Adrenergic blocking properties of MJ 1999 and butoxamine on cardiac and vascular beta-receptors.
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Anilides↗
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[Modification of the metabolic effects of catecholamines by N-butyl tertiary methoxamine (butoxamine)].
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Animals↗
Involvement of beta 2-adrenoceptor blockade and 5-hydroxytryptamine mechanism in inhibition of harmaline-induced tremors in rats.
Specific beta 1- and beta 2-adrenoceptor antagonists, acebutolol and butoxamine respectively were used to investigate the involvement of blockade of these receptors in the inhibition of harmaline-induced tremors. Both agents produced an antitremor effect in a dose-dependent manner, with butoxamine showing greater potency than acebutolol. The dose of isoprenaline (0.1 mg/kg) that markedly reduced the effect of butoxamine did not alter the effect of acebutolol, suggesting that antagonism of peripheral beta 1-adrenoceptor was not responsible for the antitremor action of acebutolol and that blockade of peripheral beta 2-receptors is involved to a great extent in the inhibition of tremors by butoxamine. The effect of acebutolol was unaltered in rats pretreated with 5-hydroxytryptophan and p-chlorophenylalanine, which on the other hand produced potentiation and a partial reduction respectively of the action of butoxamine. It appears, therefore, that butoxamine also acts centrally in association with the 5-HT system and that this action is relatively weaker than the peripheral action. The dual action on two sites may account for the potent antitremor action of butoxamine.
5-Hydroxytryptophan↗
Effects of selective beta-adrenoceptor antagonists on gastric ulceration in the rat.
Metoprolol and butoxamine, beta-adrenoceptor antagonists which act selectively at the beta 1- and beta 2-adrenoceptors, respectively, have been investigated for their actions on the ethanol, indomethacin and cold-restraint stress ulcer models. Oral administration of butoxamine but not metoprolol significantly attenuated gastric mucosal damage in the three types of ulcer model. Intraperitoneal injection of butoxamine reduced indomethacin ulceration but not that of the other two models. The stimulatory effect of butoxamine on the gastric mucosal potential difference and intramucosal mucus level correlated positively with its anti-ulcer action. Only oral administration of butoxamine significantly increased the mucosal prostaglandin E2 (PGE2) level but not after intraperitoneal injection. Oral administration of butoxamine also significantly increased the mucosal PGE2 level in the three types of ulcer model but this drug was only effective in the indomethacin ulcer model after intraperitoneal injection. Gastric acid and pepsin output were not affected by either drug. Metoprolol significantly reduced systemic blood pressure; this could be attributed to a reduction in gastric mucosal blood flow. These results imply that beta 2-adrenoceptors play a significant role in the pathogenesis of gastric ulceration. We suggest that the anti-ulcer effect of butoxamine was in part a result of strengthening of the mucosal barrier but that this was not effected by modification of acid or pepsin secretions in the stomach. Stimulation of PGE2 in the gastric mucosa could contribute in part to the anti-ulcer action of the drug, especially when given by the oral route.
Adrenergic beta-Antagonists↗
In vivo protection of normal mouse hematopoiesis by a beta 2 blocking agent during S-phase chemotherapy.
Butoxamine, a beta 2-adrenergic blocking agent, which temporarily blocks the G1-S transition of human bone marrow granulocyte precursors in vitro, was used in vivo together with 1-beta-D-arabinofuranosylcytosine (ara-C) in mice. Butoxamine alone depressed the granulocyte labeling index and granulocyte-monocyte colony-forming Cell (GM-CFC) suicide rate at a dose of 3 micrograms/g body weight. A maximum effect was produced 6 to 12 hr after injection. Butoxamine administered 8 hr before an injection of ara-C modified the proportion of GM-CFC in S phase as compared with the number found after ara-C alone. After a series of five ara-C injections, administered at intervals of 16 hr, 70% of the treated mice died within 2 weeks, whereas only 42% of mice pretreated with butoxamine 7 to 9 hr before each ara-C injection died. This difference was due to the more rapid return to normal of GM-CFC numbers and an increase in the proportion of GM-CFC and granulocyte precursors in S phase in the butoxamine-pretreated animals. These findings suggest that butoxamine may have a potential use in protecting hematopoiesis during intensive chemotherapy for cancer.
Adrenergic beta-Antagonists↗
A mechanistic study of beta-adrenoceptor antagonists on ethanol-induced gastric damage.
