可乐定对自家血灌流毁脑脊髓大鼠后肢血管平滑肌的作用

本实验观察了可乐定对自家血恒速灌流的毁脑脊髓大鼠(pithed rat)后肢血管平滑肌的作用和该处突融后膜两种α受体亚型的存在。可乐定引起灌流压(PP)升高,呈剂量依赖关系,但效能远比选择性α_1受体激动剂苯福林低。对预先用利血平处理的大鼠,可乐定的作用被显著增强。高度选择性的α_1受体阻断剂哌唑嗪0.3mg/kg iv可部分阻断可乐定100μg ia的作用,增加哌唑嗪的剂量并不能进一步增加对可乐定的阻断作用。对于哌唑嗪不能阻断的部分,α_1受体阻断剂育亨宾却能表现出十分明显的抑制作用。这些结果提示在大鼠后肢血管平滑肌突触后膜上存在有α_1和α_2肾上腺素受体,但α_1受体似乎占优势。     

α_1和α_2受体激动剂对家兔右心室乳头状肌动作电位和收缩力的影响

在普萘洛尔阻断β受体的情况下,苯福林延长动作电位时程(APD)和有效不应期(ERP),增强心肌收缩力;该作用可被哌唑嗪所拮抗。在利血平化的家兔右心室乳头状肌上,B-HT 920在较低浓度时,对动作电位及收缩力无显著影响;在较高浓度时,可明显延长APD和ERP,但B-HT 920的上述作用不能被育亨宾所拮抗。实验证明在家兔右心室乳头状肌上,突触后α受体的生理效应是由α_1受体介导的,本实验不能证实有功能性突触后α_2受体存在。     

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。     

肾上腺素能受体研究的新进展

肾上腺素能受体(以下简称受体)的亚型β受体的β_1(心脏和脂肪组织)和β_2(平滑肌)两种亚型均可与腺苷环化酶相偶联。前一亚型的拮抗剂为 metoprolol 和心得宁;后一亚型的拮抗剂为 butoxamine。α_1受体即突触后α受体,儿茶酚胺作用时可引起血管及其他平滑肌收缩以及肝脏某些代谢作用;α_2受体存在于突触前及突触后各部位。对突触前α受体的研究,阐明了儿茶酚胺反馈性抑制交感神经末梢释放去甲肾上腺素,由于它对某些激动剂如氯压啶和拮抗剂育亨宾有较大的亲和力,因此它与典型的突触后α受体在药理学上有明显     

大鼠尾动脉平滑肌中α肾上腺素受体的分析

采用离体血管收缩功能实验方法分析大鼠尾动脉平滑肌中α肾上腺素受体(α受体)各种亚型的组成及各自的功能意义,结果表明:尾动脉平滑肌中α_1,受体在功能上占绝对支配地位,包含α_(1A)与α_(1B)两种亚型,它们与去甲肾上腺素的亲和性相同,α_(1A)受体具有较大的储备,而α_(1B)受体无储备,前者在α_1受体激动剂致血管收缩效应中发挥主导作用,α_(1A)与α_(1B)受体之间可能存在协同效应。     

去甲肾上腺素和异丙肾上腺素对猪冠状动脉的舒张作用及机制研究

目的:研究去甲肾上腺素和异丙肾上腺素对冠状动脉环的舒张作用及其可能的作用途径。方法:采用离体实验方法,检测去甲肾上腺素和异丙肾上腺素对静息张力及氯化钾(KCl)预收缩冠状动脉的影响,研究两者对冠状动脉张力的作用及其可能的机制。结果:去甲肾上腺素和异丙肾上腺素对静息张力及KCl(40 mmol.L-1)预收缩冠状动脉环具有浓度依赖性舒张作用。去除内皮,用β受体阻断药普萘洛尔,β1受体抑制药阿替洛尔预处理后,均可明显减弱去甲肾上腺素和异丙肾上腺素诱导的舒张血管作用;用鸟苷酸环化酶抑制药亚甲蓝,一氧化氮合酶抑制药(L-NMMA),β2受体抑制药ICI-118551(10～5 mol.L-1)预处理后,血管舒张作用不能被阻断。α受体阻断药酚妥拉明预处理能增强去甲肾上腺素的舒张作用,对异丙肾上腺素引起的舒张无影响。结论:去甲肾上腺素和异丙肾上腺素是通过激活冠状动脉血管上的β受体(特别是β1受体)产生内皮依赖性的血管舒张作用,与NO-鸟苷酸环化酶途径无关。说明β肾上腺素能受体在猪冠状动脉血管平滑肌和血管内皮上有分布。     

