The nucleus reticularis lateralis: A region highly sensitive to clonidine

Slow bilateral microinjections of a low dose of clonidine (75 ng/kg) in the cat's nucleus reticularis lateralis (NRL) lead to significant hypotension and bradycardia. This finding confirms the existence of a ventromedullary highly sensitive site of action of clonidine. It is suggeseted that clonidine inhibits some vasopressive and cardioacceleratory structures within the NRL region.     

Effect of 6-hydroxydopamine on blood pressure and heart rate responses to intracisternal clonidine in conscious rabbits.

The effects of intracisternal injection (i.c.i.) of clonidine (1 microgram kg-1) on blood pressure and heart rate were studied in conscious rabbits with an implanted catheter in the cisterna magna. Each animal was studied under control conditions and 7 days after i.c.i. of 6-hydroxydopamine (6-OHDA) (1 microgram kg-1; n = 10) or ascorbic acid vehicle (n = 6). In the control experiments blood pressure and heart rate began to fall 1--2 min after i.c.i. of clonidine, with maximum falls at 10--20 min averaging 18 +/- 2 mmHg and 45 +/- 8 b/min and almost complete recovery by 90 min. After vehicle pretreatment neither response was significantly altered. After 6-OHDA the early component of the bradycardia was abolished and only a late fall in heart rate developed 30 min after i.c.i. clonidine. The magnitude of the hypotension was unaffected but the onset was slightly delayed, probably owing to the abolition of the bradycardia. The dose of 6-OHDA reduced spinal cord catecholamines to about 20% of the level observed after vehicle. Central catecholaminergic pathways are thus important in the early predominantly vagal component of the clonidine induced bradycardia, but play little role in the hypotensive response.     

Spinal 5-HT pathways and the antinociception induced by intramedullary clonidine in rats

Summary The possible involvement of spinal 5-hydroxytryptamine (5-HT) pathways in antinociception induced by microinjection of clonidine into the ventrolateral surface of the medulla oblongata was investigated in rats. Microinjection of clonidine (10-20 µg), but not yohimbine (1 µg) or 0.9% saline, into the lateral medulla prolonged the hot plate latency in rats. This clonidine-induced antinociception was abolished by intramedullary injection of the alpha₂-adrenoceptor antagonist, yohimbine. Selective destruction of spinal 5-HT neurons produced by intraspinal injection of 5,7-dihydroxytryptamine (5,7-DHT; 10 µg) or postsynaptic blockade of spinal 5-HT receptors produced by intrathecal injection of cyproheptadine (1 µg; a mixed 5-HT₁/5-HT₂ antagonist) also abolished clonidine-induced antinociception. Rats given 5,7-DHT intraspinally or cyproheptadine intrathecally showed a decrease in hot plate latency as compared with the controls. In anesthetized rats, the 5-HT release from the thoracic spinal cord was enhanced by microinjection of clonidine into the lateral medulla. This enhanced spinal 5-HT release evoked by intramedullary injection of clonidine was abolished by pretreatment of rats with intraspinal injection of 5,7-DHT. These results indicate that 5-HT pathways to the spinal cord mediate the antinociceptive effect induced by microinjection of clonidine into the ventrolateral surface of the medulla oblongata in rats.This study was supported by grants from the National Science Council (Taipei, Taiwan, Republic of China) Send offprint requests to M.T. Lin at the above address     

Effects of pentobarbitone and decerebration on the clonidine-induced circulatory changes.

Clonidine 5 and 15 mug/kg i.v. was given to conscious rats, to rats under pentobarbitone anaesthesia and to decerebrated rats. Clonidine 100 mug/kg was given to conscious and to decerebrated rats. Blood pressure and heart rate were recorded via indwelling catheters. The low dose of clonidine gave virtually no response in the conscious rats but produced hypotension and bradycardia in decerebrated and in anaesthetized rats. After clonidine 15 mug/kg the blood pressure of decerebrated rats decreased further, while conscious and anaesthetized rats showed a hypertensive response. The basal blood pressure and heart rate were significantly higher in the decerebrated rats than in the conscious rats. After the highest dose of clonidine, however, the blood pressure of the decerebrated rats decreased below the basal level of the conscious rats and the blood pressure of the conscious rats increased above the basal level of the decerebrated rats. The results suggest that the hypotensive response is caused by a mechanism located in the medulla oblongata. At higher concentrations clonidine may elicit a hypertensive effect by activating suprabulbar centers. The importance of this suprabulbar effect is attenuated by pentobarbitone anaesthesia.     

