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1.
Am J Cardiol ; 133: 77-80, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32843146

RESUMO

Bretylium, with an extensive pharmacologic and medicinal history, was approved by the United States Food and Drug Administration in 1986 for "short-term prevention and treatment of ventricular fibrillation (VF) and treatment of life-threatening ventricular arrhythmias and ventricular tachycardia (VT) unresponsive to adequate doses of a first-line antiarrhythmic agent, such as lidocaine." The NDA sponsor withdrew bretylium from the market in 2011, largely due to unavailability of raw materials required for its production; prior to this, bretylium was removed from the 2000 ACLS Guidelines algorithm for VF/pulseless VT given the challenges obtaining raw materials for drug manufacture. Recently, bretylium has been reintroduced into the US market by a generic pharmaceutical company with the same indications as before. This article provides a history of the salient trials evaluating the efficacy and safety of bretylium and looks to the future as bretylium finds its place in the modern day management of ventricular arrhythmia.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Compostos de Bretílio/farmacologia , Recall e Retirada de Produto , Humanos
2.
Eur J Appl Physiol ; 109(5): 915-21, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20300768

RESUMO

During mild cold exposure, elderly are at risk of hypothermia. In humans, glabrous skin at the hands is well adapted as a heat exchanger. Evidence exists that elderly show equal vasoconstriction due to local cooling at the ventral forearm, yet no age effects on vasoconstriction at hand skin have been studied. Here, we tested the hypotheses that at hand sites (a) elderly show equal vasoconstriction due to local cooling and (b) elderly show reduced response to noradrenergic stimuli. Skin perfusion and mean arterial pressure were measured in 16 young adults (Y: 18-28 years) and 16 elderly (E: 68-78 years). To study the effect of local vasoconstriction mechanisms local sympathetic nerve terminals were blocked by bretylium (BR). Baseline local skin temperature was clamped at 33 degrees C. Next, local temperature was reduced to 24 degrees C. After 15 min of local cooling, noradrenaline (NA) was administered to study the effect of neural vasoconstriction mechanisms. No significant age effect was observed in vasoconstriction due to local cooling at BR sites. After NA, vasoconstriction at the forearm showed a significant age effect; however, no significant age effect was found at the hand sites. [Change in CVC (% from baseline): Forearm Y: -76 +/- 3 vs. E: -60 +/- 5 (P < 0.01), dorsal hand Y: -74 +/- 4 vs. E: -72 +/- 4 (n.s.), ventral hand Y: -80 +/- 7 vs. E: -70 +/- 11 (n.s.)]. In conclusion, in contrast to results from the ventral forearm, elderly did not show a blunted response to local cooling and noradrenaline at hand skin sites. This indicates that at hand skin the noradrenergic mechanism of vasoconstriction is maintained with age.


Assuntos
Envelhecimento/fisiologia , Temperatura Baixa , Antebraço/irrigação sanguínea , Mãos/irrigação sanguínea , Pele/irrigação sanguínea , Vasoconstrição/fisiologia , Adolescente , Adulto , Idoso , Preservação de Sangue , Regulação da Temperatura Corporal/fisiologia , Compostos de Bretílio/farmacologia , Feminino , Humanos , Masculino , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Adulto Jovem
3.
Artigo em Inglês | MEDLINE | ID: mdl-20170742

RESUMO

The role of circulating and neural catecholamines for cardiovascular control in the Antarctic fish Pagothenia borchgrevinki was studied in vivo using pharmacological tools and with immunohistochemistry on isolated tissues. Adrenergic nerve blockade with bretylium decreased dorsal aortic pressure (P(da)) and systemic vascular resistance (R(sys)), while cardiac output (Q) did not change. The blockade of alpha-adrenoceptors with phentolamine reduced P(da) and R(sys) further, revealing that vasomotor tone was influenced by circulating catecholamines in bretylium treated fish. The physiological evidence for an adrenergic nervous control of the vasculature was corroborated by the presence of tyrosine hydroxylase (TH)-immunoreactive fibres associated with blood vessels in spleen, gonads and gastrointestinal tract. TH-immunoreactive fibres were not observed in the atrium and ventricle, but a dense population of TH-immunoreactive fibres was apparent in the bulbus arteriosus. The present study suggests that an adrenergic nervous mechanism is responsible for maintaining vasomotor tone in P. borchgrevinki. While experiments failed to demonstrate a tonic adrenergic nervous influence affecting cardiac performance, an adrenergic nervous control of bulbar compliance may be essential for optimizing gill blood flow dynamics in this species, which has a high relative stroke volume and displays profound changes in stroke volume in vivo.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/sangue , Catecolaminas/farmacologia , Coração/efeitos dos fármacos , Coração/fisiologia , Fenômenos Fisiológicos do Sistema Nervoso/efeitos dos fármacos , Perciformes/fisiologia , Animais , Regiões Antárticas , Compostos de Bretílio/farmacologia , Imuno-Histoquímica , Tirosina 3-Mono-Oxigenase/metabolismo
4.
Neurogastroenterol Motil ; 21(3): 335-45, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19254355

