• The Korean Journal of Physiology and Pharmacology
• /
• 제27권4호
• /
• pp.325-331
• /
• 2023

α₁-adrenoceptors link via the G-protein Gq/G₁₁ to both Ca²⁺ entry and release from stores, but may also activate Rho kinase, which causes calcium sensitization. This study aimed to identify the subtype(s) of α₁-adrenoceptor involved in Rho kinase-mediated responses in both rat aorta and mouse spleen, tissues in which contractions involve multiple subtypes of α₁-adrenoceptor. Tissues were contracted with cumulative concentrations of noradrenaline (NA) in 0.5 log unit increments, before and in the presence of an antagonist or vehicle. Contractions produced by NA in rat aorta are entirely α₁-adrenoceptor mediated as they are competitively blocked by prazosin. The α_1A-adrenoceptor antagonist RS100329 had low potency in rat aorta. The α_1D-adrenoceptor antagonist BMY7378 antagonized contractions in rat aorta in a biphasic manner: low concentrations blocking α_1D-adrenoceptors and high concentrations blocking α_1B-adrenoceptors. The Rho kinase inhibitor fasudil (10 µM) significantly reduced aortic contractions in terms of maximum response, suggesting inhibition of α_1B-adrenoceptor mediated responses. In the mouse spleen, a tissue in which all 3 subtypes of α₁-adrenoceptor are involved in contractions to NA, fasudil (3 µM) significantly reduced both early and late components to the NA contraction, the early component involving α_1B- and α_1D-adrenoceptors, and the late component involving α_1B- and α_1A-adrenoceptors. This suggests that fasudil inhibits α_1B-adrenoceptor mediated responses. It is concluded that α_1D- and α_1B-adrenoceptors interact in rat aorta and α_1D-, α_1A- and α_1B-adrenoceptors interact in the mouse spleen to produce contractions and these interactions suggest that one of the receptors preferentially activates Rho kinase, most likely the α_1B-adrenoceptor.

• Archives of Pharmacal Research
• /
• 제28권12호
• /
• pp.1317-1323
• /
• 2005

In an attempt to examine the ability of benzisothiazole-based drugs to interact with $\beta$-adrenoceptors, a series of 1,2-benzisothiazole derivatives, which were substituted with various propanolamine or oxypropanolamine side chains in the 2 or 3 position, were synthesised and tested. The pharmacological activity of these compounds at the ,$\beta$-adrenoceptors was examined using isolated rat atria and small intestinal segments, which preferentially express the $\beta_{1}$- and $\beta_{3}$-adrenoceptor-mediated responses, respectively. None of these products showed any $\beta$-adrenoceptor agonistic activity. In contrast, the 2- and 3-substituted isopropyl, tert-butyl, benzyl, and piperonyl derivatives 2a-d and 3a-d elicited surmountable inhibition of the isoprena­line-induced chronotropic effects in the atria, suggesting competitive antagonism at the $\beta_{1}$­recognition site. The $pA_{2}$ values revealed tert-butyl 3b and the isopropyl substituted piperonyl derivatives 3a to be the most effective. Remarkably, many of the 2-substituted propanolamines were less active than the corresponding 3-substituted oxypropanolamines. With the exception of compound 3b, none of these drugs antagonised the muscle relaxant activity of isoprenaline in the intestine, suggesting no effect on the $\beta_{3}$-adrenoceptors. These results confirm the ability of the benzisothiazole ring to interact with the $\beta$-adrenoceptors, and demonstrate that 2-substitution with propanolamine or 3-substitution with oxypropanolamine groups yields compounds with preferential antagonistic activity at the cardiac $\beta_{1}$adrenoceptors. The degree of antagonism depends strongly on both the nature of the substituent and its position on the benzisothiazole ring.

• 약학회지
• /
• 제32권2호
• /
• pp.129-136
• /
• 1988

Effects of the selective alpha-adrenoceptor agonists, clonidine, oxymetazoline and phenylephrine, on heart rate and contractile force were investigated in the isolated frog atria and it was attempted to examine the influence of adrenoceptor antagonist upon those. Clonidine produced dose-dependent negative chronotropic and positive inotropic effects. The negative chronotropic effect was significantly attenuated in the presence of prazosin and yohimbine but not propranolol. The positive inotropic effect was significantly attenuated by prazosin, yohimbine and propranolol. Oxymetazoline produced dose-dependent negative chronotropic and inotropic effects. The negative chronotropic effect was significantly attenuated in the presence of prazosin, which was partially augmented by yohimbine but was not affected by propranolol. The negative inotropic effect was not affected by propranolol but it was partially augmented by yohimbine and was partially attenuated by prazosin. Phenylephrine produced dose-dependent positive chronotropic and inotropic effects. The positive chronotropic and inotropic effect were significantly attenuated in the presence of propranolol but were not affected by prazosin and yohimbine. These results suggest that the negative chronotropic effect by clonidine and oxymetazoline is mediated by alpha-adrenoceptors, the positive chronotropic and inotropic effects by phenylephrine are mediated by beta-adrenoceptors, and alpha-adrenoceptors mediated the inhibitory chronotropic responses exists in the isolated frog atria.