α-Methylnoradrenaline induced hypotension and bradycardia after administration into the area of the nucleus tractus solitarii

Bilateral injections of α-methylnoradrenaline into the area of the nucleus tractus solitarii of the brain stem caused a dose-dependent decrease of systemic arterial blood pressure and heart rate of anesthetized rats. The effects were prevented and even reversed by a preceding injection of the α-adrenoceptor blocking agent phentolamine. Pressor doses of angiotensin II and of arginine-vasopressin at the same site failed to decrease blood pressure and heart rate.     

高血压患者心率变异性与血压变异性分析

目的 分析高血压患者心率变异性与血压变异性的关系.方法 对高血压患者120例按1999年WHO/ISH高血压诊断标准分为:1级高血压40例,2级高血压40例,3级高血压40例,另设正常血压对照组40例,均同时检测心率变异性与血压变异性.结果 各组间心率变异性差异有统计学意义(P<0.05或P<0.01),随组间血压增高,心率变异性趋向减少;各组间血压变异性差异有统计学意义(P<0.01),随组间血压增高,血压变异性趋向增大.结论 高血压患者血压分级与心率变异性和血压变异性有一定关系.     

Localization of cholinergic neurons involved in the cardiovascular response to intrathecal injection of carbachol

Recent studies in this laboratory have demonstrated the ability of acetylcholine receptor agonists to produce systemic arterial pressor responses through stimulation of spinal muscarinic receptors. In urethane-anesthetized rats a new surgical procedure was employed to permit microinjection of drugs into the cerebrospinal fluid surrounding the medulla without significant redistribution to spinal sites and vice versa. Pretreatment with intracisternal (medullarylevel) injection of 10 μg of atropine significantly inhibited the expression of the pressor response produced by intrathecal injection of 5 μg of carbachol. This inhibition was due at least partly to the interruption of a medullary component of a spinobulbar pathway involving medullary muscarinic receptors. It was not due to redistribution of atropine from medullary to spinal sites since significant levels of atropine were not detected in the spinal cord after intracisternal injection of the drug. The remainder of the pressor response to intrathecal carbachol after medullary muscarinic receptor blockade was most likely due to interactions within the spinal cord itself.     

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.     

Effect of naloxone on the cardiovascular and sympathetic response to hypovolemic hypotension in the rat

Conscious rats were exposed to acute hypovolemic-hypotension by bleeding (5 ml/300 g body weight). Treatment with the opiate antagonist naloxone (7 mg/kg intra-arterial) following hemorrhage resulted in an increase of systolic blood pressure but not heart rate. Changes in plasma catecholamine levels did not differ between control and naloxone-treated animals. From these results we suggest that the ability of naloxone to improve blood pressure after hemorrhage is not due to increased sympatho-adrenomedullary activity.     

非洛地平缓释片治疗原发性高血压的临床疗效分析

目的探讨非洛地平缓释片治疗高血压的临床效果。方法选择本院2009年12月～2011年6月收治的原发性高血压患者50例,均接受非洛地平缓释片治疗,对其临床资料进行回顾性分析,对治疗前后患者血压、心率进行观察。结果经治疗后50例患者临床总有效率为94．0％（47／50）,治疗前后心率无明显变化（P〉0．05）;与治疗前比较,治疗后患者收缩压及舒张压均明显下降,差异具有统计学意义（P〈0．05）;患者不良反应发生率为8．0％（4／50）,无严重不良反应发生,不影响继续治疗。结论非洛地平对原发性高血压治疗效果较好。不良反应发生率较低,为一种临床较为理想的降压药物。     

Influence of chronic naloxone treatment on development of hypertension in the spontaneously hypertensive rat

Summary Chronic administration of naloxone by means of miniosmotic pumps retarded the development of hypertension in young spontaneously hypertensive rats (SHRs) in a dose-related manner. Abrupt termination of naloxone treatment resulted in acceleration in the rate of the blood pressure increase, while increasing the naloxone concentration further slowed the development of hypertension in SHRs. The heart rates of SHRs undergoing chronic naloxone treatment were generally lower than those of control SHRs. Naloxone had no influence upon the mean systeolic blood pressures or heart rates of normotensive Wistar-Kyoto control rats. These findings indicate that chronic naloxone treatment can alter the development of hypertension in the SHR.     

Effects of lithium chloride on cardiovascular responses induced by cholinergic and adrenergic stimulations

Right vagus nerve of pentobarbital-anesthetized rabbits was stimulated at different voltages after infusion of normal saline and of lithium chloride solution in distilled water. Lithium chloride infusion at a rate of 0.25 mEq/0.25 ml/min for 30 min decreased the effects of vagal stimulation on blood pressure and heart rate significantly when compared to those following saline infusion. Lithium chloride also decreased the effects of exogenous acetylchlonie. However, lithium failed to modify the effects of either cardiac accelerator nerve stimulation or of injection of norepinephrine.     