RESUMO

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.


Assuntos
Canal Anal/fisiologia , Epinefrina/metabolismo , Neurotransmissores/metabolismo , Óxido Nítrico/metabolismo , Transmissão Sináptica/fisiologia , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Canal Anal/efeitos dos fármacos , Animais , Antiarrítmicos/farmacologia , Apamina/farmacologia , Compostos de Bretílio/farmacologia , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Humanos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Tono Muscular/efeitos dos fármacos , Tono Muscular/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Norepinefrina/metabolismo , Prazosina/farmacologia , Ovinos , Estresse Mecânico , Suramina/farmacologia , Transmissão Sináptica/efeitos dos fármacos
5.
J Exp Biol ; 212(Pt 7): 934-44, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19282490

RESUMO

Previous studies have suggested that flatfish lack adrenergic cardiac innervation and have a limited humoral adrenergic stress response. However, data on neurohormonal control of flatfish cardiac function is scarce, and has never been directly studied in vivo. Hence, we (1) injected neural and humoral antagonists into flounder (Pleuronectes americanus) in vivo to determine the contribution of autonomic innervation and circulating catecholamines to the control of resting cardiac function; (2) measured pre- and post-stress (90 s chase) catecholamine levels in this species; and (3) constructed in vivo catecholamine dose-response curves for cardiovascular function based on the results of the second experiment. In addition, we quantified the density (B(max)) and ligand-binding affinity (Kd) of flounder ventricular cell-surface beta-adrenoreceptors, and established whether they were of beta1 or beta2 subtype using pharmacological antagonists. The cholinergic contribution to resting flounder heart rate was comparable to other teleosts (cholinergic tonus 26%). Interestingly, however, bretylium increased heart rate, resulting in a negative resting adrenergic tonus (-11.9%), and we were unable to demonstrate that catecholamines supported cardiac function at rest or at circulating concentrations approximating those following an exhaustive chase (adrenaline, 21 nmol l(-1); noradrenaline, 14 nmol l(-1)). Myocardial B(max) was very high in the flounder (252.8 fmol mg(-1) protein), and it appears that flounder ventricular beta-adrenoreceptors are predominantly of the beta2 subtype [based on the inability of atenolol to displace [3H]CGP from the beta-adrenoreceptors, and the IC(50) value for ICI 118551 (1.91 x 10(-6) mol l(-1))]. However, the extremely low affinity (Kd 1.02 nmol l(-1)) for these receptors raises the possibility that the flounder heart is also populated by beta3-adrenoreceptors.


Assuntos
Catecolaminas/metabolismo , Linguado/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Coração/inervação , Coração/fisiologia , Receptores Adrenérgicos beta/metabolismo , Análise de Variância , Animais , Antiarrítmicos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Compostos de Bretílio/farmacologia , Débito Cardíaco/efeitos dos fármacos , Catecolaminas/farmacologia , Coração/efeitos dos fármacos , Terra Nova e Labrador
6.
Am J Physiol Heart Circ Physiol ; 296(1): H51-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19011042

