Signal transduction pathway involved in beta 3-adrenoceptor-mediated relaxation in guinea pig taenia caecum.
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Experiments were carried out to examine the components of the intracellular second messenger system that is involved in beta 3-adrenoceptor (atypical beta-adrenoceptors)-mediated relaxation in the guinea pig taenia caecum. Propranolol and butoxamine caused competitive antagonism of the relaxant response to isoprenaline. However, propranolol or butoxamine did not significantly affect the relaxant responses to CGP 12177 (4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H- benzimidazol-2-one), a beta 3-adrenoceptor agonist. The concentration-response curves of the isoprenaline-induced increase in adenosine 3',5'-cyclic monophosphate (cyclic AMP) levels were shifted to the right in a parallel manner by propranolol and butoxamine. However, propranolol or butoxamine did not significantly affect the concentration-response curve for the CGP 12177-induced increase in cyclic AMP levels. MDL 12330 (cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine) inhibited the isoprenaline- or CGP 12177-induced increase in cyclic AMP levels. These results suggest that the production of cyclic AMP contributes to the beta 3-adrenoceptor (or atypical beta-adrenoceptor)-mediated relaxation of the guinea pig taenia caecum. (+info)
Adrenergic receptors on cultured rat epididymal cells: regulation of Cl- conductances.
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Adrenergic regulation of epididymal Cl- currents was studied by the whole-cell patch-clamp technique using various alpha- and beta-receptor agonists and antagonists in primary cultured rat cauda epididymal cells. Cl- currents could be activated with varying frequency by noradrenaline (primarily alpha- and beta 1-adrenoceptor-selective agonist, 1-5 microM), isoprenaline (nonselective beta-adrenoceptor agonist, 5 microM), salbutamol (beta 2-adrenoceptor-selective agonist, 2 microM), and phenylephrine (alpha 1-adrenoceptor-selective agonist, 1-2 microM). Noradrenaline alone elicited Cl- current activation in 85% of the cells examined. In the presence of phentolamine (nonselective alpha-adrenoceptor antagonist, 15 microM), noradrenaline elicited Cl- current activation in 63% of the cells examined, whereas noradrenaline-induced activation was observed in 33% of the cells examined in the presence of both atenolol and butoxamine (beta 1- and beta 2-adrenoceptor antagonists, respectively, 10 microM). In 27% of single cells examined, a second current activation in response to salbutamol was observed after the first response to phenylephrine. When the order of stimuli was reversed, dual activation was also observed in 22% of the single cells examined, indicating the presence of both alpha- and beta-adrenoceptors in single epididymal cells. Profiles of time- and voltage-dependent Cl- current upon activation by different adrenoceptor agonists exhibited characteristics similar to those previously reported for Ca2+ and cAMP-activated Cl- currents, suggesting that regulation of epididymal Cl- conductances could be mediated by different adrenoceptor subtypes involving Ca2+ and cAMP as intracellular second messengers. (+info)
Involvement of beta 3-adrenoceptor in the relaxation response in guinea pig taenia caecum.
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beta-Adrenoceptors in the guinea pig taenia caecum were investigated by measuring relaxation responses to agonists and by a radioligand binding assay using [3H]CGP 12177. The rightward shift of the isoprenaline concentration-response curve was observed by butoxamine, a beta 2-selective antagonist, and the pA2 value for butoxamine was 6.46. In control preparations, catecholamines caused relaxation with the following rank order of potency: isoprenaline > adrenaline > noradrenaline. However, in the presence of 10(-6) M phentolamine, 3 x 10(-4) M atenolol and 10(-4) M butoxamine, the rank order of potency of the agonists was: isoprenaline > noradrenaline > adrenaline. CGP 12177 caused graded relaxation of the guinea pig taenia caecum, and this response was not influenced by 10(-6) M phentolamine, 3 x 10(-4) M atenolol, 10(-4) M butoxamine or 10(-6) M propranolol. The Scatchard plot of the specific [3H]CGP 12177 binding to microsomal fractions from the guinea pig taenia caecum showed two affinity sites of the receptor: high affinity (KD = 0.64 nM) and low affinity (KD = 142.21 nM) sites. The pKD value of the high affinity site of [3H]CGP 12177 was in agreement with its pA2 value, and that of the low affinity site was in agreement with its pD2 value. These results suggest that isoprenaline-, noradrenaline- and adrenaline-induced relaxations of the guinea pig taenia caecum predominantly involve beta 2- and beta 3-adrenoceptors, whereas CGP 12177-induced relaxation is mediated solely through beta 3-adrenoceptors. (+info)
Antiinflammatory influences of alpha-MSH molecules: central neurogenic and peripheral actions.