多沙唑嗪治疗轻中度高血压的疗效及其对血浆内皮素和降钙素基因相关肽的影响

目的观察多沙唑嗪治疗轻、中度原发性高血压的疗效,探讨多沙唑嗪对血浆内皮素(ET)和降钙素基因相关肽(CGRP)的影响。方法采用随机、对照、双盲法,将轻、中度原发性高血压48例分为两组各24例,治疗组和对照组分别给予多沙唑嗪和特拉唑嗪,均为2mg,po,qd,共治疗8周。结果治疗组和对照组降血压有效率分别为835%,783%,差异无显著性(P>005)。治疗组总胆固醇亦明显下降(P<005)。两组治疗后ET浓度下降、CGRP水平升高。结论多沙唑嗪为一安全有效的降血压药物,在降血压的同时有降血脂作用;多沙唑嗪的降血压作用可能部分与其拮抗ET、升高CGRP的浓度有关。     

Supersensitivity to the anticonvulsant and proconvulsant activity of clonidine following noradrenaline depletion induced by 6-hydroxydopamine

Electrically induced focal cortical seizures were examined in 6-hydroxydopamine (6-OHDA) pretreated or control rats in the presence of 0, 1, 2.5, 5, and 10 g/kg clonidine. In baseline determinations, rats pretreated with 6-OHDA showed lower seizure thresholds and longer behavioral and electrographic seizure than controls. Consistent with other reports, the lowest dose of clonidine (1 g/kg) inhibited seizures in control animals; 6-OHDA potentiated the anticonvulsant effect of the lowest dose of clonidine but exacerbated seizure in the presence of the highest dose of clonidine (10 g/kg). Since others have reported proconvulsant effects of clonidine at much higher doses (100 or 1,000g/kg) using control animals, the depletion of forebrain norepinephrine with 6-OHDA therefore appears to produce a supersensitivity both to the proconvulsant and to the anticonvulsant effect of clonidine. These data suggest that the receptors that mediate the proconvulsant (possibly 1 adrenoceptors) and the anticonvulsant (possibly 2 adrenoceptors) effects are located postsynaptically.     

血清脂蛋白(a)水平与高血压分级的相关性研究

目的 探讨原发性高血压患者血清脂蛋白a[Lipoprotein a,LP(a)]水平与高血压分级的相关性.方法 依据2010年《中国高血压防治指南》的高血压诊断标准及高血压分级标准,纳入高血压患者180例(其中1级组62例、2级组60例、3级组58例),同时选择同期来我院查体的60名健康体检者作为对照组,即全部研究对象为240例;采用免疫比浊法测定入选全部研究对象的血清脂蛋白(a)浓度水平.结果 血清LP(a)浓度水平在高血压1、2、3级组分别与对照组比较差异均有统计学意义(P＜0.01);2级组与1级组、3级组与2级组比较血清LP(a)浓度水平比较差异均有统计学意义(P＜0.05).结论 血清LP(a)浓度水平与高血压的分级组有较明显的相关性,血清LP(a)浓度水平能够作为原发性高血压分级的参考依据.     

高血压患者血浆ET、TXB2和6-酮-PGF1a测定的临床意义

目的了解血浆内皮素(ET)、血栓素(TXB2)、前列环素(PGF1a)在高血压病中的作用.方法应用放射免疫分析法测定55例高血压患者、38例正常人血浆中ET、TXB2、PGF1a含量.结果高血压患者血浆中ET、TXB2水平非常显著地高于正常人组(P＜0.01),而PGF1a水平则显著地低于正常人组(P＜0.01),与血压的高低密切有关.结论高血压患者血管内皮细胞存在内分泌功能紊乱、ET合成释放增加,PGF1a水平降低,两者反馈调控失衡,在高血压的发病中具有重要的临床价值.     

Potentiation by yohimbine of alpha-adrenoceptor-mediated vasoconstriction in response to clonidine in the rabbit ear vein

We investigated the pharmacological profile of the vasoconstrictive response to clonidine in the isolated rabbit ear vein, and compared the characteristics of clonidine with those of noradrenaline and moxonidine. The maximal vasoconstrictive responses to clonidine and moxonidine in the rabbit ear vein were 35.94+/-11.18% and 88.78+/-11.54% of the maximum response to noradrenaline, respectively. Prazosin 0.1 microM inhibited the vasoconstriction induced by lower concentrations of noradrenaline, and the concentration-dependent response curve for noradrenaline was significantly shifted to the right by 1 microM prazosin. Yohimbine (0.1 and 0.5 microM) only decreased the vasoconstrictive response to lower concentrations of noradrenaline, but did not affect the response to higher concentrations. Vasoconstrictive responses to lower but not higher concentrations of clonidine and moxonidine were inhibited by 0.1 microM yohimbine. In contrast, the same concentration of yohimbine significantly potentiated the maximal response to a high concentration of clonidine by 24.06%. In isolated rabbit ear vein pretreated with 0.1 microM yohimbine, prazosin competitively inhibited the concentration-response curve for clonidine with a pA(2) value of 8.05+/-0.06. We conclude that clonidine acts mainly on alpha(2)-adrenoceptors to produce vasoconstriction in the rabbit ear vein; however, in the preparation pretreated with yohimbine, the clonidine-induced vasoconstriction is mediated via alpha(1)-adrenoceptors and its maximal vasoconstriction is significantly potentiated.     