RESUMO

Slow local skin heating (LH) causes vasodilator responses, some of which are dependent on sympathetic nerve function. It is not known, however, how the rate of LH affects either the sympathetic or the nonadrenergic components of the responses to LH and whether the adrenergic effects of LH depend on tonic sympathetic activity or whether LH stimulates transmitter release. In part 1, cutaneous vascular conductance (CVC) responses to slow and fast LH (+0.1 degrees and +2 degrees C/min) from 34 degrees to 40 degrees C were compared both at control sites and at sites pretreated with bretylium tosylate (BT; blocks transmitter release from adrenergic terminals). We confirmed, as previously found, the axon reflex (AR) response to slow LH to be blocked by BT (P < 0.05). Pretreatment with BT reduced the AR only with fast LH. BT inhibited the peak vasodilation achieved with both rates of LH (P < 0.05). Longer-term LH was associated with a slow fall in CVC, the classical "die away" phenomenon, at untreated sites (P < 0.05) but not at BT-pretreated sites. Thus the LH-stimulated AR is only partially dependent on intact sympathetic function, and the "die away" phenomenon is dependent on such function. In part 2, we tested whether the conditions in part 1 (whole body and local skin temperatures of 34 degrees C) completely suppressed sympathetic nerve activity. The infusion of BT by microdialysis did not change the CVC (P > 0.05), suggesting the absence of tonic activity in those conditions and therefore that the adrenergic components of the responses in part 1 are via the stimulation of the transmitter release by LH.


Assuntos
Temperatura Alta , Pele/irrigação sanguínea , Pele/inervação , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Adulto , Axônios/fisiologia , Compostos de Bretílio/farmacologia , Feminino , Humanos , Fluxometria por Laser-Doppler , Masculino , Microdiálise , Neurotransmissores/metabolismo , Fluxo Sanguíneo Regional/fisiologia , Temperatura Cutânea/fisiologia
7.
Br J Pharmacol ; 153(4): 831-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18071295

RESUMO

BACKGROUND AND PURPOSE: The antidysrhythmic bretylium is useful experimentally because it selectively abolishes neurotransmitter release from sympathetic peripheral nerve terminals. Its mechanism of action seemed settled, but recent results from optical monitoring of single terminals now suggests a new interpretation. EXPERIMENTAL APPROACH: Orthograde transport of a dextran-conjugated Ca(2+) indicator to monitor Ca(2+) in nerve terminals of mouse isolated vas deferens with a confocal microscope. In some experiments, local neurotransmitter release was detected by monitoring neuroeffector Ca(2+) transients (NCTs) in adjacent smooth muscles, a local measure of purinergic transmission. Sympathetic terminals were identified with catecholamine fluorescence (UV excitation) or post-experiment immunohistochemistry. KEY RESULTS: Bretylium (10 microM) abolished NCTs at 60/61 junctions over the course of 2 h, indicating effective abolition of neurotransmitter release. However, bretylium did not abolish the field stimulus-induced Ca(2+) transient in most nerve terminals, but did increase both action potential delay (by 2+/-0.4 ms) and absolute refractory period (by 4+/-2 ms). Immunohistochemistry demonstrated that 85-96% of terminals orthogradely filled with a dextran-conjugated fluorescent probe contained Neuropeptide Y (NPY). A formaldehyde-glutaraldehyde-induced catecholamine fluorescence (FAGLU) technique was modified to allow sympathetic terminals to be identified with a Ca(2+) indicator present. Most terminals contained catecholamines (based on FAGLU) or secrete ATP (as NCTs in adjacent smooth muscle cells are abolished). CONCLUSIONS AND IMPLICATIONS: Bretylium can inhibit neurotransmitter release downstream of Ca(2+) influx without abolishing the nerve terminal action potential. Bretylium-induced increases in the absolute refractory period permit living sympathetic terminals to be identified.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Compostos de Bretílio/farmacologia , Neurotransmissores/metabolismo , Terminações Pré-Sinápticas/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Ducto Deferente/inervação , Trifosfato de Adenosina/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Catecolaminas/metabolismo , Imuno-Histoquímica/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal/métodos , Neuropeptídeo Y/metabolismo , Terminações Pré-Sinápticas/metabolismo , Sistema Nervoso Simpático/metabolismo , Fatores de Tempo
8.
Naunyn Schmiedebergs Arch Pharmacol ; 376(4): 265-74, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17992517

RESUMO

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.


