内源和外源去甲肾上腺素对自家血灌流毁脑脊髓大鼠肾血管平滑肌的作用

本实验用颈动脉血恒速满流毁脑脊髓大鼠(pithed rat)单侧肾脏的方法,观察了高度选择性α_1受体阻断剂哌唑嗪和α_2受体阻断剂育亨宾与去甲肾上腺素、肾上腺素及电刺激肾交感神经对肾血管平滑肌的相互作用。哌唑嗪明显抑制电刺激引起肾灌流压升高,但尚存留一小部分既不能被增加哌唑嗪的剂量所阻断也不能被育亨宾所阻断。由肾动脉直接注射去甲肾上腺素和肾上腺素引起灌流压升高作用的绝大部分可被哌唑嗪所阻断,所存留的一小部分又可被育亨宾所阻断。结果提示,在肾血管平滑肌突触后膜存α_1在和α_2两种受体亚型,以α_1受体为主,但也有很小比例的α_2受体。     

大鼠血管中α_1肾上腺素受体的两种亚型

α_1肾上腺素受体(α_1受体)激动引起的大鼠离体血管收缩,在主动脉可为不可逆性α_1受体拮抗剂CEC大部分阻断,而不受钙离子拮抗剂硝苯吡啶的影响;在肾动脉不受CEC阻断,却可为硝苯吡啶大部分阻断;在肠系膜动脉与门静脉则介于两者之间。竞争性α_1受体拮抗剂WB4101的pA_2值,肾动脉>肠系膜动脉>主动脉。根据已知α_1受体两种亚型的药理特征,上述结果提示大鼠血管中的α_1受体存在两种亚型,在主动脉内以α_(1b)亚型为主,在肾动脉内以α_(1a)亚型为主,在肠系膜动脉与门静脉内两种亚型的含量较为均衡。     

用6OHDA处理新生大鼠对脑皮层α_1和α_2受体的影响

不少作者用[~3H]二氢麦角隐亭(Dihydroergo-cryptine)与中枢神经系统α受体结合的方法,证明鼠脑中存在两类α受体,即α_1和α_2。作者用6OHDA(10Omg/kg)处理新生大鼠,以[~3H]可乐定(α_2激动剂)和[~3H]哌唑嗪(α_1拮抗剂)测定皮层膜α_1和α_2受体结合数,以观察α_1,α_2受体在大鼠皮层的确切解剖部位。     

1-(对羟苄基)-N-甲基-6-甲氧基-7-羟基异喹啉对α肾上腺素受体的作用

在大鼠输精管上,BMIQ 10μmol/L和YHB 1μmol/L都能使CLN的量效曲线平行右移,最大反应不变,表明二者均能竞争性地阻断突触前α_2受体,其pA_2值分别为6.69和7.8.大鼠肛尾肌实验表明,BMIQ亦有竞争性拮抗突触后α_1受体作用,pA_2值为5.14。其α_2/α_1阻断作用之比率为35.5,说明BMIQ对α_2受体的选择性大于α_1受体.BMIQ和YHB在毁脊髓大鼠标本上,均能使B—HT920升高舒张血压的量效曲线平行右移,最大反应不变.二者的剂量比率分别为2.7和14.8,且BMIQ抗突触后膜α_2受体作用仅为YHB的1/5.5。     

特拉唑嗪(Terazosin)(一种研制中的抗高血压药)

特拉唑嗪是喹唑啉类的一种抗高血压药。化学结构类似于哌唑嗪,它溶于水并以两种对映体形式存在。药理学特拉唑嗪因选择性阻断α_1-肾上腺素受体而呈现抗高血压作用。它是通过阻断位于血管平滑肌中的这些受体,松弛     

1-(2,6-二甲基苯氧基)-2-(3,4-二甲氧基苯乙氨基)丙烷盐酸盐对大鼠及肝硬化模型犬门静脉血液动力学的影响

本文观察了DDPH对正常大鼠及肝硬化模型犬门静脉血液动力学的影响,发现DDPH能阻断α_1受体激功剂脱羟肾上腺素(Phen)对大鼠门静脉血管床的收缩作用,DDPH能明显降低肝硬化犬的门静脉血管阻力及门静脉压力,结果证明肝脏门静脉血管床以α_1受体调节为主,DDPH通过阻断门静脉血管床的α_1,受体,而发挥其降低犬硬化肝脏的门静脉血管阻力及门静脉压力的作用。     