• Archives of Pharmacal Research
• /
• 제23권4호
• /
• pp.353-359
• /
• 2000

${\alpha}_2$-Adrenoceptor antagonists, which can enhance synaptic norepinephrine levels by blocking feedback inhibition processes, are potentially useful in the treatment of disease states such. as depression, memory impairment, impotence and sexual dysfunction. (10bS)-1,2,3,5,6,10b-Hexahydropyrrolo[2,1-a]isoquinoline oxalate (YSL-3S) was evaluated in several in vitro biological tests to establish its pharmacological profile of activities as an ${\alpha}_2$-adrenoceptor antagonist. Saturation binding assay revealed that$^{3}[H]$rauwolscine bound to the $\alpha$$_2$-adrenoceptors with a Kd value of 6.3$\pm$0.5 nM and a Bmax value of 25l$\pm$39 fmol/mg protein in rat cortical synaptic membranes. Competitive binding assay showed that YSL-3S inhibited the binding of$^3[H]$rauwolscine (1 nM) in a concentration-dependent manner with a Ki value of 98.2$\pm$12.1 nM while it did not inhibit the binding of [$^3$H]cytisine (1.25 nM) to neuronal nicotinic cholinergic receptors. The Ki values of yohimbine, clonidine and norepinephrine for $^3[H]$rauwolscine binding were 15.8$\pm$1.0, 40.1$\pm$5.9 and 40.0$\pm$11.5 nM, respectively. In addition, the binding affinity of YSL-3S for ${\alpha}_2$-adrenoceptors was higher than that of its antipode and the racemic mixture. The functional activity of YSL-3S at the presynaptic ${\alpha}_2$-adrenoceptors was assessed using the prostatic portion of the rat vas deferens. Clonidine inhibited field-stimulated contractions of the vas deference in a dose-dependent manner. The presence of YSL-3S or yohimbine caused a parallel, rightward the dose-response curve of clonidine in a dose-dependent manner, indicating an antagonistic action at the presynaptic ${\alpha}_2$-adrenoceptors. The $pA_2$values of yohimbine and YSL-3S were 7.66$\pm$0.13 and 6.64$\pm$0.18, respectively. The results indicate that YSL-3S acts as a competitive antagonist at presynaptic ${\alpha}_2$ -adrenoceptors with a potency approximately ten times lower than yohimbine, but is devoid of binding affinity for neuronal nicotinic cholinergic receptors.

• 약학회지
• /
• 제30권3호
• /
• pp.157-162
• /
• 1986

$\alpha$-Adrenoceptor subtypes in the isolated rat aortic strips were examined by using agonists and antagonists which have varying selectivity for $\alpha_1$- and $\alpha_2$- adrenoceptors. Norepinephrine and phenylephrine produced a similar magnitude of maximum contractions. $pA_2$ values for prazosin and yohimbine were not significantly different using norepinephrine or phenylephrine as the agonist, suggesting a single population of alpha-adrenoceptor. Contractile responses produced by alpha-agonists were antagonized more effectively by prazosin (approximately 1000 fold) than by yohimbine.

• 대한한의학회지
• /
• 제25권3호
• /
• pp.67-77
• /
• 2004

Objectives : Many studies have reported that acupuncture analgesia was mediated through the activation of peripheral and central opioid receptors. However, there has been little electrophysiological study on the adrenergic mechanism of acupuncture analgesia in chronic inflammatory and neuropathic pain. The present study was undertaken to elucidate the role of adrenoceptors in the production of acupuncture analgesia in the chronic pain model. Methods : In the rat with chronic inflammation and nerve injury, dorsal horn cell (DHC) responses to afferent C fiber stimulation were used as a pain index and changes in electroacupuncture (EA) analgesia were recorded before and after intravenous administration of selective adrenoceptor antagonists. EA stimulations (2Hz, 0.5msec, 3mA) were applied to the contralateral Zusanli point for 30 min. Results : EA stimulation induced long-lasting inhibition of DHC responses in the rat with chronic inflammation and nerve injury. In both models of inflammation and neuropathic pain, α-adrenoceptor antagonist (phentolamine) significantly attenuated an inhibitory effect of EA on DHC responses. Selective α2-adrenoceptor antagonist (yohimbine) also had a similar suppressive action on DHC responses to that of phentolamine. However, β-adrenoceptor antagonist (propranolol) did not have any inhibitory effect on DHC responses in either model of chronic pain. Conclusions : These experimental findings suggest that in rats with chronic pain, EA stimulation with low frequency and high intensity produced an analgesic effect which was mediated through an activation of α2-adrenoceptors.

