Excitatory inputs to the hypothalamic paraventricular nucleus contribute to tonic, but not baroreflex, control of blood pressure in chronic kidney disease: possible role of angiotensin II and superoxide
thesisposted on 2022-03-28, 21:06 authored by Conor F. Underwood
Increased cardiovascular mortality in chronic kidney disease (CKD) is in part due to hypertension and impaired baroreflex regulation of blood pressure. We tested the hypothesis that increased glutamatergic drive of the paraventricular nucleus (PVN) contributes to hypertension and baroreflex dysfunction in the Lewis Polycystic Kidney rat (LPK) model of CKD. In urethane anaesthetised adult male Lewis control and LPK rats (n=13) instrumented to record arterial pressure, heart rate (HR) and renal sympathetic nerve activity (RSNA), bilateral PVN microinjections of the glutamate receptor antagonist kynurenic acid (100mM) reduced systolic blood pressure to a greater extent in LPK vs. Lewis (-31±3 vs. -10±3mmHg P<0.01), did not influence HR in either strain (P>0.05) and transiently increased RSNA in LPK rats only (5 min post-microinjection 119±2 vs. baseline 100±1% P<0.05). Baroreflex curves for HR and RSNA were rightward shifted in LPK and gain was reduced vs. Lewis, however kynurenic acid did not influence baroreflex parameters in either strain (both P>0.05). Considering that angiotensin II-mediated superoxide production may facilitate excitation within the PVN, we assessed PVN superoxide in-situ with the redox-sensitive fluorophore dihydroethidium (DHE) in adult mixed-sex Lewis and LPK rats (n=22) that were untreated or treated with the angiotensin II AT1 receptor antagonist losartan (30mg/kg/day) from 4 weeks of age. In untreated rats, PVN DHE fluorescence was greater in LPK vs. Lewis (2.0±0.3 vs. 1.0±0.2 relative fluorescence P=0.02), but was normalised by losartan (1.3±0.1). These data suggest that enhanced PVN glutamatergic activity maintains hypertension in LPK but not baroreflex dysfunction, and implicate AT1 receptor-dependent superoxide overproduction as a possible mechanism.