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.

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.

Haemodynamic unloading reverses occlusive vascular lesions in severe pulmonary hypertension.

AIMS: An important pathogenic mechanism in the development of idiopathic pulmonary arterial hypertension is hypothesized to be a cancer-like cellular proliferation independent of haemodynamics. However, because the vascular lesions are inseparably coupled with haemodynamic stress, the fate of the lesions is unknown when haemodynamic stress is eliminated. METHODS AND RESULTS: We applied left pulmonary artery banding to a rat model with advanced pulmonary hypertension to investigate the effects of decreased haemodynamic stress on occlusive vascular lesions. Rats were given an injection of the VEGF blocker Sugen5416 and exposed to 3 weeks of hypoxia plus an additional 7 weeks of normoxia (total 10 weeks) (SU/Hx/Nx rats). The banding surgery to reduce haemodynamic stress to the left lung was done at 1 week prior to (preventive) or 5 weeks after (reversal) the SU5416 injection. All SU/Hx/Nx-exposed rats developed severe pulmonary hypertension and right ventricular hypertrophy. Histological analyses showed that the non-banded right lungs developed occlusive lesions including plexiform lesions with marked perivascular cell accumulation. In contrast, banding the left pulmonary artery not only prevented the development of but also reversed the established occlusive lesions as well as perivascular inflammation in the left lungs. CONCLUSION: Our results indicate that haemodynamic stress is prerequisite to the development and progression of occlusive neointimal lesions in this rat model of severe pulmonary hypertension. We conclude that perivascular inflammation and occlusive neointimal arteriopathy are driven by haemodynamic stress.