Assuntos
Receptores Muscarínicos/fisiologia , Ducto Deferente/fisiologia , Acetilcolina/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Compostos de Bretílio/farmacologia , Cálcio/fisiologia , Inibidores da Colinesterase/farmacologia , Ciclopentolato/farmacologia , Cobaias , Técnicas In Vitro , Masculino , Antagonistas Muscarínicos/farmacologia , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Neostigmina/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Piperidinas/farmacologia , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/inervação , Ioimbina/farmacologia
9.
Acta Otolaryngol ; 127(3): 265-72, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17364363

RESUMO

CONCLUSION: We propose that simultaneous activation of the sensory and sympathetic nervous system may adversely affect eustachian tube function, which may have a role in the genesis of Ménière's disease. OBJECTIVE: We have determined the distribution of sympathetic and nociceptive sensory axons in the mucosa of the rat eustachian tube and investigated whether sympathetic or nociceptive neurons influence the function of the eustachian tube. MATERIALS AND METHODS: We tested whether the ability of a rat to equalize air pressure in the middle ear during evoked swallowing was altered by activation or blockade of the local sympathetic nervous system, or by stimulation of nociceptive neurons with capsaicin. RESULTS: Sympathetic axons were sparse, but CGRP-immunoreactive, nociceptive axons formed a dense subepithelial plexus beneath the eustachian tube epithelium. Neither the adrenergic blocking drug, bretylium, nor electrical stimulation of the superior cervical ganglion significantly altered eustachian tube function. Capsaicin alone did not affect eustachian tube function but capsaicin applied with an alpha adrenoceptor agonist impaired the function of the eustachian tube. Capsaicin applied to the bulla also increased spontaneous swallowing in anaesthetized rats and this effect was enhanced by addition of an alpha adrenoceptor agonist and by stimulation of the superior cervical ganglion.


Assuntos
Tuba Auditiva/inervação , Tuba Auditiva/fisiopatologia , Doença de Meniere/fisiopatologia , Nociceptores/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Agonistas alfa-Adrenérgicos/farmacologia , Pressão do Ar , Animais , Axônios/patologia , Axônios/fisiologia , Compostos de Bretílio/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/farmacologia , Deglutição/fisiologia , Estimulação Elétrica , Feminino , Masculino , Doença de Meniere/patologia , Nociceptores/patologia , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Gânglio Cervical Superior/patologia , Gânglio Cervical Superior/fisiopatologia , Sistema Nervoso Simpático/patologia
10.
Am J Physiol Regul Integr Comp Physiol ; 291(3): R711-8, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16741138

RESUMO

Central venous blood pressure (P(ven)) increases in response to hypoxia in rainbow trout (Oncorhynchus mykiss), but details on the control mechanisms of the venous vasculature during hypoxia have not been studied in fish. Basic cardiovascular variables including P(ven), dorsal aortic blood pressure, cardiac output, and heart rate were monitored in vivo during normoxia and moderate hypoxia (P(W)O(2) = approximately 9 kPa), where P(W)O(2) is water oxygen partial pressure. Venous capacitance curves for normoxia and hypoxia were constructed at 80-100, 90-110, and 100-120% of total blood volume by transiently (8 s) occluding the ventral aorta and measure P(ven) during circulatory arrest to estimate the mean circulatory filling pressure (MCFP). This allowed for estimates of hypoxia-induced changes in unstressed blood volume (USBV) and venous compliance. MCFP increased due to a decreased USBV at all blood volumes during hypoxia. These venous responses were blocked by alpha-adrenoceptor blockade with prazosin (1 mg/kg body mass). MCFP still increased during hypoxia after pretreatment with the adrenergic nerve-blocking agent bretylium (10 mg/kg body mass), but the decrease in USBV only persisted at 80-100% blood volume, whereas vascular capacitance decreased significantly at 90-110% blood volume. In all treatments, hypoxia typically reduced heart rate while cardiac output was maintained through a compensatory increase in stroke volume. Despite the markedly reduced response in venous capacitance after adrenergic blockade, P(ven) always increased in response to hypoxia. This study reveals that venous capacitance in rainbow trout is actively modulated in response to hypoxia by an alpha-adrenergic mechanism with both humoral and neural components.


