A model-based approach to investigating the pathophysiological mechanisms of hypertension and response to antihypertensive therapies: extending the Guyton model
A model-based approach to investigating the pathophysiological mechanisms of hypertension and response to antihypertensive therapies: extending the Guyton model
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DOI：
10.1152/ajpregu.00039.2013
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发表时间：
2014-05-01
影响因子：
2.8
通讯作者：
Kondic, Anna Georgieva
中科院分区：
文献类型：
--
作者：
Hallow, K. Melissa;Lo, Arthur;Kondic, Anna Georgieva
在高血压患者中观察到对不同类型抗高血压药物的可再现差异反应，这可能是由于高血压病理学的个体间差异。计算模型为研究潜在疾病机制对不同作用机制的抗高血压治疗反应的影响提供了一种工具。我们提出的开发，校准，验证和应用的盖顿/Karaaslan模型的血压调节的扩展。该模型结合了一个详细的肾素-血管紧张素-醛固酮系统（RAAS）的子模型，允许靶向该途径的不同部分的治疗被区分。RAAS生物标志物和血压对不同类别治疗的反应的文献数据被用于细化ANG II和醛固酮对肾素分泌、肾血管阻力和钠重吸收的生理作用。校准模型能够准确地再现RAAS生物标志物和血压对双RAAS药物组合以及RAAS治疗与利尿剂或钙通道阻滞剂组合的反应。最终模型用于探讨高血压的潜在机制对不同类别降压药的血压反应的影响。模拟表明，高血压的潜在病因可能会影响对给定类别治疗的反应程度，使患者对一类更敏感，而对其他类别不敏感。鉴于高血压通常是多种机制的结果，而不是单一因素，这些发现使我们深入了解为什么通常需要联合治疗来充分控制血压。
Reproducibly differential responses to different classes of antihypertensive agents are observed among hypertensive patients and may be due to interindividual differences in hypertension pathology. Computational models provide a tool for investigating the impact of underlying disease mechanisms on the response to antihypertensive therapies with different mechanisms of action. We present the development, calibration, validation, and application of an extension of the Guyton/Karaaslan model of blood pressure regulation. The model incorporates a detailed submodel of the renin-angiotensin-aldosterone system (RAAS), allowing therapies that target different parts of this pathway to be distinguished. Literature data on RAAS biomarker and blood pressure responses to different classes of therapies were used to refine the physiological actions of ANG II and aldosterone on renin secretion, renal vascular resistance, and sodium reabsorption. The calibrated model was able to accurately reproduce the RAAS biomarker and blood pressure responses to combinations of dual-RAAS agents, as well as RAAS therapies in combination with diuretics or calcium channel blockers. The final model was used to explore the impact of underlying mechanisms of hypertension on the blood pressure response to different classes of antihypertensive agents. Simulations indicate that the underlying etiology of hypertension can impact the magnitude of response to a given class of therapy, making a patient more sensitive to one class and less sensitive others. Given that hypertension is usually the result of multiple mechanisms, rather than a single factor, these findings yield insight into why combination therapy is often required to adequately control blood pressure.