Gradin K, Hedner T, Persson B
Department of Pharmacology, University of Gothenburg, Sweden.
J Neural Transm Gen Sect. 1991;83(3):227-33. doi: 10.1007/BF01253392.
The present study was conducted to evaluate the antihypertensive effects of irindalone, a potent 5-HT2-receptor blocking agent with weak alpha 1-adrenoceptorblocking properties. Young spontaneously hypertensive rats (SHR) received irindalone in the food (daily intake estimated to 10 mg/kg) for 10 weeks and older SHR received irindalone subcutaneously for 2 weeks (3 mg/kg/day by osmotic pump). The indirect systolic blood pressure was measured each week (tail plethysmography) and at the end of the intervention periods the direct intraarterial blood pressure was measured in conscious rats. Subsequently a dose-response curve of pressor responses to phenylephrine was constructed in pithed rats. Chronic oral treatment with irindalone reduced the development of hypertension but influenced neither body weight nor heart weight. The subcutaneous treatment with irindalone reduced the blood pressure in relatively older SHR compared with controls. Pressor responses to phenylephrine were antagonized in rats receiving oral treatment. However, during subcutaneous treatment with irindalone the dose-response curve to phenylephrine was not influenced, suggesting that the blood pressure reduction was not directly related to a concomitant alpha 1-adrenoceptor blockade. These results demonstrate that irindalone effectively reduces the blood pressure in SHR and that no tolerance develops to its antihypertensive effects. Since the blood pressure reduction, at least following subcutaneous treatment, was not directly related to a concomitant alpha 1-blockade, it is suggested that the 5-HT2-receptor blockade may be of relevance for the antihypertensive effect.
本研究旨在评估茚达立酮的降压作用，茚达立酮是一种强效的5-HT2受体阻断剂，具有较弱的α1肾上腺素能受体阻断特性。年轻的自发性高血压大鼠（SHR）在食物中摄入茚达立酮（估计每日摄入量为10mg/kg），持续10周；年龄较大的SHR皮下注射茚达立酮，持续2周（通过渗透泵，每日3mg/kg）。每周测量间接收缩压（尾容积描记法），在干预期结束时，测量清醒大鼠的直接动脉内血压。随后，在脊髓横断大鼠中构建对去氧肾上腺素升压反应的剂量反应曲线。茚达立酮的慢性口服治疗可减缓高血压的发展，但对体重和心脏重量均无影响。与对照组相比，茚达立酮的皮下治疗可降低相对年长SHR的血压。接受口服治疗的大鼠对去氧肾上腺素的升压反应受到拮抗。然而，在茚达立酮皮下治疗期间，对去氧肾上腺素的剂量反应曲线未受影响，这表明血压降低与同时存在的α1肾上腺素能受体阻断无直接关系。这些结果表明，茚达立酮可有效降低SHR的血压，且其降压作用不会产生耐受性。由于血压降低，至少在皮下治疗后，与同时存在的α1阻断无直接关系，因此提示5-HT2受体阻断可能与降压作用有关。
