Sex-specific Computational Models of Blood Pressure Regulation

Abstract

Hypertension is a global health challenge: it affects one billion people worldwide and is estimated to account for >60% of all cases or types of cardiovascular disease. Due to our partial understanding of sex differences in blood pressure regulation mechanisms, fewer hypertensive women achieve blood pressure control compared to men, even though compliance and treatment rates are generally higher in women. Furthermore, concurrent use of typical antihypertensive treatments such as a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as “triple whammy” AKI. Diuretics and RAS inhibitors are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common.Thus, the objective of this study is to identify which factors contribute to the sexual dimorphism in response to anti-hypertensive therapies targeting the RAS. We also aim to better understand the mechanisms underlying the development of triple whammy AKI and to identify physiological factors that may increase an individual’s susceptibility.To accomplish these goals, we develop sex-specifc models of blood pressure regulation in humans. Model components include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron, and the RAS. Sex differences in the RAS, baseline aldosterone level, and the reactivity of renal sympathetic nervous activity (RSNA) are represented.Model results suggest that the main source of sexual dimorphism in treatment efficacy is how the effects of the bound RAS receptors differ between males and females -- specifically the feedback mechanisms of the angiotensin II type 1 receptor on renin secretion and the effects of the angiotensin II type two receptor on renal resistance. In regards to triple whammy AKI, model simulations suggest that individual variations in water intake or the myogenic response as well as high dosages of these drugs may predispose patients with hypertension to develop triple whammy AKI.These proposed models hold great potential for extensions to study other components of blood pressure regulation, such as the interconnectedness of K+ regulation and Na+ regulation. We present a model of K+ regulation including the aldosterone and renal function feedback controls, as well as the feedforward control stimulated by dietary K+ intake. Model results suggest that the feedforward effect is necessary for increased urinary K+ excretion during digestion and that muscle-kidney cross talk can accelerate recovery following perturbations in extracellular K+ concentration.