可乐定中枢降压作用与中枢胆碱能神经系统的关系

从猫第四脑室给药。毒扁豆碱降压作用可被阿托品及育亨宾阻断;可乐定降压作用可被育亨宾、密胆碱及阿托品阻断,不被可卡因阻断,破坏中枢去甲肾上腺素能末梢后,阿托品的阻断作用消失;可乐定减少脑室灌流液Ach释出量。提示猫延髓胆碱能和去甲肾上腺素能神经在心血管调节功能上相互影响,它们似有可能同在一心血管神经原形成突触联系共同对血压行抑制性调节;可乐定可能通过激动通路上突触后α₂受体产生降压作用。     

胍丁胺抑制麻醉大鼠颈动脉窦压力反射(英文)

目的:观察胍丁胺对颈动脉窦压力感受器反射的影响。方法:利用灌流左颈动脉窦方法,观察胍丁胺对麻醉大鼠压力反射机能参数的影响。结果:(1)胍丁胺1,5,10mmol/L均使颈动脉窦压力反射机能曲线向右上方移位,曲线最大斜率和反射性平均动脉压下降幅度均减小,提示胍丁胺对压力感受器反射有抑制作用;(2)预先应用咪唑啉受体(IR)和肾上腺素能α_2受体(α_2-AR)拮抗剂咪唑克生(idazox-an,0.1mmol/L),则可完全阻断胍丁胺5mmol/L的效应。预先应用α_2受体拮抗剂育亨宾(yohimbine,15μmol/L),则可部分阻断其效应;(3)预先应用NOS抑制剂L-NAME(500μmol/L),对胍丁胺的抑制作用无影响。结论:胍丁胺对颈动脉窦压力反射有抑制作用,并由咪唑啉受体和α_2受体介导。     

兔耳动脉的交感性血管收缩对α肾上腺素能受体拮抗剂的部分阻抗(英文)

本文利用离体组织灌流技术,对刺激家兔颈上神经节内壁交感神经引起兔耳中央动脉收缩的本质进行探讨,α受体拮抗剂仅部分阻断跨壁神经刺激(TNS)引起的收缩,若预先使用利血平耗竭离体血管内源性儿茶酚胺,由TNS引起的此种家兔耳中央动脉收缩则明显减弱,与此同时,α受体拮抗剂却增强了后期(residual)收缩反应,这种增强作用可能是因突触前膜α受体同时被阻断而引起,由此可见,交感神经冲动引起的家兔耳中央动脉收缩绝大部分是由去甲肾上腺素(NE)介导的,但后期收缩反应则可能是由另一种不明递质所介导,而这种属于外周循环系统的耳动脉交感神经与血管之间冲动传递方式又有别于大脑动脉的传递方式。     

咪唑啉受体与中枢作用性降压药物

由于精神紧张或肥胖等因素造成的高血压,其患者体内分泌的去甲肾上腺素、肾上腺素等儿茶酚胺较常人更多。儿茶酚胺作用于效应受体,促使心输出量增加,外周阻力血管不断收缩,从而血压升高。并且,儿茶酚胺对高血压患者产生的效应,又较常人高,于是促使血压进一步升高。高血压又可造成心脏肥大、动脉粥样硬化或心律失常。病理原因既由于儿茶酚胺,用肾上腺素神经β受体阻断药(如普萘洛尔)或α_1受体阻断药(如哌唑嗪)治疗,自可产生有益的效应。更进一     

Presynaptic activity of the imidazolidine derivative ST 587, a highly selective alpha 1-adrenoceptor agonist

St 587 increased the blood pressure of pithed rats. When the antagonists prazosin (alpha 1) and rauwolscine (alpha 2) were used the drug was shown to be a more selective alpha 1-adrenoceptor agonist than methoxamine. St 587 inhibited the tachycardia elicited by sympathetic stimulation in pithed rats. This effect was presynaptic and due to stimulation of alpha 1-adrenoceptors, as revealed by the different antagonism exerted by prazosin and yohimbine (alpha 2), respectively. The existence of presynaptic alpha 1-adrenoceptors is discussed.     