The beta-adrenoceptor subtypes and the roles of myeloperoxidase and prostaglandin E2 in the anti-ulcer effect of beta-adrenoceptor antagonists were studied. A non-selective beta-adrenoceptor antagonist, propranolol, or selective beta-adrenoceptor antagonists, metoprolol (a beta 1-adrenoceptor antagonist) or butoxamine (a beta 2-adrenoceptor antagonist) were used. Propranolol given either intraperitoneally or orally reduced ethanol-induced mucosal damage and myeloperoxidase activity. Oral administration of butoxamine produced similar effects. The blood neutrophil count was increased after ethanol administration and this was reversed by the two drugs. Metoprolol did not affect myeloperoxidase activity, neutrophil count and mucosal damage under these experimental conditions. Oral administration of propranolol or butoxamine increased mucosal prostaglandin E2 level. It is concluded that the inflammatory responses to ethanol, as indicated by neutrophil infiltration in gastric mucosa, can be specifically inhibited by drugs that block beta 2-adrenoceptors. This action would explain in part why propranolol and butoxamine but not metoprolol lessened gastric damage. In addition, oral administration of propranolol and butoxamine increased the mucosal prostaglandin E2 level, which could partially contribute to their anti-ulcer effects.
Adrenergic beta-Antagonists↗
Beta-adrenoceptor blockade and open-field behavior in male golden hamsters.
Open-field behavior was compared between untreated, saline-treated, and butoxamine (a beta-2-adrenoceptor antagonist) treated (15 and 5 mg/kg body weight) male golden hamsters (Mesocricetus auratus). Butoxamine-treated males spent significantly more time self-grooming than saline-treated and untreated males. Especially, untreated males and very similar saline control males showed a clear time sequential structure of behavior with two axes: a grooming-grooming sequence and a highly organized flankmark followed by scrape axis. The degree of this organization was markedly decreased in the butoxamine-treated males, showing an increase in organization of the transition between grooming acts. In general, these males displayed a more stereotypic pattern of behavior than the other. To reveal a systematic relation between the flankmark-scrape response and the exposition to butoxamine and to keep the numbers of experimental animals low, mixed samples were created through consecutive summing of the individual transition matrices of six males treated with 5 mg/kg b.wt. butoxamine to the 15 mg/kg b.wt. sample. By analyzing all samples separately, a positive linear relation between the number of low dosed males in the samples and the degree of organization of the flankmark-scrape sequence was found. The results suggest that the analysis of the transitional structure of behavior during short-term challenges can considerably contribute to an estimation of the coping style and seems to be a more sensitive method than comparing frequencies of behavioral indicators of stress.
Adrenergic beta-Antagonists↗
The influence of drugs on the overflow of noradrenaline and the identification of receptors in guinea-pig atria.
1 Salbutamol (1.0 microM) and isoprenaline (1.2 nM) significantly increased the fractional release of tritiated noradrenaline from driven left atria but phentolamine (10 microM) failed to do so. Butoxamine (4.0 microM) blocked the increase in overflow produced by isoprenaline. Isoprenaline (1.2 nM), phentolamine (10.0 microM) and salbutamol (1.0 microM) failed to increase the overflow of tritiated noradrenaline from spontaneously beating atria. 2 Spontaneously beating atria were therefore used to identify the receptors mediating chronotropism and inotropism. 3 There was no clear relationship between inotropism and chronotropism. 4 The inotropic effects of both dobutamine (0.04-4.0 microM) and isoprenaline (0.11-9.0 nM) were inhibited by practolol (4.0 microM) and by butoxamine (4.0 microM). The chronotropic effects were inhibited only by practolol (4.0 microM). 5 Both inotropic and chronotropic effects of noradrenaline (3.0-200 nM) were antagonized by practolol (4.0 microM), but not by butoxamine (4.0 microM). Thus both functions appeared to be mediated by beta 1-adrenoceptors when noradrenaline was the agonist. 6 Inotropic responses to salbutamol (0.45-7.5 microM) were inhibited by both practolol (4.0 microM) and by butoxamine (4.0 microM), but chronotropic responses were antagonized only by butoxamine (4.0 microM), Thus salbutamol acts on both beta 1-and beta 2-adrenoceptors to produce an inotropic response but only on beta 2-adrenoceptors to produce its chronotropic response. 7 It is concluded that both beta 1- and beta 2-adrenoceptors can mediate chronotropism and inotropism in guinea-pig isolated atria. Determination of the postsynaptic effects of drugs should be carried out on spontaneously beating rather than driven atria to obviate modification of the responses by noradrenaline release from sympathetic neurons.
