhibited by the bradykinin (BK) B(2) receptor antagonist HOE140 (5 microg lip(-1)) or the selective beta(1)-adrenoceptor antagonist atenolol (100 microg lip(-1)). However, the BK B(1) receptor antagonist des-Arg(9)-Leu(8)-BK (1 and 2 microg lip(-1)), antibody and/or antiserum against each of the cytokines, the adrenergic neurone blocker guanethidine (30 mg kg(-1) day(-1), s.c., for 3 days) and the cyclooxygenase(COX)-2 inhibitor celecoxib (50 and 200 microg lip(-1), s.c.; or 1 and 3 mg kg(-1), i.p.) reduced only the second phase of the response. The nonselective COX inhibitor indomethacin and the 5-lipoxygenase activating protein inhibitor MK886 did not change formalin-induced nociception. 4. Our results indicate that BK, TNF-alpha, IL-1 beta, IL-6, IL-8, sympathetic amines and PGs (but not leukotrienes) contribute significantly to formalin-induced orofacial nociception in the rat and the response seems to be more susceptible to inhibition by B(2) receptor antagonist and selective COX-2 inhibitor than by B(1) receptor antagonist or nonselective COX inhibitor.

Endogenous calcitonin gene-related peptide (CGRP) mediates adrenergic-dependent vasodilation induced by nicotine in mesenteric resistance arteries of the rat.

1. The mechanisms underlying vasodilator effect of nicotine on mesenteric resistance blood vessels and the role of calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves were studied in the rat. 2. Mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer. 3. In preparations with intact endothelium and contracted by perfusion with Krebs solution containing methoxamine, perfusion of nicotine (1 - 100 microM) for 1 min caused a concentration-dependent vasodilator response without vasoconstriction. 4. The nicotine-induced vasodilation was markedly inhibited by hexamethonium (nicotinic cholinoceptor antagonist, 10 microM) and blocked by guanethidine (adrenergic neuron blocker, 5 microM). 5. Either denervation by cold storage (4 degrees C for 72 h) or adrenergic denervation by 6-hydroxydopamine (toxin for adrenergic neurons, 2 mM for 20 min incubation, twice) blocked the nicotine-induced vasodilation. 6. Neither endothelium removal with perfusion of sodium deoxycholate (1.80 mg ml(-1), for 30 s) nor treatment with N(omega)-nitro-L-arginine (nitric oxide synthase inhibitor, 100 microM), atropine (muscarinic cholinoceptor antagonist, 10 nM) or propranolol (beta-adrenoceptor antagonist, 100 nM) affected the nicotine-induced vasodilation. 7. In preparations without endothelium, treatment with capsaicin (depleting CGRP-containing sensory nerves, 1 microM) or human CGRP[8 - 37] (CGRP receptor antagonist, 0.5 microM) markedly inhibited the nicotine-induced vasodilation. 8. These results suggest that, in the mesenteric resistanc artery of the rat, nicotine induces vasodilation, which is independent of the function of the endothelium and is involved in activation of CGRPergic nerves. It is also suggested that nicotine stimulates presynaptic nicotinic cholinoceptors on adrenergic nerves to release adrenergic neurotransmitters, which then act on CGRPergic nerves to release endogenous CGRP from the nerve.

Dissociation of inhibitory effects of guanethidine on adrenergic and on purinergic transmission in isolated canine splenic artery