CVLM咪唑啉-I和α_2-肾上腺素受体共同参与可乐定的降压效应

目的　探讨大鼠尾端延髓腹外侧区 (CVLM)咪唑啉 I受体 (I1R)和α2 肾上腺素受体 (α2 AR)在介导可乐定中枢降压机制中的作用。方法　在氨基甲酸乙酯麻醉SD大鼠中 ,观察CVLM内局部给予I1R和α2 AR阻断剂后对基础血压(BP)、心率 (HR)以及外周给予可乐定导致降压效应的变化。结果　双侧CVLM分别微量注射选择性α2 AR阻断剂育亨宾 (单侧剂量 5 0 0 pmol·L-1,10 0nl,n =8)或I1R和α2 AR混合性阻断剂idazoxan(单侧剂量 2nmol·L-1,10 0nl,n =10 )后不仅明显降低BP和HR(P <0 0 1) ,而且能明显减弱静脉给予可乐定 (5 μg·kg-1)导致的降压效应 (P <0 0 1) ,此外 ,idazoxan对可乐定降压效应的减弱作用高于育亨宾 (P <0 0 1)。结论　CVLM内I1R和α2 AR共同参与维持紧张性心血管活动和介导可乐定的降压效应     

右旋美托咪啶在神经外科麻醉中的应用

右旋美托咪啶(dexmedetomidine,DEX)是一种新型的α2肾上腺素能受体激动剂。与可乐定相比较,DEX是一种高选择性、高特异性α2受体激动剂,受体选择性(α2∶α1)DEX为1620∶1,可乐定为220∶1,DEX的活性强于可乐定,其分布半衰期约5min,清除半衰期约2h[1]。由于DEX具有剂量依赖     

可乐定对苯二氮受体激动剂和反相激动剂与大鼠皮层受体结合特性的影响(英文)

本研究旨在探讨α_2受体激动剂可乐定对苯二氮(艹卓)受体激动剂抗焦虑和反相激动剂致焦虑作用影响的可能的分子机理。在10nmol/L至1μmol/L浓度范围内,可乐定对[~3H]氟硝安定与大鼠皮层相应受体低亲和位点结合无显著影响,但非竞争性拮抗其与高亲和位点的结合。在竞争取代实验中,激动剂安定和CL218 872均表现为双位点结合的亲和力,对低亲和位点无显著影响。反相激动剂DMCM竞争结合曲线亦具有双位点结合特性。可乐定可使这种双位点结合转变成三位点结合,出现一个超高亲和位点。可乐定对拮抗剂Ro15-1788竞争结合特性无显著影响。结果提示,α_2受体激动剂可乐定与受体结合可能导致与之相邻的苯二氮(艹卓)受体发生构象变化,这种构象变化有利于激动剂与受体结合,而不利于反相激动剂的结合。     

α_1和α_2肾上腺素受体激动剂对大鼠左心房肌生理特性的影响

本文观察了选择性α_1肾上腺素受体激动剂苯福林和α_2肾上腺素受体激动剂B-HT933对大鼠左心房肌收缩性、兴奋性、自律性和功能性不应期的影响。苯福林在大鼠左心房肌标本上可致明显的正性肌力作用,同时可提高肾上腺素诱发的左房自律性、延长功能性不应期,这些作用可明显地被哌唑嗪所拮抗。但苯福林对大鼠左心房兴奋性无影响。B-HT933在同样实验条件下对大鼠左房收缩性、兴奋性、自律性和功能性不应期无影响。实验表明,突触后膜α受体兴奋所致的心脏作用由α_1亚型介导,但未能证实突触后膜α_2受体在大鼠左心房上具有功能性的作用。     

Clonidine inhibits itch-related response through stimulation of α(2)-adrenoceptors in the spinal cord in mice

The present study investigated whether clonidine – an α₂-adrenoceptor agonist known to relieve pain – is able to suppress itch-related behavior in mice. An intraplantar injection of serotonin induced biting (an itch-related response), which was inhibited by intraperitoneal and intrathecal, but not intraplantar or intracisternal, clonidine injections. The effect of intrathecal clonidine was inhibited by intrathecal injections of phentolamine (a non-selective α-adrenoceptor antagonist) and yohimbine (a selective α₂-adrenoceptor antagonist), but not by prazosin (a selective α₁-adrenoceptor antagonist). The effect of intraperitoneal clonidine was also inhibited by intrathecal yohimbine. These results suggest that clonidine is an effective antipruritic agent and that the effect is mainly mediated by the stimulation of α₂-adrenoceptors in the dorsal horn.     

THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α-ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α-adrenoceptor antagonists. The agonist used was phenylephrine. 2. Enalaprilat (1 μmol/L) potentiated the competitive α₁-adrenoceptor antagonist actions of phentolamine (10–100 nmol/L) and yohimbine (0.3–3.0 μmol/L) as well as the non-competitive antagonist action of phenoxybenzamine (50–100 pmol/L). 3. The competitive α₁-adrenoceptor antagonist action of prazosin (1–10 nmol/L) was not affected by enalaprilat. 4. For the competitive α₁-adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat. 5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle α₁-adrenoceptor function.     

The interaction between prazosin and clonidine at alpha-adrenoceptors in rats and cats.

In pithed rats prazosin (10μg/kg, i.v.) caused a prolonged antagonism of the hypertensive response to clonidine and (?)-noradrenaline, probably due to inhibition of vascular, postsynaptic α-adrenoceptors. The clonidine-induced reduction of the tachycardia evoked in pithed rats by electrical stimulation of cardiac sympathetic nerve fibres was antagonized by piperoxan and less effectively by prazosin, thus suggesting that prazosin displays a modest degree of cardiac presynaptic α-adrenoceptor blocking activity apart from its predominantly postsynaptic affinity. Prazosin (1 mg/kg, i.p.) significantly affected the hypotensive effect of clinidine (2 and 6 μg/kg, i.v.), but not the bradycardia induced by clonidine in pentobarbitone-anaesthetized, normotensive rats. Prazosin proved to be an effective hypotensive drug in anaesthetized cats. This action was peripheral as no central nervous origin could be demonstrated. Prazosin in low doses significantly reduced the central hypotensive effect of clonidine (1 μg/kg), injected into the left vertebral artery of chloralose-anaesthethized cats. Since the intravenous pretreatment with low doses of prazosin did not alter the central hypotensive response to clonidine, the interaction was likely to have occured within the brain-stem. Presumably, postsynaptic α-adrenoceptors in the brain, similarly to those in the periphery are inhibited by prazpsin, thereby preventing the central hypotensive effect of clonidine. It is submitted that clonidine and prazosin should not be combined in antihypertensive therapy in patients.     

The effects of alpha-adrenoceptor agonists on intracellular Ca2+ levels in freshly dispersed single smooth muscle cells from rat tail artery.

1. The presence of functional alpha-adrenoceptors in freshly dispersed single smooth muscle cells from rat tail arteries was investigated by use of selective alpha-adrenoceptor agonists and antagonists. 2. Cirazoline, a selective alpha 1-adrenoceptor agonist, caused a prazosin-sensitive, rapid but transient increase in intracellular Ca2+, which was partially inhibited by the voltage-dependent Ca2+ channel blocker, nifedipine. 3. TL99, an alpha 2-adrenoceptor agonist, in the presence of prazosin, initiated a slow and sustained increase in intracellular Ca2+ which was partially inhibited by yohimbine and almost completely blocked by nifedipine. 4. In rat tail artery, the effects (dose-response and time-response curves) of cirazoline and TL99 on intracellular Ca2+ levels in freshly dispersed single smooth muscle cells were comparable with those obtained with organ bath studies of ring preparations of artery. 5. In freshly dispersed single smooth muscle cells, the time-course response curves induced by the selective alpha 1-adrenoceptor agonist, phenylephrine and the selective alpha 2-adrenoceptor agonist, UK14304, were similar to those observed with cirazoline and TL99, respectively. 6. These results indicate that: (a) functional alpha 1- and alpha 2-adrenoceptors are present in freshly dispersed single smooth muscle cells from rat tail artery and (b) alpha 1- and alpha 2-adrenoceptors are coupled to different cellular processes that lead to an increase in intracellular Ca2+.     

