Impaired arterial baroreflex function as a potential mechanism for riociguat-induced hypotension: insights from a baroreflex open-loop analysis in sugen–hypoxia pulmonary hypertension rats
N Hiraki, M Fukumitsu, T Kawada, K Sato, K Ohba, M Otake, T Koyama, K Uemura, K SakuAbstract
Background
Riociguat, a soluble guanylate cyclase stimulator, is widely used to treat pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension through activation of the NO–sGC–cGMP pathway. Beyond its pulmonary vasodilatory effects, riociguat exerts systemic hemodynamic actions that may lead to hypotension and syncope, as reported in clinical trials. Arterial pressure (AP) is tightly regulated by the arterial baroreflex, which serves as a principal negative feedback mechanism for maintaining short-term hemodynamic stability. Therefore, vasodilation induced by riociguat may evoke compensatory reflex responses. However, it remains unclear whether riociguat alters baroreflex control of AP in pulmonary hypertension.
Purpose
We tested whether riociguat alters baroreflex-mediated sympathetic AP regulation using a baroreflex open-loop analysis in Sugen–hypoxia pulmonary hypertension (SuHx-PH) rats.
Methods
In eight anesthetized SuHx-PH rats, we measured sympathetic nerve activity (SNA), AP, pulmonary arterial pressure (PAP), and aortic flow (AoF) in response to stepwise changes in carotid sinus pressure (CSP) before and during riociguat infusion (3 µg·kg−1·min−1). We then estimated the CSP–SNA (neural arc) and SNA–AP (peripheral arc) relationships to construct a baroreflex equilibrium diagram. The gain at the operating point, a key determinant of sympathetic AP buffering, was calculated from the product of the tangential slope of the neural arc and the slope of the peripheral arc. The relationships between SNA and systemic and pulmonary vascular resistances (SVR and PVR, respectively) were also evaluated.
Results
Riociguat reduced the intercept of the SNA–PVR relationship (0.58 ± 0.08 vs. 0.38 ± 0.04 mmHg·min·mL−1, P = 0.008), whereas it increased the intercept of the SNA–AoF relationship (45.8 ± 5.5 vs. 50.0 ± 5.2 mL·min−1, P = 0.039). Riociguat attenuated the slope of the peripheral arc (0.62 ± 0.08 vs. 0.36 ± 0.05 mmHg·%−1, P = 0.008) with a reduction in the slope of the SNA–SVR relationship (9.00 ± 1.38 ×10−3 vs. 3.51 ± 0.48 ×10−3 mmHg·min·mL−1·%−1, P = 0.008). It also decreased the maximum gain of the neural arc (1.89 ± 0.28 vs. 1.45 ± 0.26 %·mmHg−1, P = 0.008). These changes led to significant reductions in operating-point AP (90.2 ± 5.2 vs. 64.2 ± 4.7 mmHg, P = 0.008) and operating-point gain (0.54 ± 0.19 vs. 0.07 ± 0.03 mmHg·mmHg−1, P = 0.008).
Conclusion
Riociguat improves pulmonary hemodynamics by reducing PVR. However, it may also induce systemic hypotension, which could be accompanied by a reduction in baroreflex operating-point gain. Under riociguat-induced hypotension, the reduction in SVR cannot be adequately buffered due to impaired baroreflex function, potentially resulting in prolonged hypotension.ESC_Figure_NanaHirakiFor image description, please refer to the figure legend and surrounding text.