Sympathetic Nerve Activity and Baroreflex Dysfunction Paralleled the Progression of Pulmonary Arterial Hypertension in Monocrotaline Induced Rat Model

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a fatal disease characterized by progressive pulmonary vascular remodeling and extremely high pulmonary artery (PA) resistance. Although patients with advanced PAH are known to have excessive sympathoexcitation and baroreflex dysfunction, the relationship between autonomic dysfunction and the progression of PAH remains unknown. Thus, we investigated how the progression of PAH alters sympathetic nerve activity (SNA) and baroreflex function in monocrotaline (MCT) induced PAH rats.MethodsIn 7 weeks‐old Sprague‐Dawley rats (220–260g), we subcutaneously injected MCT (60 mg/kg) or saline for control (CTL). One, 3 and 3.5 weeks after MCT injection (MCT1W, MCT3W and MCT3.5W, respectively), we assessed right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) (,‐the weight ratio of right to left ventricular) to evaluate the severity of PAH. We estimated SNA by 24 hours urine norepinephrine (U‐NE) and plasma norepinephrine (P‐NE). To measure open loop baroreflex function, we isolated bilateral carotid sinus regions and changed carotid sinus pressure (CSP) while measuring splanchnic SNA and arterial pressure (AP).ResultsRVSP significantly increased 3 and 3.5 week after MCT injection (CTL: 39±6, MCT3W: 73±6, MCT3.5W: 96±9 mmHg, p<0.05). RVH markedly increased in MCT3.5W (CTL: 0.29±0.04, MCT3.5W: 0.49±0.08, p<0.05). Both U‐NE and P‐NE paralleled RVSP (Fig. 1). In the baroreflex open loop analysis, increasing in CSP sigmoidally decreased SNA (neural arc), whereas SNA lineally increased AP (peripheral arc). The relationship between CSP and AP (i.e., baroreflex total loop function) was sigmoidal in both CTL and MCT3W, while the baroreflex induced maximum AP was lower in MCT3W than in CTL (Fig. 2). PAH lowered the baroreflex total loop gain at the operating point (CTL: −1.22±0.22, MCT3W:−0.35±0.14, p<0.05) (Fig. 3).ConclusionSympathetic activation paralleled the progression of PAH. RVH and excessive SNA may deteriorate the baroreflex function in rats with advanced PAH.