Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension.

NEW FINDINGS: What is the central question of this study? The impact of pulmonary arterial hypertension on open-loop baroreflex function, which determines how powerfully and rapidly the baroreflex operates to regulate arterial pressure, remains poorly understood. What is the main finding and its importance? The gain of the baroreflex total arc, indicating the baroreflex pressure-stabilizing function, is markedly attenuated in rats with monocrotaline-induced pulmonary arterial hypertension. This is caused by a rightward shift of the baroreflex neural arc and a downward shift of the peripheral arc. These findings contribute greatly to our understanding of arterial pressure regulation by the sympathetic nervous system in pulmonary arterial hypertension. ABSTRACT: Sympathoexcitation has been documented in patients with established pulmonary arterial hypertension (PAH). Although the arterial baroreflex is the main negative feedback regulator of sympathetic nerve activity (SNA), the way in which PAH impacts baroreflex function remains poorly understood. In this study, we conducted baroreflex open-loop analysis in a rat model of PAH. Sprague-Dawley rats were injected with monocrotaline (MCT) s.c. to induce PAH (60 mg kg-1 ; n = 11) or saline as a control group (CTL; n = 8). At 3.5 weeks after MCT injection, bilateral carotid sinuses were isolated, and intrasinus pressure (CSP) was controlled while SNA at the coeliac ganglia and arterial pressure (AP) were recorded. To examine the static baroreflex function, CSP was increased stepwise while steady-state AP (total arc) and SNA (neural arc) responses to CSP and the AP response to SNA (peripheral arc) were measured. Monocrotaline significantly decreased the static gain of the baroreflex total arc at the operating AP compared with CTL (-0.80 ± 0.31 versus -0.22 ± 0.22, P < 0.05). Given that MCT markedly increased plasma noradrenaline, an index of SNA, by approximately 3.6-fold compared with CTL, calibrating SNA by plasma noradrenaline revealed that MCT shifted the neural arc to a higher SNA level and shifted the peripheral arc downwards. Monocrotaline also decreased the dynamic gain of the baroreflex total arc (-0.79 ± 0.16 versus -0.35 ± 0.17, P < 0.05), while the corner frequencies that reflect the speed of the baroreflex remained unchanged (0.06 ± 0.02 versus 0.08 ± 0.02 Hz, n.s.). In rats with MCT-induced PAH, the suppressed baroreflex peripheral arc overwhelms the augmented neural arc and, in turn, attenuates the gain of the total arc, which determines the pressure-stabilizing capacity of the baroreflex.

Baroreflex failure increases the risk of pulmonary edema in conscious rats with normal left ventricular function.

In heart failure with preserved ejection fraction (HFpEF), the complex pathogenesis hinders development of effective therapies. Since HFpEF and arteriosclerosis share common risk factors, it is conceivable that stiffened arterial wall in HFpEF impairs baroreflex function. Previous investigations have indicated that the baroreflex regulates intravascular stressed volume and arterial resistance in addition to cardiac contractility and heart rate. We hypothesized that baroreflex dysfunction impairs regulation of left atrial pressure (LAP) and increases the risk of pulmonary edema in freely moving rats. In 15-wk Sprague-Dawley male rats, we conducted sinoaortic denervation (SAD, n = 6) or sham surgery (Sham, n = 9), and telemetrically monitored ambulatory arterial pressure (AP) and LAP. We compared the mean and SD (lability) of AP and LAP between SAD and Sham under normal-salt diet (NS) or high-salt diet (HS). SAD did not increase mean AP but significantly increased AP lability under both NS (P = 0.001) and HS (P = 0.001). SAD did not change mean LAP but significantly increased LAP lability under both NS (SAD: 2.57 ± 0.43 vs. Sham: 1.73 ± 0.30 mmHg, P = 0.01) and HS (4.13 ± 1.18 vs. 2.45 ± 0.33 mmHg, P = 0.02). SAD markedly increased the frequency of high LAP, and SAD with HS prolonged the duration of LAP > 18 mmHg by nearly 20-fold compared with Sham (SAD + HS: 2,831 ± 2,366 vs. Sham + HS: 148 ± 248 s, P = 0.01). We conclude that baroreflex failure impairs volume tolerance and together with salt loading increases the risk of pulmonary edema even in the absence of left ventricular dysfunction. Baroreflex failure may contribute in part to the pathogenesis of HFpEF.