Pharmacological characterization of presynaptic alpha-adrenoceptors in the modulation of the 5-hydroxytryptamine release from vascular adrenergic nerves in the rat

The role of presynaptic alpha-adrenoceptors in modulation of the 5-hydroxytryptamine (5-HT) release from vascular adrenergic nerves was investigated in the perfused mesenteric vascular bed of the rat. After treatment with 5-HT (10 microM) for 15 min, the vasoconstrictor response to periarterial nerve stimulation (PNS, 4 to 16 Hz, 2 msec in duration for 30 sec) was greatly potentiated without significantly affecting the pressor response to exogenously administered noradrenaline (0.5 nmol). The potentiating effect was more pronounced at low frequencies of PNS (4 and 8 Hz). The potentiation of the pressor response to PNS after 5-HT treatment did not occur in the presence of LY53857 (0.01 microM), a selective 5-HT2 receptor antagonist. The enhanced pressor response to PNS seen after 5-HT treatment was further exaggerated in the presence of clonidine (0.1 and 1 microM), a preferential alpha 2-adrenoceptor agonist, while methoxamine (1 and 10 microM), a selective alpha 1-adrenoceptor agonist, did not affect the enhanced PNS response. This effect of clonidine was more pronounced in low frequencies of PNS (4 and 8 Hz) and was abolished by LY53857 (0.01 microM). In the perfused mesenteric vascular bed labelled with [3H]-5-HT, PNS (8 Hz) evoked an increase of tritium efflux in the perfusate. The PNS-evoked tritium efflux was facilitated by yohimbine (0.1 to 1 microM), an alpha 2-adrenoceptor antagonist, and prazosin, a selective alpha 1-adrenoceptor antagonist, at a high concentration (1 microM), while LY53857 (0.01 to 0.1 microM) and a low concentration of prazosin (0.1 microM) had no effect on the tritium efflux. Clonidine (0.01 to 1 microM) produced a dose-dependent increase of PNS-evoked tritium efflux, while methoxamine (0.1 to 10 microM) was without effect. The monoamine uptake inhibitor, cocaine (10 microM) produced a significant inhibition of the PNS-evoked tritium efflux. The effects of clonidine and cocaine on the PNS-evoked tritium efflux were antagonized by yohimbine (1 microM). These results suggest that the release of 5-HT from adrenergic nerve endings by PNS is modulated by presynaptic alpha 2-adrenoceptors.     

Lack of effect of D600 on alpha 1-adrenoceptor-mediated contractions of rat isolated anococcygeus muscle

The experiments concerned the contractile responses of rat anococcygeus muscle to the selective alpha 1-adrenoceptor agonists cirazoline, phenylephrine, methoxamine, St 587, Sgd 101/75, amidephrine and SK&F 89748-A and the effect of the calcium entry blocker D600 on the responses. The effects of noradrenaline, adrenaline, K+, tyramine and electrical field stimulation were studied as well. The potency series of the various agonists on rat anococcygeus muscle differed from the series for rat and guinea-pig aorta, indicating differences in the structure of the alpha 1-adrenoceptors on these tissues. D600 was ineffective in inhibiting contractions of rat anococcygeus muscle to the various agonists, but effectively attenuated the responses to K+ in anococcygeus muscle from rats pretreated with reserpine or in prazosin-induced preparations. These data indicate that alpha 1-adrenoceptor activation in rat anococcygeus muscle triggers contractions which do not primarily require the influx of extracellular calcium. In this respect, the smooth muscle from the rat anococcygeus muscle differs from vascular smooth muscle from this species.     

Characterization of the alpha-adrenoceptors in the female rabbit urethra.

A radioligand binding technique was used to evaluate the proportions of alpha 1- and alpha 2-adrenoceptors in crude membrane preparations obtained from the female rabbit bladder base and urethra. In addition, urethral rings were studied in vitro in an attempt to determine if alpha 1- and/or alpha 2-adrenoceptors are located postjunctionally in the urethral smooth muscle. Studies of the inhibition of [3H]-dihydroergocryptine binding by the selective alpha 1-adrenoceptor antagonist prazosin or the selective alpha 2-adrenoceptor antagonist rauwolscine revealed the alpha-adrenoceptor population to consist of approximately 25% alpha 1-adrenoceptors and 75% alpha 2-adrenoceptors. These proportions were confirmed in saturation studies with [3H]-prazosin and [3H]-rauwolscine. The sum of alpha 1- and alpha 2-adrenoceptors labelled by these selective alpha 1- and alpha 2-adrenoceptor antagonists was about equal to the number labelled by the non-selective alpha-adrenoceptor antagonist [3H]-dihydroergocryptine. Noradrenaline, as well as the selective alpha 1-adrenoceptor agonist phenylephrine and the selective alpha 2-adrenoceptor agonist clonidine, induced contractions of urethral ring preparations. Prazosin blocked contractions induced by phenylephrine to a greater extent than contractions induced by clonidine. The opposite was true for the inhibitory effect of rauwolscine. In addition to showing that both alpha 1- and alpha 2-adrenoceptor binding sites exist in membrane preparations of the rabbit bladder base and urethra, the results reveal the presence of both adrenoceptor subtypes postjunctionally in the rabbit urethra; and both mediate contraction of the smooth muscle.     