Albuterol↗
Effect of beta adrenergic agonists and beta blocking agents on hemopoiesis in human bone marrow.
The effect of propranolol (non specific blocking agent), acebutolol (beta 1 blocking agent), butoxamine (beta 2 blocking agent) and several beta adrenergic agonists was studied on 3H-thymidine (3H-TdR) incorporation and granulo-monocyte colony formation in agar by human bone marrow. Only butoxamine and propranolol decreased 3H-TdR incorporation by total normal bone marrow cells at concentrations above 10(-6) M for butoxamine and 10(-5) M for propranolol. Autoradiography showed that inhibition of 3H-TdR incorporation by butoxamine was slightly more pronounced on neutrophil precursors than on red cell precursors (neutrophil series LI..53 and erythroblasts .67 compared to control bone marrow cells at 10(-5) M concentration). The development of granulo-monocyte colonies in agar culture was delayed by preincubation with butoxamine at concentrations above 5 X 10(-6) M. Hydroxyurea suicide showed that this was due to a decrease in the number of CFU-C in S phase. beta 2 blocking agents are able to decrease the number of normal hematopoietic cells entering S phase. This effect is seen on both neutrophil and erythroblastic precursors and on granulo-monocyte progenitors. It could be used as a means of protecting bone marrow cells during cancer intensive chemotherapy.
Adrenergic beta-Agonists↗
Calcium channel blockers enhance extrarenal potassium disposal in the rat.
The effect of calcium channel blockers on the extrarenal disposition of an acute potassium load was examined in acutely nephrectomized rats infused with KCl (0.75 meq X kg-1 X h-1 for 60 min) alone or in combination with either verapamil or nifedipine. The increment in plasma potassium concentration during the potassium infusion (delta PK) with either verapamil or nifedipine was less than control (P less than 0.05 and 0.01, respectively). Studies were repeated in acutely adrenalectomized rats (ADX) to evaluate whether the changes in plasma potassium were consequent to the enhanced activity of epinephrine and other adrenal hormones. delta PK with ADX was higher than control (P less than 0.01). Verapamil or nifedipine with ADX resulted in a lower delta PK than ADX alone (P less than 0.05). Further studies were then conducted with the selective beta 2-adrenergic blocker butoxamine hydrochloride to rule out enhanced peripheral sympathetic activity of the beta 2-adrenergic system in facilitating the potassium disposal. delta PK with butoxamine was greater than control (P less than 0.01) but not significantly different from ADX. Verapamil or nifedipine in conjunction with butoxamine resulted in a lower delta PK than butoxamine alone (P less than 0.01). Changes in arterial pH and plasma bicarbonate were similar in all groups. In conclusion, during potassium infusion the delta PK is lower in the presence of calcium channel blockers. The alteration in potassium transport produced by calcium channel blockers does not appear to be dependent on adrenal function or peripheral sympathetic activity. Impaired calcium entry into cells may alter potassium transport in the intact animal.
Adrenalectomy↗
Involvement of beta 3-adrenoceptor in the relaxation response in guinea pig taenia caecum.
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.
Adrenergic beta-Antagonists↗
Signal transduction pathway involved in beta 3-adrenoceptor-mediated relaxation in guinea pig taenia caecum.
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.
Adenylyl Cyclases↗
Effects of alpha, beta 1, and beta 2 adrenergic antagonists on the Na and K concentrations of sympathetic-nerve stimulated rat saliva.
Selective alpha and beta 1 and beta 2 adrenergic antagonists were used with electrical stimulation of the sympathetic innervation to parotid and submandibular glands of rats in order to delineate the role of the beta 1 and beta 2 adrenoceptors in regulation of salivary flow rate, Na reabsorption and K secretion from these glands. In parotid gland, [Na] of sympathetically evoked saliva in the presence of phentolamine (3 mg/kg, i.p.) was not different from that of nerve-evoked saliva in the presence of phentolamine and butoxamine (3 mg/kg, i.p.), except for the last 20 min of stimulation when [Na] of nerve-elicited saliva was higher. [K] of saliva with sympathetically evoked stimulation was the same in the presence of phentolamine alone as it was or in the presence of phentolamine and butoxamine. Again, there was no difference in salivary flow rate induced by either kind of stimulation, except for the first 10 min of stimulation, during which salivary flow rate of nerve-evoked saliva in the presence of phentolamine was lower than under the other conditions indicated. On the other hand, with submandibular gland, [Na] and [K] of nerve-elicited saliva in the presence of phentolamine were generally higher than levels of sympathetically evoked saliva in the presence of phentolamine and butoxamine. However, salivary flow rate of nerve-evoked saliva in the presence of phentolamine was generally lower than that of sympathetically evoked saliva in the presence of phentolamine and butoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Stimulation of beta-adrenoceptors activates astrocytes and provides neuroprotection.
