Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada.
Department of Biology and Schools of Computer Science and Pharmacology, University of Waterloo, Waterloo, Ontario, Canada.
Am J Physiol Renal Physiol. 2020 Apr 1;318(4):F888-F900. doi: 10.1152/ajprenal.00376.2019. Epub 2020 Feb 10.
In the past decades, substantial effort has been devoted to the development of computational models of the cardiovascular system. Some of these models simulate blood pressure regulation in humans and include components of the circulatory, renal, and neurohormonal systems. Although such human models are intended to have clinical value in that they can be used to assess the effects and reveal mechanisms of hypertensive therapeutic treatments, rodent models would be more useful in assisting the interpretation of animal experiments. Also, despite well-known sexual dimorphism in blood pressure regulation, almost all published models are gender neutral. Given these observations, the goal of this project is to develop the first computational models of blood pressure regulation for male and female rats. The resulting sex-specific models represent the interplay among cardiovascular function, renal hemodynamics, and kidney function in the rat; they also include the actions of the renal sympathetic nerve activity and the renin-angiotensin-aldosterone system as well as physiological sex differences. We explore mechanisms responsible for blood pressure and renal autoregulation and notable sexual dimorphism. Model simulations suggest that fluid and sodium handling in the kidney of female rats, which differs significantly from males, may contribute to their observed lower salt sensitivity as compared with males. Additionally, model simulations highlight sodium handling in the kidney and renal sympathetic nerve activity sensitivity as key players in the increased resistance of females to angiotensin II-induced hypertension as compared with males.
在过去的几十年中，人们投入了大量精力来开发心血管系统的计算模型。其中一些模型模拟人类的血压调节，包括循环、肾脏和神经激素系统的组成部分。虽然这些人类模型旨在具有临床价值，因为它们可用于评估高血压治疗的效果并揭示其机制，但啮齿动物模型在协助解释动物实验方面将更为有用。此外，尽管血压调节存在众所周知的性别二态性，但几乎所有已发表的模型都是性别中立的。鉴于这些观察结果，该项目的目标是为雄性和雌性大鼠开发第一个血压调节计算模型。由此产生的性别特异性模型代表了大鼠心血管功能、肾脏血液动力学和肾功能之间的相互作用；它们还包括肾脏交感神经活动和肾素-血管紧张素-醛固酮系统的作用以及生理性别差异。我们探讨了导致血压和肾脏自身调节以及显著性别二态性的机制。模型模拟表明，与雄性相比，雌性大鼠肾脏中的液体和钠处理存在显著差异，这可能导致它们观察到的盐敏感性降低。此外，模型模拟强调了肾脏中的钠处理和肾脏交感神经活动敏感性作为女性对血管紧张素 II 诱导的高血压的抗性增加的关键因素。