Vasopressor nerve responses in the pithed rat, previously identified as α2-adrenoceptor mediated, may be α1D-adrenoceptor mediated

Responses to pressor nerve stimulation in the pithed rat have been variously described as mediated, at least in part, by α(2)-adrenoceptors and by α(1A) and α(1D)-adrenoceptors. We have examined the subtypes of α-adrenoceptor involved in rises in diastolic blood pressure in the pithed rat preparation produced by vasopressor nerve stimulation with 10 pulses at 1 Hz or 20 pulses at 5 Hz. Vasopressor nerve responses to 1 Hz stimulation were markedly inhibited by the α(1A)-adrenoceptor antagonist RS 100329 (0.1mg/kg) and by the α(1D-)adrenoceptor antagonist BMY 7378 (0.1mg/kg). The α(2)-adrenoceptor antagonist yohimbine (0.1mg/kg) significantly increased pressor nerve responses to 1 Hz stimulation, but yohimbine (1mg/kg) significantly reduced pressor nerve responses. However, following BMY 7378 (0.1mg/kg), yohimbine (1mg/kg) did not produce any further inhibition of pressor nerve responses to 1 Hz stimulation. The α(2A)-adrenoceptor antagonist BRL 44408 (1mg/kg) did not reduce pressor responses to 1 Hz stimulation. BMY 7378 produced much less inhibition of pressor nerve responses to 5 Hz stimulation, whereas RS 100329 produced similar inhibition of 1 Hz and 5 Hz responses. Yohimbine (0.1 and 1mg/kg) did not significantly affect pressor nerve responses to 5 Hz stimulation. In conclusion, pressor nerve responses in the pithed rat involve both α(1A) and α(1D)-adrenoceptor, but there is no clear evidence for the involvement of α(2)-adrenoceptors.     

The hypotensive effects and mechanism of SGB-483, a newly-synthesized hypotensive agent

The effects of SGB-483, a newly-synthesized hypotensive agent, on the blood pressure were studied in unanesthetized and anesthetized rats. SGB-483 produced a significant hypotensive action in the conscious SHR and renal hypertensive (clipping) rats, and it caused reversal of the pressor response to adrenaline in the anesthetized Wistar-Imamichi rats, SHR, and clipping rats. In an isolated guinea pig aorta preparation, SGB-483 competitively inhibited the contractile response to phenylephrine with a pA2 value of 7.64 +/- 0.08. In pithed rats that were pretreated with beta-adrenoceptor blocker, the pressor effect of adrenaline (1 microgram/kg) was not completely blocked by either prazosin (1 mg/kg), an alpha 1-selective blocker, or yohimbine (1 mg/kg), an alpha 2-selective blocker. SGB-483 (1 mg/kg) had no effects on the prazosin-resistant part of the pressor effect of adrenaline, but significantly inhibited the yohimbine-resistant part. Clonidine-induced reversal of the tachycardia induced in the pithed rat by cardiac sympathetic nerve stimulation was unaffected by SGB-483, indicating that SGB-483 is a selective antagonist of the alpha 1-adrenoceptor.     