Assuntos
Catecolaminas/metabolismo , Hipóxia/metabolismo , Oncorhynchus mykiss/metabolismo , Capacitância Vascular/efeitos dos fármacos , Capacitância Vascular/fisiologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Compostos de Bretílio/farmacologia , Prazosina/farmacologia
11.
Am J Physiol Gastrointest Liver Physiol ; 290(3): G511-8, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16223946

RESUMO

We characterized the influence of the selective corticotropin-releasing factor 2 (CRF(2)) receptor agonist human urocortin 2 (Ucn 2), injected intracisternally, on gastric emptying and its mechanism of action compared with intracisternal CRF or urocortin (Ucn 1) in conscious rats. The methylcellulose phenol red solution was gavaged 20 min after peptide injection, and gastric emptying was measured 20 min later. The intracisternal injection of Ucn 2 (0.1 and 1 microg) and Ucn 1 (1 microg) decreased gastric emptying to 37.8 +/- 6.9%, 23.1 +/- 8.6%, and 21.6 +/- 5.9%, respectively, compared with 58.4 +/- 3.8% after intracisternal vehicle. At lower doses, Ucn 2 (0.03 microg) and Ucn 1 (0.1 microg) had no effect. The CRF(2) antagonist astressin(2)-B (3 microg ic) antagonized intracisternal Ucn 2 (0.1 microg) and CRF (0.3 microg)-induced inhibition of gastric emptying. Vagotomy enhanced intracisternal Ucn 2 (0.1 or 1 microg)-induced inhibition of gastric emptying compared with sham-operated group, whereas it blocked intracisternal CRF (1 microg) inhibitory action (45.5 +/- 8.4% vs. 9.7 +/- 9.7%). Sympathetic blockade by bretylium prevented intracisternal and intracerebroventricular Ucn 2-induced delayed gastric emptying, whereas it did not influence intravenous Ucn 2-, intracisternal CRF-, and intracisternal Ucn 1-induced inhibition of gastric emptying. Prazosin abolished the intracisternal Ucn 2 inhibitory effect, whereas yohimbine and propranolol did not. None of the pretreatments modified basal gastric emptying. These data indicate that intracisternal Ucn 2 induced a central CRF(2)-mediated inhibition of gastric emptying involving sympathetic alpha(1)-adrenergic mechanisms independent from the vagus contrasting with the vagal-dependent inhibitory actions of CRF and Ucn 1.


Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Esvaziamento Gástrico/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Nervo Vago/fisiologia , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Compostos de Bretílio/farmacologia , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Liberador da Corticotropina/farmacologia , Humanos , Masculino , Fragmentos de Peptídeos/farmacologia , Prazosina/farmacologia , Ratos , Urocortinas , Vagotomia , Ioimbina/farmacologia
12.
Br J Pharmacol ; 146(7): 927-34, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16170331

RESUMO

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.


Assuntos
Contração Muscular/efeitos dos fármacos , Sistema Nervoso Parassimpático/fisiologia , Ducto Deferente/inervação , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Compostos de Bretílio/farmacologia , Ciclopentolato/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neostigmina/farmacologia , Nicotina/farmacologia , Prazosina/farmacologia , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologia , Ioimbina/farmacologia
13.
Endocrinology ; 146(9): 3861-7, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15919744

RESUMO

Nociceptin (N/OFQ) exerts multiple effects in the gastrointestinal tract after central or peripheral administration. In the present study, we examined the possible peripheral mechanisms mediating gastric protection by N/OFQ in rats. Gastric mucosal lesions were induced by 50% ethanol (1 ml/rat intragastrically). N/OFQ, administered either intracerebroventricularly (3 microg/rat) or ip (10 microg/kg), significantly reduced macroscopic and histological damage. The protective effect of intracerebroventricular N/OFQ was blocked by atropine, subdiaphragmatic vagotomy, and bretylium. The effect of both central and peripheral N/OFQ was blocked by functional ablation of afferent nerves produced by capsaicin, by the antagonist of calcitonin gene-related peptide, CGRP(8-37), and by the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester. These results indicate that N/OFQ increases gastric mucosal resistance to ethanol by operating both in the central nervous system and in the periphery. Vagal cholinergic and sympathetic pathways mediate the central activity of N/OFQ, whereas vagal nonmuscarinic pathways mediate the peripheral activity of the peptide. The neuronal circuit involving extrinsic sensory neurons, calcitonin gene-related peptide, and nitric oxide is activated by central as well as peripheral N/OFQ. The study provides evidence that N/OFQ contributes to neurally mediated gastric mucosal protection.


