Role of the heart in blood pressure lowering during chronic baroreflex activation: insight from an in silico analysis

Abstract

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.

Keywords: atrial natriuretic peptide; baroreflex; blood pressure; modeling; sympathetic nervous system.

Fig. 1.

Changes in mean arterial pressure (MAP), heart rate [HR; in beats/min (bpm)], and Na⁺ excretion during 3 wk of baroreflex activation. Red bars indicate experimental data. Values are means ± SE; n = 6 dogs. Black lines show the results from the simulation.

Fig. 2.

Changes in plasma concentrations of norepinephrine (NE) and atrial natriuretic peptide (ANP), plasma renin activity (PRA), and either NE spillover (red bars) or renal sympathetic nerve activity (black line) during 3 wk of baroreflex activation. Red bars indicate experimental data. Values are means ± SE; n = 6 dogs. Black lines show the results from the simulation.

Fig. 3.

Simulations showing changes in mean arterial pressure (MAP), heart rate [HR; in beats/min (bpm)], cardiac output (CO), and total peripheral resistance (TPR) during 3 wk of baroreflex activation. Simulations are 1) for normal conditions (normal), 2) without suppression of renal sympathetic outflow (renal clamp), 3) without changes in cardiac autonomic activity (cardiac clamp), and 4) without suppression of renal sympathetic outflow and without changes in cardiac autonomic activity combined (renal + cardiac clamp).

Fig. 4.

The four simulations described in Fig. 3 showing changes in extracellular fluid (ECF) Na⁺, extracellular fluid volume (ECFV), plasma volume (PV), and right atrial pressure (RAP) during 3 wk of baroreflex activation. Simulations are 1) for normal conditions (normal), 2) without suppression of renal sympathetic outflow (renal clamp), 3) without changes in cardiac autonomic activity (cardiac clamp), and 4) without suppression of renal sympathetic outflow and without changes in cardiac autonomic activity combined (renal + cardiac clamp).

Fig. 5.

The four simulations described in Fig. 3 showing changes in plasma levels of angiotensin II, aldosterone, and atrial natriuretic peptide (ANP) during 3 wk of baroreflex activation. Simulations are 1) for normal conditions (normal), 2) without suppression of renal sympathetic outflow (renal clamp), 3) without changes in cardiac autonomic activity (cardiac clamp), and 4) without suppression of renal sympathetic outflow and without changes in cardiac autonomic activity combined (renal + cardiac clamp).

Fig. 6.

The four simulations described in Fig. 3 showing changes in renin secretion and its primary determinants during 3 wk of baroreflex activation. The direct effect of sympathetic activity on renin secretion is illustrated by β-adrenergic stimulation of juxtaglomerular (JG) cells. The indirect influence of renal sympathetic nerve activity and atrial natriuretic peptide on renin secretion, mediated through changes in NaCl delivery to the macula densa, is included in the overall macula densa effect. Simulations are 1) for normal conditions (normal), 2) without suppression of renal sympathetic outflow (renal clamp), 3) without changes in cardiac autonomic activity (cardiac clamp), and 4) without suppression of renal sympathetic outflow and without changes in cardiac autonomic activity combined (renal + cardiac clamp).

Fig. 7.

The four simulations described in Fig. 3 showing changes in glomerular filtration rate (GFR), fractional Na⁺ reabsorption in the proximal tubule (PT FNaR), and concentration of Na⁺ in the macula densa during 3 wk of baroreflex activation. Simulations are 1) for normal conditions (normal), 2) without suppression of renal sympathetic outflow (renal clamp), 3) without changes in cardiac autonomic activity (cardiac clamp), and 4) without suppression of renal sympathetic outflow and without changes in cardiac autonomic activity combined (renal + cardiac clamp).

Fig. 8.

The four simulations described in Fig. 3 showing the influence of the major determinants of Na⁺ reabsorption in the proximal tubule during 3 wk of baroreflex activation. The determinants are renal sympathetic nerve activity (RSNA), renal interstitial fluid pressure (RIFP), and plasma concentrations of angiotensin II and atrial natriuretic peptide (ANP). Simulations are 1) for normal conditions (normal), 2) without suppression of renal sympathetic outflow (renal clamp), 3) without changes in cardiac autonomic activity (cardiac clamp), and 4) without suppression of renal sympathetic outflow and without changes in cardiac autonomic activity combined (renal + cardiac clamp).

Fig. 9.

The four simulations described in Fig. 3 showing changes in afferent arteriolar resistance and its determinants during 3 wk of baroreflex activation. The determinants are renal sympathetic nerve activity (RSNA), plasma atrial natriuretic peptide (ANP) concentration, tubuloglomerular feedback (TGF), the myogenic mechanism, and blood viscosity.

Fig. A1.

Determinants of Na⁺ reabsorption in nephron segments. ANP, atrial natriuretic peptide.

Fig. A2.

Determinants of afferent and efferent arteriolar conductance. TGF, tubuloglomerular feedback; ANP, atrial natriuretic peptide.

Fig. A3.

Determinants of glomerular filtration rate (GFR). FF, filtration fraction; SNGFR, single nephron GFR; PT, proximal tubule; RBF, renal blood flow.

Fig. A4.

Diagram of the relationships between the nervous, cardiac, and renal systems in HumMod. JG, juxtaglomerular cells; MD, macula densa; ANP, atrial natriuretic peptide.

Fig. A5.

Physiological effects of atrial natriuretic peptide (ANP) during baroreflex activation. PT, proximal tubule; CD, collecting duct; MD, macula densa; TGF, tubuloglomerular feedback.

Fig. A6.

Simulations showing changes in mean arterial pressure (MAP), heart rate [HR; in beats/min (bpm)], stroke volume (SV), cardiac output (CO), right atrial pressure (RAP), and concentration of plasma atrial natriuretic peptide (ANP) during 3 wk of baroreflex activation. Simulations are 1) for normal conditions, 2) without changes in cardiac β-adrenergic receptor activity (β clamp), 3) without changes in cardiac vagal activity (vagus clamp), and 4) without changes in cardiac β-adrenergic receptor activity and without changes in cardiac vagal activity combined (β + vagus clamp).