Involvement of α2-Adrenoceptors in mechanism of intragastric nicotine protection against ethanol injury in rat stomach

To elucidate the role of - and -adrenoceptors in the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury, the following studies were performed. At 0.5-hr prior to the injury study, rats were pretreated with: subcutaneous control, prazosin (0.5 mg/kg) or yohimbine (5 mg/kg) to block ₁- or ₂-adrenoceptors; or intraperitoneal control, metoprolol (2 mg/kg) or butoxamine (4 mg/kg) to block ₁- or ₂-adrenoceptors, respectively. At 1-hr intervals, rats received intragastric vehicle or nicotine (4 mg/kg) and 40% ethanol (10 ml/kg). Total lengths of the linear gastric corpus mucosal lesions were measured by an unbiased observer using a caliper. In a separate study, 0.5-hr after subcutaneous control or yohimbine (5 mg/kg), rats were treated with intragastric vehicle or nicotine (4 mg/kg). One hour later, gastric mucus volume, gastric juice volume and pH, and titratable acid in the gastric juice were measured. In the rat stomach, the intragastric nicotine protection against 40% ethanol-induced mucosal injury was not blocked by selective ₁-(prazosin), ₁-(metoprolol), or ₂-(butoxamine) adrenoceptor antagonists. The protection was significantly reduced although not completely abolished by selective ₂-(yohimbine) adrenoceptor antagonist. Yohimbine also significantly reduced basal and nicotine-stimulated increase in gastric mucus volume. These data suggest that ₂-adrenoceptors are involved in the protective effect of intragastric nicotine against 40% ethanol-induced gastric mucosal injury possibly by a mucus-dependent mechanism.Supported by Veternas Administration Medical Research Funds, and in part by research grants (0162-01, 02, and 291-01) from the Smokeless Tobacco Research Council, Inc., and by funds (1RT 80) provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco-Related Disease Research Program of the University of California to F.W.L. Dr. Endoh is a recipient of the University of California Tobacco-Related Disease Research Program Research Fellowship Award (FT 37).     

Drugs interacting with alpha adrenoceptors

Summary Alpha adrenoceptors should be divided into various subtypes, comprising pre/postsynaptic and alpha₁/alpha₂-subpopulations, respectively. This classification implicates important functional differences between the various alpha-receptor subtypes, including certain differences in signal transduction following receptor stimulation. After a brief synopsis of the modern classification of alpha-adrenoceptors and its functional implications, the emphasis of the present survey is laid upon the various drugs that interact with the different alpha-adrenoceptor subtypes. Accordingly, agonists and antagonists towards alpha₁- and alpha₂-adrenoceptors are discussed with respect to the pharmacologic basis of their therapeutic activity. Some attention is paid to alpha₁-adrenoceptor antagonists with additional pharmacological activities, e.g., labetalol, ketanserin, and urapidil. Finally, the indirect and rather subtle interaction of calcium antagonists and ACE inhibitors with alpha-adrenoceptor-triggered vasoconstriction is also dealt with, in particular with respect to the influence of these drugs on receptor-operated calcium channels and signal transduction following receptor stimulation.     

卡维地洛对高血压大鼠心脏成纤维细胞胶原合成的抑制作用

目的 :探讨卡维地洛、比索洛尔、哌唑嗪对培养的 SHR和 Wistar大鼠心脏成纤维细胞 （ CFs）胶原合成的影响。方法 :采用胰酶消化法培养 CFs,用3 H-脯氨酸掺入法分别观察卡维地洛、比索洛尔、哌唑嗪干预下两组大鼠 CFs胶原合成的情况。结果 :1各种浓度的卡维地洛 （ 0 .0 1～ 10μmol/ L ）可以浓度依赖的方式抑制 CFs 3 H-脯氨酸掺入量 ,与 Wistar大鼠组相比 ,SHR组 CFs受抑制的效应更强。2同等浓度比索洛尔对两组大鼠 CFs3 H-脯氨酸掺入量表现出轻度抑制。 3同等浓度哌唑嗪对两组大鼠 CFs3 H-脯氨酸掺入量均无明显影响。结论 :卡维地洛呈浓度依赖性抑制 CFs合成胶原 ,其作用机制部分与阻滞β1 受体有关。     

Hypovolaemia inhibits acid-induced alkaline transport in the rat duodenum via an alpha-2 adrenergic mechanism

Acid exposure of the duodenal mucosa is a well-known stimulant of the mucosal alkaline secretion. We have previously reported that a minor blood loss inhibits this secretory increment via activation of the splanchnic nerves. In the present study the pharmacological characteristics of the splanchnic neural inhibition of the alkaline secretion were investigated. Duodenal HCO^-₃ secretion was measured by in-situ titration in chloralose-anaesthetized rats. Exposure of the duodenal mucosa to hydrochloric acid (0.01 m, 5 min) increased the secretion by approximately 60%. A 10% decrease in blood volume simultaneously to the luminal acidification abolished the secretory increase, as previously reported. Treatment with either guanethidine or yohimbine blocked the bleeding-induced inhibition of the secretion after acid-exposure. Neither prazosin nor propranolol did prevent such hypovolaemia-induced inhibition of duodenal alkaline secretion. The present results suggest that the splanchnic neural inhibition of acid-induced duodenal HCO^-₃ secretion is mediated via adrenergic nerve fibres and alpha-2 adrenoceptors.     