Optimal Titration Is Important to Maximize the Beneficial Effects of Vagal Nerve Stimulation in Chronic Heart Failure.

BACKGROUND: Although vagal nerve stimulation (VNS) benefits patients with chronic heart failure (CHF), the optimal dose of VNS remains unknown. In clinical trials, adverse symptoms limited up-titration. In this study, we evaluated the impact of various voltages of VNS which were titrated below symptom threshold on cardiac function and CHF parameters in rat myocardial infarction (MI) models. METHODS AND RESULTS: We randomly allocated MI rats to vagal (VNS; n = 41) and sham (Sham; n = 16) stimulation groups. We stimulated the right vagal nerve with 20 Hz at 3 different voltages for 4 weeks. We defined Max as the highest voltage that did not evoke any symptom, Half as one-half of Max, and Quarter as one-fourth of Max. All 3 VNS groups significantly reduced biventricular weight compared with Sham (P < .05). In contrast, only Half decreased left ventricular (LV) end-diastolic pressure (Half: 17.5 ± 2.0 mm Hg; Sham: 24.2 ± 1.2 mm Hg; P < .05) and increased LV ejection fraction (Half: 37.9 ± 3.1%; Sham: 28.4 ± 2.3%,-P < .05) and LV maximum +dP/dt (Half: 5918.6 ± 2.0 mm/Hg/s; Sham: 5001.2 ± 563.2 mm Hg/s; P < .05). The number of large vagal nerve fibers was reduced with Max (Max: 163.1 ± 43.0 counts/bundle; Sham: 360.0 ±61.6 counts/bundle; P < .05), indicating significant neural damage by VNS. CONCLUSION: The optimal titration of VNS would maximize benefits for CHF and minimize adverse effects.

Smart Baroreceptor Activation Therapy Strikingly Attenuates Blood Pressure Variability in Hypertensive Rats With Impaired Baroreceptor.

Increased blood pressure (BP) variability (BPV) is an independent risk factor of cardiovascular events among hypertensive patients. The arterial baroreceptor reflex is a powerful regulator of BP and attenuates BPV via a sympathetic negative feedback control. Conventional baroreceptor activation therapy (cBAT) electrically stimulates the carotid baroreceptors with constant stimulation parameters. While cBAT lowers BP, it does not mount a pressure feedback mechanism. We hypothesized that baroreceptor activation therapy with a pressure feedback system (smart BAT [sBAT]) is able to reduce BPV as well as lower BP. We developed sBAT that electrically stimulated baroreceptors at a frequency proportional to the difference between instantaneous BP and a preset reference pressure, and compared its performance with cBAT. In 14-week-old spontaneously hypertensive rats (n=6), we implanted BP telemeter and created impaired arterial baroreceptors by modified sino-aortic denervation. One week after surgical preparation, we administered sBAT, cBAT or no stimulation (sham) for 15 minutes and compared BP and BPV under freely moving condition. Both cBAT and sBAT significantly lowered mean BP (sham, 141.3±12.8; cBAT, 114.3±11.4; and sBAT, 112.0±7.3 mm Hg). Conventional BAT did not affect BPV at all, while sBAT significantly reduced BPV (sham, 15.4±2.6; cBAT, 16.0±5.2; and sBAT, 9.7±3.3 mm Hg). sBAT also prevented transient excessive BP rise and fall. In conclusion, sBAT was capable of reducing BP and attenuating BPV in hypertensive rats with impaired baroreceptor. sBAT is a novel treatment option for hypertensive patients with increased BPV.

The impact of volume loading-induced low pressure baroreflex activation on arterial baroreflex-controlled sympathetic arterial pressure regulation in normal rats.