Our previous studies established that induction of growth factor synthesis and neuroprotection by the beta(2)-adrenoceptor agonist clenbuterol in vitro and in vivo was associated with the activation of astrocytes, the major source of trophic factors in the brain. In the present study, we further investigated the specificity of beta(2)-adrenoceptor-mediated effects on astrocyte activation and neuroprotection. In mixed hippocampal cultures neuroprotection against glutamate-induced cell death by clenbuterol (1 microM) was blocked by the beta(1/2)-adrenoceptor antagonist propranolol and the specific beta(2)-adrenoceptor antagonists 1-[2,3-(Dihydro-7-methyl-1H-inden-4-yl)-oxy]-3-[(1-methylethyl)-amino]-2-butanol (ICI 118,551, 10 microM) and butoxamine (10 microM), while the beta(1)-adrenoceptor-selective antagonist metoprolol (10 microM) showed no effect. The beta(2)-adrenoceptor agonists clenbuterol (1-100 microM) and salmeterol (0.01-1 microM) induced profound morphological changes of cultured astrocytes which transformed into activated astroglia with pronounced dendrite-like processes. This phenomenon was blocked by butoxamine (1 mM) and propranolol (10 microM), but not by metoprolol (10 microM). However, similar morphological changes in astrocytes were also observed after stimulation of beta(1)-adrenoceptors by dobutamine (1-10 microM) and norepinephrine (1-10 microM). This effect was blocked by propranolol (10 microM) and metoprolol (10 microM) but not by butoxamine (1 mM), suggesting that stimulation of either beta(1)- or beta(2)-adrenoceptors was sufficient to induce activation of astrocytes. In addition, beta(1)-adrenoceptor stimulation by dobutamine (1-10 microM) protected hippocampal neurons against glutamate toxicity. In a model of focal cerebral ischemia in mice the cerebroprotective effect of clenbuterol (0.3 mg/kg) was blocked by propranolol (5 mg/kg) and butoxamine (5 mg/kg). Interestingly, the infarct size was reduced after co-treatment with clenbuterol (0.3 mg/kg) and metoprolol (5 mg/kg) as compared to clenbuterol treatment (0.3 mg/kg) alone. In conclusion, activation of astrocytes and neuroprotection can be achieved by stimulation of either beta(1)- or beta(2)-adrenoceptors in vitro, whereas in vivo neuroprotection is preferentially mediated through beta(2)-adrenoceptors.
Adrenergic beta-Agonists↗
The beta adrenergic receptors of chromatophores of the frog, Rana pipiens.
The isolated skin of Rana pipiens was found to be a suitable model for the quantitative study of chromatophore beta adrenergic receptors uninfluenced by prejunctional phenomena. Cumulative concentration-response curves for adrenergic agonists were obtained in preparations in which effective alpha adrenergic blockade had been produced with phenoxybenzamine. The beta adrenergic agonists darkened the preparation, as did melanocyte-stimulating hormone, but the maximum effects differed. The maximum of the l-isoproterenol cumulative concentration-response curve was approximately 50% less than that of melanocyte-stimulating hormone, while the maxima for l-epinephrine and l-norepinephrine were significantly less than that for isoproterenol. Microscopic examination revealed a qualitative difference: while maximal darkening produced by melanocyte-stimulating hormone was associated with maximal changes in both interspot melanophores and iridophores, maximal adrenergic-induced darkening was associated with maximal iridophore granule concentration only. No qualitative differences could be observed in the darkening caused by the three adrenergic agonists. The beta adrenergic potencies of l-norepinephrine and l-isoproterenol relative to l-epinephrine were determined by four-point bioassay. Isoproterenol was found to be 138 times as potent as epinephrine, while norepinephrine was 4 times as potent. Similarly, antagonism of isoproterenol-induced darkening of phenoxybenzamine-pretreated skin samples by the beta adrenergic blocking agents dl-propranolol, dl-sotalol, dl-practolol, l-butoxamine and d-butoxamine was studied, and their KB and pA2 values, respectively, were found to be: dl-propranolol (1.44 X 10(-8)M, 7.81); dl-sotalol (7.25 X 10(-8)M, 7.23); l-butoxamine (6.92 X 10(-6)M, 5.10); dl-practolol (1.91 X 10(-5)M, 4.96); d-butoxamine (no activity). Comparison of the potency ratios and pA2 values cited above with similar parameters obtained by other investigators in several mammalian tissues suggests that there is wide variation among beta adrenergic receptors.