Alpha 2-adrenoceptor agonists enhance responses to certain other vasoconstrictor agonists in the rat tail artery.

1. The effects of the alpha2-adrenoceptor agonists clonidine, rilmenidine, TL99 and UK14304 on the vasoconstrictor response to sympathetic nerve stimulation and on the concentration-response curves to noradrenaline and phenylephrine were compared in two isolated, perfused vascular tissues: the rat tail artery (which has both postjunctional alpha 1- and alpha 2-adrenoceptors), and the rabbit ear artery (in which only alpha 1-adrenoceptors are present postjunctionally). 2. In the rabbit ear artery, the first observable effect of alpha 2-adrenoceptor agonists was inhibition of vasoconstrictor responses to sympathetic nerve stimulation. This occurred with concentrations of the alpha 2-adrenoceptor agonists which were far below those producing vasoconstriction. Responses to noradrenaline were not affected. 3. In contrast, in the rat isolated perfused tail artery, alpha 2-adrenoceptor agonists, in concentrations that produced no other observable effects, enhanced the vasoconstrictor responses to sympathetic nerve stimulation and to noradrenaline. Much higher concentrations of alpha 2-adrenoceptor agonists produced vasoconstriction in most preparations and only then reduced the response to sympathetic nerve stimulation. The enhancing effect of alpha 2-adrenoceptor agonists was blocked by idazoxan, but not by prazosin. 4. Vasoconstrictor responses in the rat tail artery to the relatively selective alpha 1-adrenoceptor agonist phenylephrine were enhanced by alpha 2-adrenoceptor agonists. The enhancement of the response to phenylephrine was greater than that to the mixed alpha 1- and alpha 2-adrenoceptor agonist noradrenaline. 5. Vasoconstrictor responses in the rat tail artery to vasopressin, ATP and KCl, like those to alpha 1-adrenoceptor agonists, were enhanced by alpha 2-adrenoceptor agonists.2+owever, vasoconstrictor responses to     

CONTRIBUTION OF α2-ADRENOCEPTORS TO THE CENTRAL CARDIOVASCULAR EFFECTS OF CLONIDINE AND S 8350 IN ANAESTHETIZED RATS

1. The α₂-adrenoceptor agonist clonidine elicits centrally mediated effects through an interaction with both α₂-adrenoceptors and imidazoline binding sites. 2. We selected a new oxazoline derivative, S 8350, which competes with [³H]-yohimbine for binding to cerebral α₂-adrenoceptors (IC₅₀, 67 ± 17 nmol/L) and displays a higher affinity (35-fold) for α₂- than for α₁-adrenoceptors. 3. As observed for clonidine, intravenous (i.v.) administration of S 8350 resulted in a brief pressor effect followed by a prolonged hypotension. When S 8350 was administered i.v. to spinally pithed rats, only a rise in blood pressure was observed. 4. In order to discriminate the cardiovascular effects related to the central imidazoline receptor or α₂-adrenoceptor activation, the effects of intracisternal (i.c.) administration of clonidine and S 8350 were investigated in the rat. 5. In the anaesthetized rat, both clonidine and S 8350 displayed a profound central (i.c. route) hypotensive effect associated with a bradycardia. 6. The cardiovascular effects of S 8350 were abolished by the central administration of the selective α₂-adrenoceptor antagonist rauwolscine. Conversely, rauwolscine completely prevented bradycardia but it induced only a partial reversion of the hypotension elicited by clonidine. 7. These results suggest that central α₂-adrenoceptors are responsible for hypotension and bradycardia while imidazoline binding sites do not apparently contribute to heart rate control.