Assuntos
Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/fisiologia , Peptídeos Opioides/farmacologia , Animais , Antiarrítmicos/farmacologia , Atropina/farmacologia , Compostos de Bretílio/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Bloqueadores Ganglionares/farmacologia , Mucosa Gástrica/inervação , Hexametônio/farmacologia , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Mióticos/farmacologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Óxido Nítrico/metabolismo , Sistema Nervoso Parassimpático/citologia , Sistema Nervoso Parassimpático/fisiologia , Parassimpatolíticos/farmacologia , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Sistema Nervoso Simpático/citologia , Sistema Nervoso Simpático/fisiologia , Vagotomia , Nociceptina
14.
J Appl Physiol (1985) ; 98(3): 829-37, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15489258

RESUMO

The role of skin temperature in reflex control of the active cutaneous vasodilator system was examined in six subjects during mild graded heat stress imposed by perfusing water at 34, 36, 38, and 40 degrees C through a tube-lined garment. Skin sympathetic nerve activity (SSNA) was recorded from the peroneal nerve with microneurography. While monitoring esophageal, mean skin, and local skin temperatures, we recorded skin blood flow at bretylium-treated and untreated skin sites by using laser-Doppler velocimetry and local sweat rate by using capacitance hygrometry on the dorsal foot. Cutaneous vascular conductance (CVC) was calculated by dividing skin blood flow by mean arterial pressure. Mild heat stress increased mean skin temperature by 0.2 or 0.3 degrees C every stage, but esophageal and local skin temperature did not change during the first three stages. CVC at the bretylium tosylate-treated site (CVC(BT)) and sweat expulsion number increased at 38 and 40 degrees C compared with 34 degrees C (P < 0.05); however, CVC at the untreated site did not change. SSNA increased at 40 degrees C (P < 0.05, different from 34 degrees C). However, SSNA burst amplitude increased (P < 0.05), whereas SSNA burst duration decreased (P < 0.05), at the same time as we observed the increase in CVC(BT) and sweat expulsion number. These data support the hypothesis that the active vasodilator system is activated by changes in mean skin temperature, even at normal core temperature, and illustrate the intricate competition between active vasodilator and the vasoconstrictor system for control of skin blood flow during mild heat stress.


Assuntos
Temperatura Corporal , Transtornos de Estresse por Calor/fisiopatologia , Reflexo , Pele/irrigação sanguínea , Pele/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Vasodilatação , Adulto , Regulação da Temperatura Corporal , Compostos de Bretílio/farmacologia , Feminino , Humanos , Masculino , Descanso , Pele/inervação , Sistema Nervoso Simpático/efeitos dos fármacos
15.
J Physiol ; 559(Pt 3): 975-84, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15272048

RESUMO

Nicotine affects the regulation of skin blood flow (SkBF), but the mechanisms involved are not well understood. We tested the hypothesis that acute exposure to nicotine inhibits both the initial neurally mediated component and the later sustained component of SkBF responses to local heating of non-glabrous skin in humans. SkBF (measured by laser-Doppler) responses to local heating of forearm skin from 32 to 42 degrees C were measured in 11 chronic smokers. Heating occurred at one site over 15 min (RAMP) and over 90 s (STEP) at another site, and was maintained for an additional 30 min. STEP heating was also applied to a site pretreated with bretylium via iontophoresis to inhibit noradrenergic neurotransmission. Responses were measured before and after acute administration of nicotine via cigarettes or nasal spray in two experimental sessions. Nicotine decreased resting skin blood flow (P < 0.05); this response was inhibited by bretylium. During RAMP, nicotine increased the initial SkBF at 42 degrees C (by approximately 12%, P < 0.05). For STEP, nicotine increased the initial peak response (by approximately 25%, P < 0.05), and decreased the sustained plateau value (by approximately 10%, P < 0.05). In skin pretreated with bretylium, the increase caused by nicotine in the initial peak value persisted, but the plateau value was not different from pre-nicotine. These data suggest that in abstinent cigarette smokers, nicotine augments initial responses to both gradual and rapid non-painful heating of non-glabrous skin by sensitizing the sensory nerves that mediate the axon reflex associated with rapid vasodilatation. In contrast, nicotine decreases SkBF responses to prolonged heating by activating noradrenergic nerves.