Adrenergic beta-Agonists↗
Effect of beta-adrenergic antagonists on experimentally induced drinking in female rats.
The nonspecific beta-adrenergic antagonist d,l propranolol, the specific beta 1-adrenergic antagonist atenolol, and the specific beta 2-adrenergic antagonist butoxamine were administered intraperitoneally (IP) to ovariectomized female rats in order to determine the role of beta-adrenergic receptors in drinking. D,l propranolol and atenolol administered at doses of 6, 12, and 18 mg/kg significantly attenuated the one-hour water intakes of rats administered angiotensin II (200 micrograms/kg, SC) and the water intakes of rats deprived of water for 24 hours. D propranolol, which has little beta-adrenergic blocking ability, administered at doses of 6 and 12 mg/kg, and butoxamine, administered at doses of 25 and 35 mg/kg, had no significant effects on the water intakes of angiotensin II treated or water deprived rats. Regardless of the dose, d,l propranolol, atenolol, and butoxamine failed to significantly alter the water intakes of rats administered 1.0 M NaCl (10 ml/kg, IP) The results provide evidence that beta 1-adrenergic receptors, but not beta 2-adrenergic receptors, are involved in mediating the increased water intakes induced by angiotensin II and water deprivation. On the other hand the increased water intake due to administration of hypertonic saline does not appear to mediated by beta-adrenergic receptors.
Adrenergic beta-Antagonists↗
Effect of beta-adrenergic antagonists on the spontaneous appetite for NaCl solution in rats.
Chronic dietary administration of the beta-adrenergic antagonist, propranolol (1.6-2.0 g/kg), to both male and female rats induced an appetite for 0.25 M NaCl solution when the rats were offered a choice between distilled water and salt solution to drink. Treatment was also accompanied by a significant reduction in both water and food intakes. In addition, increases in intake of NaCl solution during treatment with propranolol were correlated significantly with increases in urinary sodium output. To test for completeness of beta-adrenergic blockade, treated and control rats in the first study were administered isoproterenol (25 micrograms/kg b.w., SC) acutely and given only water to drink. The increased 1 hr water intake characteristically accompanying acute administration of isoproterenol was blocked completely by propranolol. Additional experiments were carried out with butoxamine, a selective beta 2-adrenoceptor antagonist, (1.5 and 3.0 g/kg of food) to determine its effect on intake of 0.25 M NaCl solution. Butoxamine failed to produce a significant effect on salt appetite. The results indicate that chronic treatment with propranolol, but not butoxamine, induces an appetite for NaCl solution. They further suggest, but do not prove, that beta 1-adrenoceptors may be involved in the appetite for NaCl solutions in rats.
Adrenergic beta-Agonists↗
Dynamic behavior of fully solvated beta2-adrenergic receptor, embedded in the membrane with bound agonist or antagonist.
Recently we predicted the 3D structure of the human beta2-adrenergic receptor (beta2AR) and of the binding site of several agonists and antagonists to beta2AR. These predictions (MembStruk and HierDock) included no explicit water and only a few lipid molecules. Here we include explicit H(2)O and an infinite lipid bilayer membrane in molecular dynamics (MD) simulations of three systems: apo-beta2AR, epinephrine-bound beta2AR, and butoxamine-bound beta2AR (epinephrine is an endogenous agonist, and butoxamine is a beta2AR selective antagonist). The predicted structures for apo-beta2AR and butoxamine-beta2AR are stable in MD, but in epinephrine-beta2AR, extracellular water trickles into the binding pocket to mediate hydrogen bonding between the catechol of epinephrine and Ser-204 on helix 5. The epinephrine-beta2AR structure shows dynamic flexibility with small, piston-like movements of helices 3 and 6 and transient interhelical hydrogen bonding between Ser-165 on transmembrane 4 and Ser-207 on transmembrane 5. These couplings and motions may play a role in protein activation. The apo-beta2AR shows less dynamic flexibility, whereas the antagonist-beta2AR structure is quite rigid. This MD validation of the structure predictions for G protein-coupled receptors in explicit lipid and water suggests that these methods can be trusted for studying the mechanism of activation and the design of subtype-specific agonists and antagonists.
Adrenergic beta-2 Receptor Agonists↗