哌唑嗪对去甲肾上腺素诱导心肌细胞凋亡的影响

目的：研究α受体拮抗剂哌唑嗪对去甲肾上腺素诱导的原代培养心肌细胞凋亡的影响。方法：采用噻唑蓝（MTT）法分析原代培养心肌细胞存活率;乳酸脱氢酶（LDH）外漏实验和吉姆萨染色实验观察原代心肌细胞损伤;JC-1免疫荧光实验检测线粒体膜电位变化;Annexin V-FITC/PI双染,流式细胞仪检测细胞凋亡。结果：NE（100 μmol·L^-1）作用于原代培养心肌细胞48 h,细胞存活率降低;LDH外漏增加;细胞形态改变,细胞数减少、胞体膨大、胞核居中、胞间间隙增大,呈明显病理学特征;线粒体膜电位降低;心肌细胞凋亡率增加。哌唑嗪明显改善去甲肾上腺素诱导的原代培养心肌细胞损伤,增加MTT值、降低LDH外漏量、改善心肌细胞病理形态、增加心肌细胞线粒体膜电位、降低心肌细胞凋亡率（P<0.05或P<0.01）。结论：哌唑嗪能显著抑制去甲肾上腺素诱导的心肌细胞凋亡,本实验为α受体阻断剂改善高交感诱导心肌细胞凋亡提供实验基础与理论指导。     

家兔第四脑室内注射促甲状腺素释放激素对呼吸的影响

以呼吸频率、潮气量和每分通气量为指标,在氨基甲酸乙酯麻醉、自然呼吸的家兔上,观察到第四脑室内注射促甲状腺素释放激素(TRH,5μg)后呼吸频率加快,20min时达峰值,由给药前的53±4次/min,增至9l±10次/min,每分通气量增加,其最大增加值由给药前的1728.4±144.4ml/min,增至2617.9±265.6ml/min。而第四脑室内注射生理盐水(pH和容积与TRH相同)或静脉注射同样剂量的TRH,对上述指标均无明显影响。第四脑室内预先注射α_1受体阻断剂哌唑嗪(1μg),可部分拮抗TRH的呼吸增频和每分通气量增加的效应。结果表明,TRH具有中枢性呼吸兴奋作用,此作用可能部分由脑内α_1受体介导。     

Subchronic treatment with prazosin improves passive avoidance learning in aged mice: possible relationships to α1-receptor up-regulation

Summary. While many evidences indicate that deficits of central noradrenergic neurotransmission are involved in the age-related decline of cognitive functions in animals and man, very little is known about the specific role of central α₁-adrenergic receptors. Therefore, this problem was specifically addressed in the present communication using the α₁-adrenoceptor antagonist prazosin as pharmacological tool. While the acute administration of prazosin did not affect passive avoidance learning of young or aged mice, an improvement of learning capabilities was seen after subchronic treatment, but for the aged animals only. An U-shaped dose response curve was seen. 0.3 mg/kg prazosin was most effective. Very interestingly, only for this dose a significant up-regulation of the density of α₁-adrenoceptors in the mouse brain was found in the aged animals only. The data suggest a possible causal relationship between effects of prazosin on passive avoidance learning and central α₁-receptor density. Received February 25, 2000; accepted June 8, 2000     

Hemodynamic Effects at Rest and during Exercise in Long-term Treatment with Prazosin in Chronic Congestive Heart Failure

ABSTRACT. The long-term effects of prazosin in chronic congestive heart failure were studied in 10 patients (New York Heart Association class III-IV) in a double-blind cross-over study. Patients with systolic blood pressure > 120 mmHg and left ventricular filling pressure > 15 mmHg were included. Prazosin lowered the arteriovenous oxygen difference both at rest and during exercise (p < 0.05), increased cardiac index (p < 0.01) and reduced right atrial pressure and systemic vascular resistance (p < 0.05) during exercise. Left ventricular filling pressure was also reduced, but not significantly, during exercise. Our data show that prazosin has beneficial long-term effects during exercise in patients with chronic congestive heart failure.     

Effects of losartan,prazosin and a vasopressin V1‐receptor antagonist on renal and femoral blood flow in conscious sheep

The regulation of blood flow to different organs is determined by the autonomic nervous system and systemic and/or local vasoactive substances. Although the cardiovascular effects of the renin‐angiotensin system (RAS), the sympathoadrenal system and vasopressin (AVP) have been thoroughly studied, there are relatively few investigations on these systems with concomitant measurements of systemic haemodynamics and regional blood flow in conscious unstressed individuals. We therefore studied effects of pharmacological blockade of AVP V₁‐, angiotensin II (ANG II) AT₁‐and adrenergic α‐receptors on central and regional (renal and femoral blood flow) haemodynamics in adult conscious ewes. Eight adult cross‐bred ewes were chronically intrumented with peri‐vascular ultrasonic flow probes implanted unilaterally around the renal and the femoral artery. While standing in their habitual environment, systemic and regional haemodynamics were measured before and after the following treatments as single intravenous injections. Animals in group A (n=6) were given isotonic saline (NaCl) followed by the AT₁‐receptor blocker losartan (LOS, 10 mg kg^–1) 30 min later; group B (n=6) animals were given the α‐adrenoceptor blocker prazosin (PRAZ, 0.2 mg kg^–1); and group C (n=6) the vasopressin V₁ receptor antagonist [d(CH₂)₅Tyr(Me)AVP] (AVP‐a, 10 μg kg^–1). PRAZ reduced mean arterial pressure (MAP) by 11% concomitant with an increase in heart rate (HR) (32%), whereas the other substances where without effect on those variables. Femoral blood flow (FBF) was enhanced (increased by 82%) by injection of PRAZ only. Administration of LOS increased the renal blood flow (RBF) by 11% while the other drugs were without effect on that parameter. We conclude that basal renal vascular tone in conscious unstressed sheep is dependent on angiotensinergic mechanism and that blockade of this influence causes a local increase in flow without concomitant effects on systemic haemodynamics.