• Archives of Pharmacal Research
• /
• 제12권4호
• /
• pp.243-248
• /
• 1989

Effects of B-HT 920 on the vagally stimulated gastric acid secretion were studied in anesthetized and gastric fistula rats. When the gastric acid secretion was increased by stimulation of the vagus nerve, B-HT 920 was partially attenuated by prazosin, $\alpha_1-$adrenoceptor antagonist and virtually abolished by yohimbine, $\alpha_2-$adrenoceptor antagonist. On the other hand, when the gastric acid secretion was increased by the infusion of bethanechol, a muscarinic parasympathetic stimulant, B-HT 920 had no effect on the bethanechol-induced gastric acid secretion. These results suggest that B-HT 920 inhibits vagally induced gastric acid secretion by activation of presynaptic $\alpha-$adrenoceptors located on the vagally stimulated pathways in the gastric wall and this effect of B-HT 920 is more related to $\alpha_2-$adrenoceptors than $\alpha_1-$adrenoceptors.

• Archives of Pharmacal Research
• /
• 제11권1호
• /
• pp.65-73
• /
• 1988

The effects of clonidine on the negative chronotropic response induced by stimulation of vagus nerve were studied in the presence of propranolol in reserpinized and anesthetized rats. When the heart rate was decreased by stimulation of the vagus nerve, clonidine significantly inhibited vagally induced heart rate decrease (negative chronotropic response) in dose dependent manner. This inhibitory effect of clonidine was virtually abolished by phentolamine, ${\alpha}_1-\;and\;{\alpha}_2-adrenoceptor$ antagonist, and partially antagonized by prazosin, ${\alpha}_1-adrenoceptor$ antagonist. On the other hand, when the heart rate was decreased by the infusion of bethanechol, a muscarinic parasympathetic stimulant, clonidine had no effect on the bethanechol-induced heart rate decrease. These results suggest that clonidine inhibits vagally induced negative chronotropic response by activation of presynaptic ${\alpha}-adrenoceptors$ located on the parasympathetic cholinergic nerve terminal in the heart and this effect of clonidine is more related to ${\alpha}_2-adrenoceptors$ than ${\alpha}_1-adrenoceptors$.

• 대한약리학회지
• /
• 제32권2호
• /
• pp.189-199
• /
• 1996

Myocardial ${\alpha}_1-adrenoceptors$ have been shown to mediate a biphaslc inotropic response that was characterized by a transient decline followed by a sustained increasing phase in guinea pig ventricular muscle. Recently one group reported that an ${\alpha}_1-adrenoceptors-induced$ intracellular $Na^+$ decrease is linked to fast $Na^+$ channel inhibition and another group reported that it is linked to $Na^+$-$K^+$ pump activation by ${\alpha}_{1b}-adrenoceptors$. But until now, its mechanism is not clear. Therefore, to see whether the $Na^+$channel or $Na^+-K^+$ pump is related to a decrease in intracellular $Na^+$ activity and/or the negative inotropic response, and which ${\alpha}_1-adrenoceptor$ subtype was involved in the decrease in intracellular $Na^+$activity by phenylephrine, we used conventional and sodium selective microelectrodes, and tension transducer to determine the effects of ${\alpha}_1-adrenergic$ stimulation on membrane potential, intracellular $Na^+$ activity, and twitch force in guinea pig ventricular muscles. $10^{-5}$ M Phenylephrine produced a slight hyperpolarization of the diastolic membrane potential, a decrease or increase in $a_N^i_a$, and a biphasic inotropic response. The negative inotropic response accompanied by a decrease in intracellular $Na^+$activity, whereas in muscles showing a remarkable positive inotropic response without initial negative inotropic effect was accompanied by an increase in intracellular $Na^+$ activity. The decrease in intracellular $Na^+$ activity was apparently inhibited by WB4101, an antagonist of the ${\alpha}_{1a}-adrenoceptors$. The decrease in intracellular $Na^+$ activity caused by phenylephrine was not abolished or reduced by a block of the fast $Na^+$ channels. $V_{max}$ also was not affected by phenylephrine. Phenylephrine produced an increase in intracellular $Na^+$ activity in the presence of a high concentration of extracellular $Ca^{2+}$ (in quiescent muscle) or phorbol dibutyrate, a protein kinase C activator(in beating muscle). These suggest that the ${\alpha}_{1a}-adrenoceptors-mediated$ decrease in intracellular $Na^+$ activity may be related to the protein kinase C.

• 대한수의학회지
• /
• 제30권3호
• /
• pp.277-281
• /
• 1990

Xylazine is commonly used for anesthesia in veterinary medicine and various adverse effects are developed. To examine if the severe hypotensive response associated with xylazine-induced anesthesia might be resulted from the stimulation of presynaptic alpha-2 adrenoceptors or the increase of vagal tone, effects of yohimbine, atropine and atropine with vagotomy on xylazine-induced severe and long-lasting hypotensive responses were investigated in rabbits. The results were summarized as follows: 1) Intravenously injected xylazine(1mg/kg)-induced hypotensive responses were inhibited by yohimbine(p<0.001). 2) Intravenously injected xylazine(1mg/kg)-induced hypotensive responses were not changed by atropine. 3) Intravenously administered xylazine(1mg/kg)-induced hypotensive responses are not changed by atropine with vagotomy. These results indicate that xylazine is thought to cause severe hypotensive response during anesthesia primarily by stimulating presynaptic alpha-2 adrenoceptors and other receptors or mechanisms may participate in the hgpotensive response of xylazine.