Richer C, Gobert J, Noyer M, Wülfert E, Giudicelli J F
Department de Pharmacologie, Faculté de Médecine Paris-Sud, France.
Fundam Clin Pharmacol. 1996;10(6):529-37. doi: 10.1111/j.1472-8206.1996.tb00611.x.
Mivazerol is a new compound that could potentially reduce perioperative cardiovascular morbidity and mortality in patients with or at risk of coronary disease and submitted to surgery. This action of mivazerol depends on a well documented centrally mediated reduction in sympathetic nerve activity, but a direct peripheral decrease in sympathetic neurotransmitter release induced by activation of prejunctional alpha 2-adrenoceptors located on sympathetic nerve endings could also contribute. To investigate this issue, the effects of mivazerol on the pressor, systemic and regional hemodynamic (pulsed Doppler technique) as well as on the cardiac responses to electrical stimulation of the spinal cord (SCS) were measured in pithed rats in the absence and in the presence of mivazerol. Mivazerol exerted strong sympathoinhibitory effects: SCS-induced increases in blood pressure, total peripheral resistance and heart rate were dose-dependently reduced by mivazerol, but among the regional vascular beds investigated, only the hindlimb vasoconstrictor responses were significantly drug-affected. All these sympathoinhibitory effects of mivazerol were abolished by prior yohimbine administration. Simultaneously, mivazerol did not induce any postjunctional adrenoceptor blockade as it did not affect noradrenaline cardiac and hemodynamic effects. On the contrary, through postjunctional alpha 2-adrenoceptor stimulation, mivazerol, in this pithed preparation, dose-dependently increased blood pressure, total peripheral and hindlimb vascular resistances, but heart rate was not affected. We conclude that, in the pithed rat, mivazerol exerts strong peripheral sympathoinhibitory effects. The mechanism involved is prejunctional alpha 2-adrenoceptor activation as i) mivazerol does not display any postsynaptic alpha-adrenoceptor blocking effect--it even behaves as as postsynaptic alpha 2-adrenoceptor agonist--and ii) yohimbine abolishes mivazerol's sympathoinhibitory effects. Thus, direct peripheral together with central mechanisms contribute to mivazerol's sympathoinhibitory effects and ultimately to its cardioprotective action.
米伐折罗是一种新型化合物，它有可能降低患有冠心病或有冠心病风险且接受手术的患者围手术期心血管发病率和死亡率。米伐折罗的这一作用依赖于交感神经活动经充分证实的中枢介导性降低，但位于交感神经末梢的节前α₂肾上腺素能受体激活所诱导的交感神经递质释放的直接外周减少也可能起作用。为研究此问题，在去脑大鼠中测量了米伐折罗在有无米伐折罗存在时对升压、全身和局部血流动力学（脉冲多普勒技术）以及对脊髓电刺激（SCS）的心脏反应的影响。米伐折罗发挥了强烈的交感抑制作用：米伐折罗剂量依赖性地降低了SCS诱导的血压、总外周阻力和心率升高，但在所研究的局部血管床中，只有后肢血管收缩反应受到药物的显著影响。米伐折罗的所有这些交感抑制作用在预先给予育亨宾后均被消除。同时，米伐折罗并未诱导任何节后肾上腺素能受体阻滞，因为它不影响去甲肾上腺素的心脏和血流动力学效应。相反，在这种去脑制剂中，通过节后α₂肾上腺素能受体刺激，米伐折罗剂量依赖性地升高血压、总外周和后肢血管阻力，但心率不受影响。我们得出结论，在去脑大鼠中，米伐折罗发挥强烈的外周交感抑制作用。所涉及的机制是节前α₂肾上腺素能受体激活，因为：i）米伐折罗未表现出任何突触后α肾上腺素能受体阻滞作用——它甚至表现为突触后α₂肾上腺素能受体激动剂——且ii）育亨宾消除了米伐折罗的交感抑制作用。因此，直接外周机制与中枢机制共同促成了米伐折罗的交感抑制作用，并最终促成其心脏保护作用。
