Laboratory of Pharmacology, F.E.S.-Cuautitlan, 7180Universidad Nacional Autonoma de Mexico, Cuautitlan Izcalli, Mexico, Mexico.
Laboratory of Pharmacodynamics, Escuela Superior de Medicina, 27740Instituto Politecnico Nacional, D.F., Mexico, Mexico.
J Cardiovasc Pharmacol Ther. 2021 Sep;26(5):490-499. doi: 10.1177/10742484211001861. Epub 2021 Mar 29.
Clinical guidelines suggest the combination of 2 drugs as a strategy to treat hypertension. However, some antihypertensive combinations have been shown to be ineffective. Therefore, it is necessary to determine whether differences exist between the results of monotherapy and combination therapy by temporal monitoring of the responses to angiotensin II and norepinephrine, which are vasoconstrictors involved in the development of hypertension. Thus, the purpose of this work was to determine the vascular reactivity to angiotensin II and norepinephrine in spontaneously hypertensive rat (SHR) aortic rings after treatment with valsartan, lisinopril, nebivolol, nebivolol-lisinopril, and nebivolol-valsartan for different periods of time. In this study, male SHR and Wistar Kyoto normotensive (WKY) rats were divided into 7 groups treated for 1, 2, and 4 weeks: (1) WKY + vehicle, (2) SHR + vehicle; (3) SHR + nebivolol; (4) SHR + lisinopril; (5) SHR + valsartan; (6) SHR + nebivolol-lisinopril; and (7) SHR + nebivolol-valsartan. Blood pressure was measured by the tail-cuff method, and vascular reactivity was determined from the concentration-response curve to angiotensin II and norepinephrine in aortic rings. The results showed that the combined and individual treatments reduced mean blood pressure at all times evaluated. All treatments decreased vascular reactivity to angiotensin II; however, in the case of lisinopril and nebivolol-lisinopril, the effect observed was significant up to 2 weeks. All treatments decreased the reactivity to norepinephrine up to week 4. These results show a time-dependent difference in vascular reactivity between the pharmacological treatments, with nebivolol-valsartan and nebivolol-lisinopril being both effective combinations. Additionally, the results suggest crosstalk between the renin-angiotensin and sympathetic nervous systems to reduce blood pressure and to improve treatment efficacy.
临床指南建议将两种药物联合使用作为治疗高血压的策略。然而，一些降压联合用药已被证明无效。因此，有必要通过对血管紧张素 II 和去甲肾上腺素反应的时间监测来确定单药治疗和联合治疗的结果是否存在差异，这两种血管收缩剂与高血压的发生有关。因此，本工作的目的是确定缬沙坦、赖诺普利、比索洛尔、比索洛尔-赖诺普利和比索洛尔-缬沙坦治疗不同时间后自发性高血压大鼠（SHR）主动脉环对血管紧张素 II 和去甲肾上腺素的血管反应性。在这项研究中，雄性 SHR 和 Wistar Kyoto 正常血压（WKY）大鼠分为 7 组，分别治疗 1、2 和 4 周：（1）WKY+载体，（2）SHR+载体；（3）SHR+比索洛尔；（4）SHR+赖诺普利；（5）SHR+缬沙坦；（6）SHR+比索洛尔-赖诺普利；（7）SHR+比索洛尔-缬沙坦。通过尾套法测量血压，从主动脉环对血管紧张素 II 和去甲肾上腺素的浓度-反应曲线确定血管反应性。结果表明，联合和单独治疗在所有评估时间均降低平均血压。所有治疗均降低血管对血管紧张素 II 的反应性；然而，在赖诺普利和比索洛尔-赖诺普利的情况下，观察到的效果在 2 周时显著。所有治疗均降低了对去甲肾上腺素的反应性，直至第 4 周。这些结果显示，血管反应性在药理学治疗之间存在时间依赖性差异，比索洛尔-缬沙坦和比索洛尔-赖诺普利均为有效的联合治疗。此外，结果提示肾素-血管紧张素和交感神经系统之间存在串扰，以降低血压并提高治疗效果。