Characterization of alpha-adrenoceptors mediating sympathetic vasoconstriction in rat autoperfused hindlimb: effects of SK&F 104078

In the autoperfused hindlimb of pithed rats, vasoconstrictor responses to intra-arterial infusions of the selective alpha 2-adrenoceptor agonist, B-HT 933, were antagonized by the alpha 2-adrenoceptor antagonist, rauwolscine (1 mg/kg i.v.), and by the selective postjunctional alpha 2-adrenoceptor antagonist, SK&F 104078 (1 mg/kg), but not by the selective alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg). In contrast, responses to the selective alpha 1-adrenoceptor agonist, methoxamine, were antagonized by prazosin, but not by rauwolscine or SK&F 104078. Vasopressor responses to stimulation of sympathetic nerves were inhibited by prazosin, increased by rauwolscine, and not affected by SK&F 104078. The results indicate that vascular neuroeffector transmission in rat hindlimb is mediated by postjunctional alpha 1-adrenoceptors, and that SK&F 104078 is a selective antagonist of postjunctional alpha 2-adrenoceptor, and lacks the prejunctional alpha 2-adrenoceptor antagonist action of rauwolscine.     

Nisoldipine inhibits adrenergic responses in the hindquarters vascular bed of the cat

The effects of the calcium entry blocking agent nisoldipine on adrenergic vasoconstrictor responses were investigated in the hindquarters vascular bed of the cat under conditions of controlled blood flow. Nisoldipine dilated the hindquarters vascular bed and inhibited vasoconstrictor responses to Bay K 8644, a nifedipine analog which promotes calcium entry. During infusion of nisoldipine, vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine, and tyramine were inhibited in a reversible manner. In addition to blocking responses to nerve-released and exogenous norepinephrine, the calcium entry antagonist decreased responses to methoxamine and BHT 933, alpha 1- and alpha 2-adrenoceptor agonists. Responses to methoxamine were reduced by prazosin, an alpha 1-adrenoceptor antagonist, but not by yohimbine, an alpha 2-adrenoceptor blocking agent, whereas responses to BHT 933 were decreased by yohimbine but not by prazosin. The results of these studies suggest that vasoconstrictor responses to neuronally released and exogenous norepinephrine, as well as to selective alpha 1- and alpha 2-adrenoceptor agonists, are dependent in part on an extracellular source of calcium in resistance vessels of the feline hindquarters vascular bed. The inhibitory effect of nisoldipine on vasoconstrictor responses to neuronally released norepinephrine may be important in the antihypertensive actions of calcium entry blocking agents.     

PRESYNAPTIC DOPAMINE RECEPTORS MEDIATE THE INHIBITORY ACTION OF DOPAMINE AGONISTS ON STIMULATION-EVOKED PRESSOR RESPONSES IN THE RAT

1 The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-din propyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 μg/kg i.v.) and NNPD (1 mg/kg i.v.), but not TL-99 (1–30 μg/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 μg/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1–30 μg/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimbine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selectively antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic α₂-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic α₂-adrenoreceptors.     

Evidence for two distinct types of postsynaptic α-adrenoceptor in vascular smooth muscle in vivo

1 The effects of the highly selective α₁-adrenoceptor antagonist, prazosin, and the relatively selective α₂-adrenoceptor antagonist, yohimbine, on the pressor responses to intravenous injections of phenylephrine and noradrenaline have been examined in anaesthetized cats and pithed rats in an attempt to determine whether α₁- and α₂-adrenoceptors are located postsynaptically on vascular smooth muscle.

2 In anaesthetized cats prazosin caused a much greater reduction in the pressor responses to phenylephrine than to noradrenaline or splanchnic nerve stimulation (after adrenalectomy). Yohimbine was of similar potency in reducing the pressor responses to each stimulus.

3 A differential blocking activity of prazosin against intra-arterial injections of phenylephrine and noradrenaline was also demonstrated in the blood-perfused cat hind limb. As in the whole animal, prazosin was more potent against phenylephrine than noradrenaline. A similar, though less marked, effect was seen in the mesenteric circulation, but not in the renal circulation, where prazosin was almost equipotent in reducing responses to phenylephrine and noradrenaline.

4 In pithed rats prazosin was a potent, competitive antagonist of phenylephrine, but had little effect against noradrenaline; only the responses to high doses of noradrenaline were reduced by prazosin. Yohimbine was approximately equipotent as an antagonist of phenylephrine and noradrenaline. In the anococcygeus muscle, prazosin was as potent an antagonist of noradrenaline as it was of phenylephrine on vascular smooth muscle.