The aim of this study was both to investigate the effects of progressive inhibition of adrenergic neurons by increasing concentrations of guanethidine (0.1–10 μM) on the double-peaked vasoconstrictor responses to electrical periarterial nerve stimulation in the isolated and perfused canine splenic artery, and to clarify whether release of noradrenaline is presynaptically separate from release of adenosine 5′-triphosphate (ATP). Double-peaked vasoconstrictions (biphases of vasoconstrictions) were consistently observed under the conditions of 30-s trains of pulses at 1–10 Hz frequencies. Guanethidine, at a lower concentration (0.1 μM) did not modify the first (1st) phase vasoconstriction at low frequencies (1–2 Hz), but markedly inhibited the second (2nd) responses. On the other hand, it slightly but significantly inhibited the double-peaked vasoconstrictor responses at high frequencies (6–10 Hz). Furthermore, a 10-fold increase of concentration of guanethidine (1 μM) almost completely inhibited the 2nd phase responses at any frequencies used but did not completely inhibit the 1st phase response. A further increased concentration of guanethidine (10 μM) failed to enhance the 1 μM guanethidine-induced inhibition. The 1 μM guanethidine-resistant 1st phase responses at any frequencies used (1–10 Hz) were sensitive to tetrodotoxin (30 nM). Treatment with 0.1 μM prazosin did not modify the 1st phase response at any frequencies used in the 1 μM guanethidine-treated preparation. The responses remaining after 1 μM guanethidine and 0.1 μM prazosin were completely suppressed by a subsequent application of 1 μM α,β-methylene ATP at any frequencies used. The results indicated that guanethidine, an adrenergic neuron blocker, may exert a dominant inhibitory effect on adrenergic rather than on purinergic components of sympathetic nerve co-transmission, indicating that guanethidine-sensitive mechanisms may mainly contribute to determine noradrenaline secretion from neurosecretory vesicles rather than ATP secretion.

ADVERSE DRUG INTERACTIONS IN DENTAL PRACTICE: INTERACTIONS ASSOCIATED WITH VASOCONSTRICTORS: PART V OF A SERIES

Adrenergic vasoconstrictors are commonly used by dentists to enhance the pain-relieving action of local anesthetics and to control local bleeding. Although normally considered safe for these applications, vasoconstrictors can participate in drug interactions that potentially are harmful to patients. The faculty of a March 1998 symposium entitled "Adverse Drug Interactions in Dentistry: Separating the Myths From the Facts" extensively reviewed the literature on drug interactions. They then established a significance rating of alleged adverse drug interactions pertaining to dentistry, based on the quality of documentation and severity of effect. The author of this article focused on the adrenergic vasoconstrictors epinephrine and levonordefrin. Vasoconstrictor drug interactions involving tricyclic antidepressants, nonselective beta-adrenergic blocking drugs, certain general anesthetics and cocaine are well-documented in both humans and animals as having the potential for causing serious morbidity or death. Evidence for adverse interactions involving adrenergic neuronal blocking drugs, drugs with alpha-adrenergic blocking activity, local anesthetics and thyroid hormones is much less compelling, suggesting for the most part that clinically significant reactions may occur only when both the vasoconstrictor and the interacting drug are used in excessive doses. In the case of monoamine oxidase inhibitors, there is no credible evidence of a significant interaction with epinephrine or levonordefrin. Potentially serious adverse drug interactions involving adrenergic vasoconstrictors can occur in dental practice. In most circumstances, careful administration of small doses of vasoconstrictors and avoidance of gingival retraction cord containing epinephrine, coupled with monitoring of vita signs, will permit these drugs to be used with no risk or only minimally increased risk. Only in the case of cocaine intoxication must adrenergic vasoconstrictors be avoided completely. For optimal patient safety, dentists must recognize potential drug interactions involving adrenergic vasoconstrictors and modify their use of these agents accordingly.

Motor responses elicited by local electrical stimulation of the distal colon in the anaesthetized rat.