Although low pressure baroreflex (LPB) has been shown to elicit various cardiovascular responses, its impact on sympathetic nerve activity (SNA) and arterial baroreflex (ABR) function has not been fully elucidated. The aim of this study was to clarify how volume loading-induced acute LPB activation impacts on SNA and ABR function in normal rats. In 20 anesthetized Sprague-Dawley rats, we isolated bilateral carotid sinuses, controlled carotid sinus pressure (CSP), and measured central venous pressure (CVP), splanchnic SNA, and arterial pressure (AP). We infused blood stepwise (3 mL/kg/step) to activate volume loading-induced LPB. Under the ABR open-loop condition, stepwise volume loading markedly increased SNA by 76.8 ± 21.6% at CVP of 3.6 ± 0.2 mmHg. In contrast, further volume loading suppressed SNA toward the baseline condition. Bilateral vagotomy totally abolished the changes in SNA by volume loading. To assess the impact of LPB on ABR function, we changed CSP stepwise. Low volume loading (CVP = 3.6 ± 0.4 mmHg) significantly shifted the sigmoidal CSP-SNA relationship (central arc) upward from baseline, whereas high volume loading (CVP = 5.4 ± 0.4 mmHg) returned it to the baseline level. Volume loading shifted the linear SNA-AP relationship (peripheral arc) upward without significant changes in slope. In conclusions, volume loading-induced acute LPB activation evoked two-phase changes, an initial increase followed by decline from baseline value, in SNA via resetting of the ABR central arc. LPB may contribute greatly to stabilize AP in response to volume status.

Pulmonary arterial input impedance reflects the mechanical properties of pulmonary arterial remodeling in rats with pulmonary hypertension.

AIMS: Although pulmonary arterial remolding in pulmonary hypertension (PH) changes the mechanical properties of the pulmonary artery, most clinical studies have focused on static mechanical properties (resistance), and dynamic mechanical properties (compliance) have not attracted much attention. As arterial compliance plays a significant role in determining afterload of the right ventricle, we evaluated how PH changes the dynamic mechanical properties of the pulmonary artery using high-resolution, wideband input impedance (ZPA). We then examined how changes in ZPA account for arterial remodeling. Clarification of the relationship between arterial remodeling and ZPA could help evaluate arterial remodeling according to hemodynamics. MAIN METHODS: PH was induced in Sprague-Dawley rats with an injection of Sugen5416 (20 mg/kg) and 3-week exposure to hypoxia (10% oxygen) (SuHx). ZPA was evaluated from pulmonary artery pressure and flow under irregular pacing. Pulmonary histology was examined at baseline and 1, 3, and 8 weeks (n = 7, each) after Sugen5416 injection. KEY FINDINGS: SuHx progressively increased pulmonary arterial pressure. ZPA findings indicated that SuHx progressively increased resistance (baseline: 9.3 ±â€¯3.6, SuHx1W: 20.7 ±â€¯7.9, SuHx3W: 48.8 ±â€¯6.9, SuHx8W: 62.9 ±â€¯17.8 mm Hg/mL/s, p < 0.01) and decreased compliance (baseline: 11.9 ±â€¯2.1, SuHx1W: 5.3 ±â€¯1.7, SuHx3W: 2.1 ±â€¯0.7, SuHx8W: 1.9 ±â€¯0.6 × 10-3 mL/mm Hg, p < 0.01). The time constant did not significantly change. The progressive reduction in compliance was closely associated with wall thickening of small pulmonary arteries. SIGNIFICANCE: The finding that changes in resistance were reciprocally associated with those in compliance indicates that resistant and compliant vessels are anatomically inseparable. The analysis of ZPA might help evaluate arterial remodeling in PH according to hemodynamics.

Central chemoreflex activation induces sympatho-excitation without altering static or dynamic baroreflex function in normal rats.