Assuntos
Temperatura Alta , Nicotina/farmacologia , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo/fisiologia , Compostos de Bretílio/farmacologia , Feminino , Humanos , Masculino , Vasodilatação/fisiologia
16.
Blood Cells Mol Dis ; 32(3): 394-400, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15121098

RESUMO

The quaternary amine, bretylium, is a class III antiarrhythmic drug used to treat ventricular tachycardia and fibrillation. The primary mode of action for bretylium is thought to be inhibition of voltage-gated K(+) channels. While the Na,K-ATPase has been the pharmacological target of cardiac glycosides for over a century, recent evidence has shown that bretylium may also inhibit the Na pump. Our experimental findings support and extend these previous reports and provide definitive evidence supporting the previous suggestion that bretylium and K compete for the Na pump. We find that bretylium inhibits the Na pump in a dose-dependent manner in both Na,K-ATPase (IC(50) 4.5 mM) and Rb flux experiments (IC(50) 3.5 mM). Furthermore, we show that bretylium and Rb(+) competes for an extracellular site by measuring ouabain-sensitive (86)Rb flux in intact human red blood cells; that is, there is an apparent increase in K(m) for Rb(+) in the presence of 5 mM bretylium, while V(max) remains unchanged. We also determined that unlike K(+), bretylium does not facilitate the hydrolysis of E2-P. However, it stabilizes this conformation by reducing the ability of K(+) to facilitate dephosphorylation. Finally, we show that bretylium, like K(+), reduces [(3)H]ouabain binding to the Na pump. Taken together, these data are consistent with bretylium binding to the extracellular facing cation site within the E2-P state of the enzyme. Moreover, these findings suggest that bretylium may serve as an effective tool for freezing the pump in an extracellularly cation-bound phosphorylated intermediate, which will aid in future structural analyses.


Assuntos
Antiarrítmicos/farmacologia , Compostos de Bretílio/farmacologia , Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Sítios de Ligação , Ligação Competitiva , Relação Dose-Resposta a Droga , Eritrócitos/metabolismo , Humanos , Cinética , Fosforilação , Conformação Proteica , Compostos de Amônio Quaternário/farmacologia , Rubídio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo
17.
J Pharmacol Exp Ther ; 306(3): 995-1002, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12754319

RESUMO

The effect of reboxetine on sympathetic neuroeffector transmission in rabbit isolated carotid artery was examined. Reboxetine (10-8-3 x 10-6 M) and cocaine (10-6-3 x 10-5 M), but not desipramine (10-8-3 x 10-7 M), increased contractions evoked by electrical field stimulation. At higher concentrations, reboxetine (10-4 M), cocaine (3 x 10-4 M), and desipramine (3 x 10-7-10-5 M) inhibited the neurogenic contractions. The enhancement seen with reboxetine and cocaine was partially reversible, whereas the inhibition was readily reversible. Reboxetine (10-7 M) and cocaine (10-5 M) prevented the inhibitory action of bretylium (10-6 M). Reboxetine (10-8-10-5 M), desipramine (10-7-10-4 M), and cocaine (10-6-10-5 M) increased the stimulation-evoked [3H]norepinephrine release. Pargyline (5 x 10-4 M) augmented the facilitatory effect of reboxetine (3 x 10-9-10-6 M) and cocaine (10-7-3 x 10-5 M). Reboxetine (10-8-10-6 M), desipramine (10-8-10-6 M), and cocaine (3 x 10-8-10-5 M) reduced the [3H]norepinephrine (10-8 M) uptake. Reboxetine (10-7 M) and cocaine (10-5-2 x 10-4 M) enhanced the contractions evoked by phenylephrine and norepinephrine. Higher concentrations of reboxetine antagonized the contractions. Reboxetine (10-5-6 x 10-5 M) antagonized the contractions evoked by potassium. The contractions evoked by tyramine (3 x 10-6-10-3 M) was reduced by reboxetine (3 x 10-8-10-6 M) and by cocaine (10-7-10-5 M). We conclude that reboxetine inhibits the membrane amine pump (uptake-1) in the terminals of postganglionic adrenergic neurons in a cocaine-like manner.