Adrenergic mechanisms during hypertension induced by sucrose and/or salt in the spontaneously hypertensive rat

Summary Spontaneously hypertensive rats received tap water, 1% NaCl, 5% sucrose or NaCl and sucrose in combination for 4 weeks. The blood pressure (tail plethysmography) and renal excretions of sodium and catecholamines were followed. After 4 weeks the noradrenaline turnover (disappearance after -methyltyrosine) was assessed in the heart and brain. In pithed rats the pressor responses to intravenous noradrenaline and to electrical stimulation of the spinal sympathetic nerves (SNS) were determined together with the rise in plasma noradrenaline concentrations during the SNS. Salt alone caused an increase in peripheral sympathetic activity, measured as turnover of noradrenaline in the heart and spillover of noradrenaline in the urine, a modest enhancement of vascular responsiveness to noradrenaline and a blood pressure elevation. Sucrose alone increased the peripheral sympathetic activity but influenced neither the vascular responsiveness to noradrenaline nor the basal blood pressure. The largest increase in sympathetic activity and in blood pressure was observed with sucrose and salt in combination. The release of noradrenaline from the sympathetic nerve endings was not significantly influenced by any diet regime. The changes in noradrenaline turnover in the heart was accompanied by reciprocal changes in brain stem noradrenaline turnover. Send offprint requests to K. Gradin     

Effects of morphine on central catecholamine turnover,blood pressure and heart rate in the rat

Summary In the unanaesthetized rat morphine caused increased dopamine (DA) turnover, unchanged or possibly increased central noradrenaline (NA) turnover (utilization), hypertension and tachycardia. In the anaesthetized rat, brain DA turnover was not affected, whereas the NA-turnover was decelerated, particularly in some brain regions, e.g. cerebral cortex and medulla oblongata, and hypotension and bradycardia was obtained. Both biochemical and cardiovascular effects of morphine were antagonized by naloxone. A very small dose of morphine (1 mg/kg) caused tachycardia also in the anaesthetized rat. Decerebration just inferior to the inferior colliculus abolished the cardiovascular, excitatory effects of morphine in the conscious rat, but left the circulatory, depressant actions of the drug unchanged.The morphine-induced cardiovascular effects, particularly the hypotension and bradycardia in the anaesthetized animal, are suggested to be related to, or mediated by, the effects of the drug on brain NA-mechanisms, especially in view of several similarities between morphine and the antihypertensive -adrenergic agonist clonidine. Whereas higher brain structures appear important in the excitatory, circulatory effects of morphine, structures below the decerebration level, e.g. medulla oblongata, appear primarily involved in the hypotension and bradycardia obtained in the anaesthetized animal. Possibly, morphine has a diphasic dose-response curve with respect to cardiovascular function and, by inference, on brain noradrenergic mechanisms.     

Severe impairment of CGRP-induced hypotension in vivo and vasorelaxation in vitro in elderly rats.

The aim of this study was to investigate the effects of aging on hypotension in vivo and vasorelaxation in vitro induced by calcitonin gene-related peptide (CGRP), using young (3 months old) and elderly (20 and 28 months old) Sprague-Dawley rats. Vasorelaxant responses were measured in isolated rings of rat thoracic aorta and rat caudal artery, which show endothelium-dependent and endothelium-independent responses to CGRP, respectively. The CGRP-induced vasorelaxations were significantly diminished in 28-month-old male rats in both aorta (39.3% of responses in young controls at 10 nM CGRP) and caudal artery (28.5% of responses in young controls at 10 nM CGRP). Acetylcholine caused vasorelaxations in aortic rings of young male rats, but vasocontractions in aortic rings of 28-month-old male rats. Hypotension induced by CGRP was significantly diminished in both 20-month-old male rats (47.7% of young controls) and 20-month-old female rats (34.4% of young controls). Moreover, ovariectomy, known to decrease CGRP-induced hypotension in young female rats, did not further decrease hypotension to CGRP in elderly female rats. In conclusion, vasorelaxant responses in vitro and hypotensive responses in vivo induced by the neuropeptide CGRP are severely impaired in elderly rats as compared to young rats. The data suggest that the vasodilatory responses to CGRP in both large arteries and the small resistance-sized arteries regulating arterial blood pressure are damaged or down-regulated by the aging process.