Upregulated Angiotensin Ia Receptors in the Hypothalamic Paraventricular Nucleus Sensitize Neuroendocrine Vasopressin Release and Blood Pressure in a Rodent Model of Polycystic Kidney Disease

Article

Author: Burke, Peter G R ; Hildreth, Cara M ; Underwood, Conor F ; McMullan, Simon ; Kumar, Natasha N ; Phillips, Jacqueline K ; Goodchild, Ann K

Introduction: Angiotensin (Ang) II signalling in the hypothalamic paraventricular nucleus (PVN) via Ang type-1a receptors (AT1R) regulates vasopressin release and sympathetic nerve activity – two effectors of blood pressure regulation. We determined the cellular expression and function of AT1R in the PVN of a rodent model of polycystic kidney disease (PKD), the Lewis polycystic kidney (LPK) rat, to evaluate its contribution to blood pressure regulation and augmented vasopressin release in PKD. Methods: PVN AT1R gene expression was quantified with fluorescent in situ hybridization in LPK and control rats. PVN AT1R function was assessed with pharmacology under urethane anaesthesia in LPK and control rats instrumented to record arterial pressure and sympathetic nerve activity. Results: AT1R gene expression was upregulated in the PVN, particularly in corticotrophin-releasing hormone neurons, of LPK versus control rats. PVN microinjection of Ang II produced larger increases in systolic blood pressure in LPK versus control rats (36 ± 5 vs. 17 ± 2 mm Hg; p < 0.01). Unexpectedly, Ang II produced regionally heterogeneous sympathoinhibition (renal: −33%; splanchnic: −12%; lumbar: no change) in LPK and no change in controls. PVN pre-treatment with losartan, a competitive AT1R antagonist, blocked the Ang II-mediated renal sympathoinhibition and attenuated the pressor response observed in LPK rats. The Ang II pressor effect was also blocked by systemic OPC-21268, a competitive V1A receptor antagonist, but unaffected by hexamethonium, a sympathetic ganglionic blocker. Discussion/Conclusion: Collectively, our data suggest that upregulated AT1R expression in PVN sensitizes neuroendocrine release of vasopressin in the LPK, identifying a central mechanism for the elevated vasopressin levels present in PKD.

01 Dec 2019·Journal of Biomedical ScienceQ2 · MEDICINE

Arginine vasopressin modulates electrical activity and calcium homeostasis in pulmonary vein cardiomyocytes

Q2 · MEDICINE

ArticleOA

Author: Chen, Shih-Ann ; Chen, Yao-Chang ; Huang, Jen-Hung ; Lin, Yung-Kuo ; Lu, Yen-Yu ; Chen, Yi-Jen

AbstractBackgroundAtrial fibrillation (AF) frequently coexists with congestive heart failure (HF) and arginine vasopressin (AVP) V1 receptor antagonists are used to treat hyponatremia in HF. However, the role of AVP in HF-induced AF still remains unclear. Pulmonary veins (PVs) are central in the genesis of AF. The purpose of this study was to determine if AVP is directly involved in the regulation of PV electrophysiological properties and calcium (Ca2+) homeostasis as well as the identification of the underlying mechanisms.MethodsPatch clamp, confocal microscopy with Fluo-3 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, Ca2+ homeostasis, and Ca2+ regulatory proteins in isolated rabbit single PV cardiomyocytes incubated with and without AVP (1 μM), OPC 21268 (0.1 μM, AVP V1 antagonist), or OPC 41061 (10 nM, AVP V2 antagonist) for 4–6 h.ResultsAVP (0.1 and 1 μM)-treated PV cardiomyocytes had a faster beating rate (108 to 152%) than the control cells. AVP (1 μM) treated PV cardiomyocytes had higher late sodium (Na+) and Na+/Ca2+ exchanger (NCX) currents than control PV cardiomyocytes. AVP (1 μM) treated PV cardiomyocytes had smaller Ca2+i transients, and sarcoplasmic reticulum (SR) Ca2+ content as well as higher Ca2+ leak. However, combined AVP (1 μM) and OPC 21268 (0.1 μM) treated PV cardiomyocytes had a slower PV beating rate, larger Ca2+i transients and SR Ca2+ content, smaller late Na+ and NCX currents than AVP (1 μM)-treated PV cardiomyocytes. Western blot experiments showed that AVP (1 μM) treated PV cardiomyocytes had higher expression of NCX and p-CaMKII, and a higher ratio of p-CaMKII/CaMKII.ConclusionsAVP increases PV arrhythmogenesis with dysregulated Ca2+ homeostasis through vasopressin V1 signaling.

01 Jan 2019·Journal of HypertensionQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: Conor F. Underwood ; Cara M. Hildreth ; Rochelle Boyd ; Jacqueline K. Phillips

BACKGROUNDHypertension and baroreflex dysfunction confer poorer outcomes in patients with polycystic kidney disease (PKD).METHODWe examined whether hypothalamic paraventricular nucleus (PVN) activation or circulating vasopressin contribute to hypertension and baroreflex dysfunction in the Lewis polycystic kidney (LPK) rat.RESULTSBilateral 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).CONCLUSIONOur 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.

100 Deals associated with OPC-21268

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Indication	Highest Phase	Country/Location	Organization	Date
Nephrotoxicity	Phase 2	JP	Otsuka Pharmaceutical Co., Ltd.	06 Jan 1998
Diabetic Nephropathies	Phase 2	JP	-	-
Heart Failure	Phase 2	JP	-	-
Heart Failure	Phase 2	-	Otsuka Holdings Co., Ltd.	-
Hypertension	Phase 2	JP	Otsuka Pharmaceutical Co., Ltd.	-
Hypertension	Phase 2	-	Otsuka Holdings Co., Ltd.	-
Postmyocardial infarction syndrome	Phase 2	JP	-	-
Stomach Diseases	Phase 2	JP	-	-

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