Assuntos
Artérias Carótidas/efeitos dos fármacos , Cocaína/farmacologia , Morfolinas/farmacologia , Junção Neuroefetora/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Compostos de Bretílio/farmacologia , Artérias Carótidas/fisiologia , Desipramina/farmacologia , Junção Neuroefetora/fisiologia , Norepinefrina/farmacologia , Pargilina/farmacologia , Potássio/farmacologia , Coelhos , Reboxetina , Sistema Nervoso Simpático/fisiologia , Trítio
18.
J Appl Physiol (1985) ; 94(3): 930-4, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12571128

RESUMO

To test for a diurnal difference in the vasoconstrictor control of the cutaneous circulation, we performed whole body skin cooling (water-perfused suits) at 0600 (AM) and 1600 (PM). After whole body skin temperature (T(sk)) was controlled at 35 degrees C for 10 min, it was progressively lowered to 32 degrees C over 18-20 min. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry at three control sites and at a site that had been pretreated with bretylium by iontophoresis to block noradrenergic vasoconstriction. After whole body skin cooling, maximal cutaneous vascular conductance (CVC) was measured by locally warming the sites of SkBF measurement to 42 degrees C for 30 min. Before whole body skin cooling, sublingual temperature (T(or)) in the PM was significantly higher than that in the AM (P < 0.05), but CVC, expressed as a percentage of maximal CVC (%CVC(max)), was not statistically different between AM and PM. During whole body skin cooling, %CVC(max) levels at bretylium-treated sites in AM or PM were not significantly reduced from baseline. In the PM, %CVC(max) at control sites fell significantly at T(sk) of 34.3 +/- 0.01 degrees C and lower (P < 0.05). In contrast, in the AM %CVC(max) at control sites was not significantly reduced from baseline until T(sk) reached 32.3 +/- 0.01 degrees C and lower (P < 0.05). Furthermore, the decrease in %CVC(max) in the PM was significantly greater than that in AM at T(sk) of 33.3 +/- 0.01 degrees C and lower (P < 0.05). Integrative analysis of the CVC response with respect to both T(or) and T(sk) showed that the cutaneous vasoconstrictor response was shifted to higher internal temperatures in the PM. These findings suggest that during whole body skin cooling the reflex control of the cutaneous vasoconstrictor system is shifted to a higher internal temperature in the PM. Furthermore, the slope of the relationship between CVC and T(sk) is steeper in the PM compared with that in the AM.


Assuntos
Ritmo Circadiano/fisiologia , Fenômenos Fisiológicos da Pele , Temperatura Cutânea/fisiologia , Vasoconstrição/fisiologia , Adolescente , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Compostos de Bretílio/administração & dosagem , Compostos de Bretílio/farmacologia , Temperatura Baixa , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Iontoforese , Masculino , Reflexo/fisiologia , Estresse Fisiológico/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
19.
J Appl Physiol (1985) ; 94(3): 1045-53, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12433866

RESUMO

Reflex vasodilation is attenuated in aged skin during hyperthermia. We used laser-Doppler imaging (LDI) to test the hypothesis that the magnitude of conductance and the spatial distribution of vasodilation are altered with aging. LDI of forearm skin was compared in 12 young (19- to 29-yr-old) and 12 older (64- to 75-yr-old) men during supine passive heating. Additionally, iontophoresis of bretylium tosylate was performed in a subset of subjects to explore the involvement of sympathetic vasoconstriction in limiting skin blood flow. Passive heating with water-perfused suits clamped mean skin temperature at 41.0 +/- 0.5 degrees C, causing a ramp increase in esophageal temperature (T(es)) to

Assuntos
Envelhecimento/fisiologia , Pele/irrigação sanguínea , Vasodilatação/fisiologia , Adulto , Idoso , Limiar Anaeróbio/fisiologia , Compostos de Bretílio/farmacologia , Febre/fisiopatologia , Antebraço/irrigação sanguínea , Humanos , Processamento de Imagem Assistida por Computador , Iontoforese , Fluxometria por Laser-Doppler , Masculino , Concentração Osmolar , Fluxo Sanguíneo Regional/fisiologia
20.
Am J Physiol Heart Circ Physiol ; 282(5): H1915-23, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11959659

RESUMO

The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 microg) into normal isolated perfused swine right ventricles (RVs) stained with 4-[beta-[2-(di-n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 +/- 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 +/- 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10-20 mM, n = 6), bretylium (10-20 microg/ml, n = 3), and verapamil (2-4 microg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the "aconitine" site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.


Assuntos
Aconitina , Diacetil/análogos & derivados , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/induzido quimicamente , Fibrilação Ventricular/fisiopatologia , Aconitina/administração & dosagem , Potenciais de Ação , Animais , Antiarrítmicos/farmacologia , Compostos de Bretílio/farmacologia , Simulação por Computador , Diacetil/farmacologia , Eletrocardiografia , Feminino , Masculino , Suínos , Verapamil/farmacologia
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