A method to study electrically induced distal colonic motility in the rat in vivo is reported. The animals were anaesthetized with methohexital and chloralose and were artificially ventilated. Motility of a segment (2 cm) of the distal colon was monitored as volume changes of an intraluminal balloon, introduced via the anus. Local electrical stimulation of the wall of the segment was achieved by means of a bipolar electrode folded around the gut. Stimulations produced reproducible contractile responses in a frequency dependent fashion. Stimulation characteristics resembled those of other autonomic neuro-effector systems. The adrenergic neuron-blocker, guanethidine, significantly lowered colonic tone, but had no other effects on spontaneous or electrically induced motility. Atropine significantly lowered colonic tone. After the administration of this compound the electrically induced contractions were significantly smaller with a shorter duration and, furthermore, appeared upon the cessation of stimulation ('off' or 'rebound' contraction). Following the administration of tetrodotoxin (TTX, given close i.a. via a cannula with its tip in distal aorta) basal colonic tone and the number of spontaneously occurring contractions increased. The amplitude and duration of the electrically induced responses were significantly attenuated and, furthermore, appeared as 'rebound' contractions which were preceded by a relaxation. Such TTX-resistant responses may be myogenic, but a neurogenic origin cannot be excluded. The present study showed that local electrical stimulation of the distal colon elicits cholinergic contractions, but also atropine- and TTX-resistant motor responses.

The actions of bretylium: Adrenergic neurone blocking and other effects

The actions of bretylium: Adrenergic neurone blocking and other effects

The actions of bretylium: adrenergic neurone blocking and other effects. 1959.

Bretylium caused a specific and lasting depression of many excitatory and inhibitory responses evoked by electrical stimulation of the peripheral sympathetic nervous system, probably by impairing conduction of impulses in adrenergic neurones with consequent failure of noradrenaline and adrenaline release. This effect, which will be referred to as the adrenergic neurone blocking action, was preceded by weak sympathomimetic effects. In the presence of bretylium the effects of adrenaline and noradrenaline were increased, as after sympathectomy. Concentrations producing blocking of adrenergic neurones did not prevent the release of adrenaline and noradrenaline from the adrenal medulla by splanchnic nerve stimulation or by the injection of dimethylphenylpiperazinium iodide, nor did they cause antiparasympathetic or parasympathomimetic effects. No action on the central nervous system has been detected. Curare‐like neuromuscular block occurred with 10 to 30 times the amount required to block the response to adrenergic nerve stimulation alone and was accompanied by signs of temporary synaptic block in autonomic ganglia. A drenergic. nerve trunks and sensory nerves in the skin were readily blocked for long periods by topical application of bretylium, whereas the phrenic nerve of the rat was not. Bretylium had little effect on gastrointestinal propulsion or on the sensitivity of smooth muscle to acetylcholine, 5‐hydroxytryptamine, adrenaline, or noradrenaline, but moderate amounts depressed the peristaltic reflex and the sensitivity of the guinea‐pig ileum to histamine. Bretylium caused postural hypotension in the cat in doses which had little effect on the supine blood pressure. Experiments on the nictitating membrane indicated that compensation for the effects of bretylium on low rates of stimulation of postganglionic sympathetic nerves could be attained by a small increase in the rate of stimulation, whereas compensation for its effects on high rates required an increase in the rate of stimulation beyond physiological limits.

Coexistense of substance P- and CGRP-like immunoreactivity in DRG neurons of the articular nerves

The effect of perivascular nerve stimulation (PNS) and capsaicin treatment on the release of calcitonin gene-related peptide (CGRP) was examined by radioimmunoassay (RIA) in isolated, perfused rat mesenteric arteries. In the preparation precontracted by methoxamine and treated with guanethidine, an adrenergic neuron blocker, PNS and capsaicin induced vasodilator responses and increase of CGRP-like immunoreactivity (CGRP-LI) in the perfusate in a frequency-dependent manner. The CGRP-LI released by capsaicin was identified as CGRP and its oxidized form by high-performance liquid chromatography coupled with RIA. After the tissue was treated with capsaicin, PNS didn't cause both the vasodilator response and the increase of CGRP-LI in the perfusate. These findings suggest that CGRP plays a neurotransmitter role in capsaicin-sensitive vasodilator nerves in rat mesenteric arteries.