Differential Contribution of Afferent and Central Pathways to the Development of Baroreflex Dysfunction in Chronic Kidney Disease

Abstract

The effects of chronic kidney disease on baroreflex control of renal sympathetic nerve activity (RSNA) and deficits in afferent and central components of the baroreflex were studied in juvenile and adult male Lewis Polycystic Kidney (LPK) and control Lewis rats under anesthesia (n=35). Blood pressure (BP), heart rate (HR), aortic depressor nerve activity (ADNA), and RSNA were determined after pharmacological manipulation of BP. Responses to ADN stimulation (4.0 V, 2.0 ms, 1–24 Hz) were determined, and the aortic arch was collected for histomorphometry. In juvenile LPK versus age-matched Lewis rats, gain of RSNA (−1.5±0.2 versus −2.8±0.2%/mm Hg; P <0.05) and ADNA (2.5±0.3 versus 5.0±0.6%/mm Hg; P <0.05), but not HR barocurves, were reduced. BP, HR, and RSNA responses to ADN stimulation were normal or enhanced in juvenile LPK. In adult LPK versus age-matched Lewis, the gain and range of RSNA (gain: −1.2±0.1 versus −2.2±0.2%/mm Hg, range: 62±8 versus 98±7%) and HR (gain: −0.7±0.1 versus −3.5±0.7 bpm/mm Hg, range: 44±8 versus 111±19 bpm) barocurves were reduced ( P <0.05). The gain and range of the ADNA barocurves were also reduced in adult LPK versus Lewis [1.5±0.4 versus 5.2±1.1 (%/mm Hg) and 133±35 versus 365±61 (%) P <0.05] and correlated with aortic arch vascular remodeling. BP, HR, and RSNA responses to ADN stimulation were significantly reduced in adult LPK. Our data demonstrate a deficit in the afferent component of the baroreflex that precedes the development of impaired central regulation of RSNA and HR in chronic kidney disease, and that progressive impairment of both components is associated with marked dysfunction of the baroreflex pathway.

The effect of losartan on differential reflex control of sympathetic nerve activity in chronic kidney disease

“…Baroreflex dysfunction is common in CKD patients [1,2], and in the current study, we confirm our previous findings that baroreflex control of rSNA is impaired in the LPK rats [19] and extend this to show that baroreflex control of sSNA under the same experimental conditions is similarly impaired. The sensitivity of the lumbar sympathetic baroreflex response, however, was not different from the Lewis controls, which is comparable to muscle SNA baroreflex responses in CKD patients, where despite elevated basal SNA levels, baroreflex control is not consistently reported as reduced [1,16,17].…”

“…While not elucidated in the current study, given that baroreflex function is inversely correlated with kidney function in this model [19] and CKD patients [2], the level of kidney disease is likely a key determinant. Thus, the degree of baroreflex dysfunction may become more widespread and include more sympathetic outflows as the severity of CKD worsens.…”

“…We have demonstrated previously that baroreflex regulation of renal SNA (rSNA) in the LPK becomes compromised once a significant decline in renal function is evident [19]. In comparison, our previous study examining splanchnic SNA (sSNA) has demonstrated that baroreflex control of sSNA is not overtly compromised [20], suggesting that the central processing of renal and splanchnic sympathetic outflows is differentially regulated.…”

“…The baroreflex control of SNA was examined by measuring the reflex changes in sSNA, rSNA and lSNA in response to changes in MAP induced by sequential i.v. injections of PE (10-40 mg/kg) and SNP (10-50 mg/kg) [19]. The peripheral chemoreflex was tested by ventilating the animal with 100% N 2 for 12 s [24].…”

Long-Term Angiotensin II Receptor Blockade Limits Hypertension, Aortic Dysfunction, and Structural Remodeling in a Rat Model of Chronic Kidney Disease

“…Tissue was processed for paraffin embedding using an automated tissue processor (ASP2005, Leica GmbH, Wetzlar, Germany) and 5-µm sections were obtained using a microtome (Leica Microm HH325). Aortic sections were then stained for elastin (Shikata's Orcein), collagen deposition and smooth muscle cell nuclei (Martius Scarlet Blue) and calcium deposition (von Kossa), as previously described [26]. Images were acquired at 20× magnification (Zeiss Axiovision v4.8.2.0, Carl Zeiss Microimaging, Gottingen, Germany) and histomorphometric analysis was performed using Image J customized automated image-processing software [27], as described previously [26,28].…”