Central chemoreflex activation induces sympatho-excitation. However, how central chemoreflex interacts with baroreflex function remains unknown. This study aimed to examine the impact of central chemoreflex on the dynamic as well as static baroreflex functions under open-loop conditions. In 15 anesthetized, vagotomized Sprague-Dawley rats, we isolated bilateral carotid sinuses and controlled intra-sinus pressure (CSP). We then recorded sympathetic nerve activity (SNA) at the celiac ganglia, and activated central chemoreflex by a gas mixture containing various concentrations of CO2 Under the baroreflex open-loop condition (CSP = 100 mmHg), central chemoreflex activation linearly increased SNA and arterial pressure (AP). To examine the static baroreflex function, we increased CSP stepwise from 60 to 170 mmHg and measured steady-state SNA responses to CSP (mechanoneural arc), and AP responses to SNA (neuromechanical arc). Central chemoreflex activation by inhaling 3% CO2 significantly increased SNA irrespective of CSP, indicating resetting of the mechanoneural arc, but did not change the neuromechanical arc. As a result, central chemoreflex activation did not change baroreflex maximum total loop gain significantly (-1.29 ± 0.27 vs. -1.68 ± 0.74, N.S.). To examine the dynamic baroreflex function, we randomly perturbed CSP and estimated transfer functions from 0.01 to 1.0 Hz. The transfer function of the mechanoneural arc approximated a high-pass filter, while those of the neuromechanical arc and total (CSP-AP relationship) arcs approximated a low-pass filter. In conclusion, central chemoreflex activation did not alter the transfer function of the mechanoneural, neuromechanical, or total arcs. Central chemoreflex modifies hemodynamics via sympatho-excitation without compromising dynamic or static baroreflex AP buffering function.

Carotid Body Denervation Markedly Improves Survival in Rats With Hypertensive Heart Failure.

BACKGROUND: Hypertension is a major cause of heart failure. Excessive sympathoexcitation in patients with heart failure leads to poor prognosis. Since carotid body denervation (CBD) has been shown to reduce sympathetic nerve activity in animal models of hypertension and heart failure, we examined if bilateral CBD attenuates the progression of hypertensive heart failure and improves survival. METHODS: We randomly allocated Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age into CBD (n = 31) and sham-operation (SHAM; n = 50) groups, and conducted CBD or SHAM at 7 weeks of age. We examined the time course of 24-hour urinary norepinephrine (uNE) excretion, blood pressure (BP) and the percent fractional shortening assessed by echocardiography, and estimated the pressure-natriuresis relationship at 14 weeks of age. Finally, we assessed hemodynamics, histological findings, and survival at 16 weeks of age. RESULTS: Compared to SHAM, CBD significantly reduced 24-hour uNE at 12, 14, and 16 weeks of age, shifted the pressure-natriuresis relationship leftward without changing its slope, and attenuated the increase in BP. CBD preserved percent fractional shortening (34.2 ± 1.2 vs. 29.1 ± 1.3%, P < 0.01) and lowered left ventricular end-diastolic pressure (5.0 ± 0.9 vs. 9.0 ± 1.4 mm Hg, P < 0.05). Furthermore, CBD significantly attenuated myocardial hypertrophy (P < 0.01) and fibrosis (P < 0.01). Consequently, CBD markedly improved survival (relative risk reduction: 64.8%). CONCLUSIONS: CBD attenuated the progression of hypertension and worsening of heart failure possibly through sympathoinhibition, and markedly improved survival in a rat model of hypertensive heart failure.

The Akt-mTOR axis is a pivotal regulator of eccentric hypertrophy during volume overload.

The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-dependent manner, mTOR inhibition suppressed eccentric hypertrophy and induced cardiac atrophy even under VO. Notably, Akt was ubiquitinated and phosphorylated in response to VO, and blocking the recruitment of Akt to the membrane completely abolished mTOR activation. Various growth factors were upregulated during VO, suggesting that these might be involved in Akt-mTOR activation. Furthermore, the rate of eccentric hypertrophy progression was proportional to mTOR activity, which allowed accurate estimation of eccentric hypertrophy by time-integration of mTOR activity. These results suggested that the Akt-mTOR axis plays a pivotal role in eccentric hypertrophy, and mTOR activity quantitatively determines the rate of eccentric hypertrophy progression. As eccentric hypertrophy is an inherent system of the heart for regulating cardiac output and LVEDP, our findings provide a new mechanistic insight into the adaptive mechanism of the heart.