Increased excitatory regulation of the hypothalamic paraventricular nucleus and circulating vasopressin results in the hypertension observed in polycystic kidney disease

Conor F. Underwood, Rochelle Boyd, Jacqueline K. Phillips, Cara M. Hildreth

Research output: Contribution to journalArticle

Abstract

Background: Hypertension and baroreflex dysfunction confer poorer outcomes in patients with polycystic kidney disease (PKD). Method: We examined whether hypothalamic paraventricular nucleus (PVN) activation or circulating vasopressin contribute to hypertension and baroreflex dysfunction in the Lewis polycystic kidney (LPK) rat. Results: Bilateral PVN inhibition with muscimol reduced SBP further in urethane-anaesthetized adult LPK rats than in control Lewis rats (-43 ± 4 vs. -18 ± 3 mmHg; P < 0.0001, n = 14), but was not associated with a greater reduction in sympathetic nerve activity (SNA) or improvement in HR or SNA baroreflex function. Blockade of ionotropic glutamatergic input to the PVN with kynurenic acid also reduced SBP (P < 0.001), but not SNA, further in both adult and juvenile LPK rats. No differences in AMPA or NMDA receptor mRNA expression were noted. Systemic V1A receptor antagonism using OPC-21268 reduced SBP in adult LPK rats only (P < 0.001) and had no effect on the depressor response to PVN inhibition (P = 0.39). Combined peripheral V1A receptor antagonism and PVN inhibition, however, normalized SBP in adult LPK rats (122 ± 11 vs. 115 ± 6 mmHg; LPK vs. Lewis, P > 0.05, n = 10). Conclusion: Our data show that in the LPK rat model of PKD, hypertension is contributed to by increased PVN neuronal activity and, through an independent mechanism, systemic V1A receptor activation. Treatments that reduce PVN neuronal activity and/or inhibit peripheral V1A receptors may provide novel treatment strategies to ameliorate hypertension in individuals with PKD and limit overall disease progression.

Original languageEnglish
Pages (from-to)109-115
Number of pages7
JournalJournal of Hypertension
Volume37
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • baroreceptor reflex
  • hypertension
  • polycystic kidney disease
  • sympathetic nerve activity
  • vasopressin

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