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alpha-Melanocyte-stimulating hormone (alpha-MSH1-13) and its COOH-terminal tripeptide alpha-MSH11-13 (Lys Pro Val) inhibit inflammation when administered systemically. Recent evidence indicates that alpha-MSH1-13 can likewise inhibit inflammation in the skin solely via an action within the brain. Because of the potential importance of this discovery to understanding the control of inflammation and because alpha-MSH molecules might be useful for treatment of inflammation, experiments were performed to learn more about the mechanisms of action of these peptides. In tests on inflammation induced in the mouse ear by intradermal injections of recombinant human interleukin-1 beta, alpha-MSH1-1-13 administered intracerebroventricularly effectively reduced inflammation. This effect of centrally administered alpha-MSH1-13 was inhibited by systemic injection of the nonspecific beta-adrenergic receptor blocker propranolol and by administration of a specific beta 2-adrenergic receptor antagonist; the effect was not altered by blockade of cholinergic, alpha-adrenergic, or beta 1-adrenergic receptors. In mice with inflammation induced in a hind paw and with the spinal cord transected, the antiinflammatory effect of centrally administered alpha-MSH1-13 was prevented, indicating that intact descending neuronal pathways are required for the antiinflammatory influence of the central peptide. Systemic injection of alpha-MSH1-13 in animals with spinal cord transection had a smaller and later antiinflammatory effect, which suggests that the molecule also has an action, albeit lesser, in the periphery. However, alpha-MSH11-13 injected intraperitoneally had marked antiinflammatory activity in animals with spinal cord transection.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Evidence for receptor and G-protein regulation of a phosphatidylethanolamine-hydrolysing phospholipase A1 in guinea-pig heart microsomes: stimulation of phospholipase A1 activity by DL-isoprenaline and guanine nucleotides.
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While evidence has been presented for the receptor-mediated activation of phospholipases A2, C and D, the activation of phospholipase A1 subsequent to receptor activation has not been established. Phospholipase A1-catalysed hydrolysis of 1-palmitoyl-2-linoleoyl-glycerophosphoethanolamine (GPE) by guinea-pig heart microsomes was stimulated 40-60% by isoprenaline. This isoprenaline-mediated increase in activity was blocked by propranolol and butoxamine, a specific beta 2-adrenergic antagonist, but not by atenolol, a specific beta 1-adrenergic antagonist. Neither clonidine nor phenylephrine, alpha 1- and alpha 2-adrenergic agonists respectively, had a stimulatory effect on the hydrolysis of the PE substrate. Guanosine 5'(-)[gamma-thio]triphosphate (GTP[S]) and guanosine 5'(-)[beta,gamma-imido]triphosphate, but not guanosine 5'(-)[beta-thio]diphosphate (GDP[S]) or adenosine 5'(-)[gamma-thio]triphosphate, stimulated the hydrolysis of 1-palmitoyl-2-linoleoyl-GPE by phospholipase A1. GDP[S] inhibited the isoprenaline-mediated stimulation of phospholipase A1 activity. Phospholipase A1 hydrolysis of 1-palmitoyl-2-linoleoyl-GPE was not dependent on cations; however, the stimulatory effects of isoprenaline and GTP[S] on the hydrolytic activity were abolished by cation chelators. The above data suggest that phospholipase A1 activity in guinea-pig heart microsomes is activated by the binding of isoprenaline to beta 2-adrenergic receptors. Furthermore the stimulation of phospholipase A1 activity by the agonist may be mediated via activation of G-proteins. (+info)
The effect of distension of the stomach on peripheral blood flow in anaesthetized pigs.
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The present study was undertaken in anaesthetized pigs to determine the primary reflex effects of gastric distension on the peripheral circulation. Changes in blood flow in the splenic, superior mesenteric, left renal and left external iliac arteries were assessed using electromagnetic flowmeters during distension of a balloon in the stomach, performed at constant aortic blood pressure and heart rate, with 0.6 l of Ringer solution (mean gastric transmural pressure of about 12 mmHg). In fourteen pigs, a decrease in splenic, renal and iliac flows and variable changes in mesenteric flow were obtained. A decrease in mesenteric flow and more marked decreases in the other flows occurred in response to the distension after the administration of propranolol or butoxamine. In five pigs, the vasoconstrictive responses were graded by step increments in gastric distending volume from 0.4 to 0.8 l. The above responses were abolished by the administration of phentolamine (eight pigs) and by bilateral cervical vagotomy (six pigs). The results showed that innocuous distension of the stomach in anaesthetized pigs reflexly caused vasoconstriction in the splenic, renal and iliac vascular beds; vasoconstriction also occurred in the mesenteric vascular bed but only after beta-blockade. These reflex responses were mediated by sympathetic mechanisms which involved both alpha and beta vascular adrenoceptors and their afferent limb was in the vagal nerves. (+info)