5 The results suggest that there are two types of α-adrenoceptor in the vasculature of cats and rats. Phenylephrine produces pressor responses by stimulating one type of postsynaptic α-adrenoceptor that is blocked by prazosin and yohimbine; these are α₁-adrenoceptors. Noradrenaline exerts some of its effect via these receptors but most of its effect appears to be exerted through prazosin-insensitive receptors. The latter receptors appear to differ from α₂-adrenoceptors.

     

Yohimbine antagonises α1A- and α1D-adrenoceptor mediated components in addition to the α2A-adrenoceptor component to pressor responses in the pithed rat

We have recently shown that responses to pressor nerve stimulation in the pithed rat are mediated by α(1A)- and α(1D)-adrenoceptors, with no evidence for α(2)-adrenoceptor involvement, and that responses previously identified as α(2)-adrenoceptor mediated are actually α(1D)-adrenoceptor mediated. We have now re-examined the subtypes of α-adrenoceptor involved in pressor responses produced by exogenous agonists in the pithed rat preparation to confirm whether α(2)-adrenoceptors are involved in these responses. The α(2)-adrenoceptor and α(1D)-adrenoceptor antagonist yohimbine (1mg/kg) and the α(2A)-adrenoceptor antagonist methoxy-idazoxan (5 mg/kg) significantly shifted, but the α(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspir o[4.5]decane-7,9-dione dihydrochloride) (1 mg/kg) did not affect, the pressor potency of the α(2)-adrenoceptor agonist xylazine. α(1)-adrenoceptor antagonists showed low potency against pressor responses to xylazine. The pressor potency of the α(1)-adrenoceptor agonist amidephrine was not affected by BMY 3778 (1 mg/kg) but significantly shifted by prazosin (0.01 mg/kg) and by yohimbine (1 mg/kg). In contrast, the pressor potency of phenylephrine was significantly shifted by both yohimbine and BMY 7378 (1 mg/kg), but to a greater extent by the α(1A)-adrenoceptor antagonist RS 100329 (5-Methyl-3-[3-[3-[4-[2-(2,2,2,trifluroethoxy) phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione] hydrochloride) (0.1 mg/kg). In conclusion, we have identified and separated α(1A)-, α(1D)- and α(2A)-adrenoceptor antagonist actions of yohimbine against pressor responses. Pressor responses to exogenous agonists in the pithed rat involve both α(1A)- and α(1D)-adrenoceptors and in addition, α(2A)-adrenoceptors.     

Possible role of alpha 1- and alpha 2-adrenoceptors in the modulation of the sympathetic component of the baroreflex

In anaesthetized and bilaterally vagotomized dogs, reflex bradycardia elicited by intravenous injection of noradrenaline was facilitated by AR-C 239, a new alpha 1-adrenoceptor blocking drug and inhibited by the alpha 2-adrenoceptor antagonist, yohimbine. Both alpha-blocking drugs were administered into the vertebral artery. In another group of bilaterally vagotomized dogs, unilateral electrical stimulation of the carotid sinus nerve induced a frequency-dependent decrease in mean blood pressure solely mediated through the sympatho-inhibitory component of the baroreflex. Administration of the alpha 1-adrenoceptor blocking drugs, AR-C 239 and prazosin (5 micrograms/kg) into the vertebral artery decreased basal mean blood pressure and increased depressor responses to the carotid sinus nerve stimulation, whereas the intracisternal injection of phenylephrine (30 micrograms/kg), a preferential alpha 1-agonist, increased mean blood pressure but inhibited the hypotension resulting from electrical stimulation. In addition, the injection into the vertebral artery of yohimbine (100 micrograms/kg), an alpha 2-adrenoceptor blocking agent which caused no change in mean arterial pressure, inhibited the decrease in the sympathetic component. In conclusion, these results suggest the possible participation of the two types of alpha-adrenoceptors in the modulation of the sympathetic component of the baroreflex: alpha 1-adrenoceptor stimulation could inhibit, whereas alpha 2-adrenoceptor activation facilitates the reflex activity in the sympathetic fibres.     

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.