Attenuated dopaminergic tone in the paraventricular nucleus contributing to sympathoexcitation in rats with Type 2 diabetes

The study was conducted to investigate the role for dopamine in the centrally mediated sympathoexcitatory response in rats with Type 2 diabetes (T2D). T2D was induced by a combination of high-fat diet (HFD) and low-dose streptozotocin (STZ). HFD/STZ treatment for 12–14 wk resulted in significant increase in the number of FosB-positive cells in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM). In anesthetized rats, administration of exogenous dopamine (dopamine hydrochloride, 20 mM) in the PVN, but not in the RVLM, elicited decreases in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in control rats and but not in the T2D rats. Blocking the endogenous dopamine with dopamine D1/D5 receptor antagonist SCH39166 (2 mM) in the PVN and RVLM, resulted in increases in RSNA, MAP, and heart rate (HR) in both control and T2D rats. These responses were significantly attenuated in T2D rats compared with control rats (PVN − ΔRSNA: 21 ± 10 vs. 44 ± 2%; ΔMAP: 7 ± 3 vs. 19 ± 6 mmHg, ΔHR: 17 ± 5 vs. 32 ± 4 bpm, P < 0.05). There were no significant increases in response to dopamine D2/D3 receptor antagonist raclopride application in the PVN and RVLM of both control and T2D rats. Furthermore, there were decreased dopamine D1 receptor and D2 receptor expressions in the PVN of T2D rats. Taken together, these data suggest that reduced endogenous dopaminergic tone within the PVN may contribute to the sympathoexcitation in T2D.

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EP3 receptors mediate PGE2-induced hypothalamic paraventricular nucleus excitation and sympathetic activation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00262.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. H1559-H1569 ◽

Cited By ~ 28

Author(s):

Zhi-Hua Zhang ◽

Yang Yu ◽

Shun-Guang Wei ◽

Yoshiko Nakamura ◽

Kazuhiro Nakamura ◽

...

Keyword(s):

Receptor Antagonist ◽

Paraventricular Nucleus ◽

Hypothalamic Paraventricular Nucleus ◽

Prostaglandin E ◽

Renal Sympathetic Nerve Activity ◽

Ep Receptors ◽

Ep Receptor ◽

Immunohistochemical Studies ◽

The Brain ◽

Renal Sympathetic

Prostaglandin E2 (PGE2), an important mediator of the inflammatory response, acts centrally to elicit sympathetic excitation. PGE2 acts on at least four E-class prostanoid (EP) receptors known as EP1, EP2, EP3, and EP4. Since PGE2 production within the brain is ubiquitous, the different functions of PGE2 depend on the expression of these prostanoid receptors in specific brain areas. The type(s) and location(s) of the EP receptors that mediate sympathetic responses to central PGE2 remain unknown. We examined this question using PGE2, the relatively selective EP receptor agonists misoprostol and sulprostone, and the available selective antagonists for EP1, EP3, and EP4. In urethane-anesthetized rats, intracerebroventricular (ICV) administration of PGE2, sulprostone or misoprostol increased renal sympathetic nerve activity, blood pressure, and heart rate. These responses were significantly reduced by ICV pretreatment with the EP3 receptor antagonist; the EP1 and EP4 receptor antagonists had little or no effect. ICV PGE2 or misoprostol increased the discharge of neurons in the hypothalamic paraventricular nucleus (PVN). ICV misoprostol increased the c-Fos immunoreactivity of PVN neurons, an effect that was substantially reduced by the EP3 receptor antagonist. Real-time PCR detected EP3 receptor mRNA in PVN, and immunohistochemical studies revealed sparsely distributed EP3 receptors localized in GABAergic terminals and on a few PVN neurons. Direct bilateral PVN microinjections of PGE2 or sulprostone elicited sympathoexcitatory responses that were significantly reduced by the EP3 receptor antagonist. These data suggest that EP3 receptors mediate the central excitatory effects of PGE2 on PVN neurons and sympathetic discharge.

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The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep

The Journal of Physiology ◽

10.1113/jphysiol.2012.236059 ◽

2012 ◽

Vol 591 (1) ◽

pp. 93-107 ◽

Cited By ~ 34

Author(s):

Rohit Ramchandra ◽

Sally G. Hood ◽

Robert Frithiof ◽

Michael J. McKinley ◽

Clive N. May

Keyword(s):

Heart Failure ◽

Paraventricular Nucleus ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Nerve Activity ◽

Renal Sympathetic Nerve Activity ◽

Renal Sympathetic Nerve ◽

Renal Sympathetic

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Role of vasopressin on cardiovascular changes during hemorrhage in conscious rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.267.5.h1713 ◽

1994 ◽

Vol 267 (5) ◽

pp. H1713-H1718 ◽

Cited By ~ 7

Author(s):

Y. Fujisawa ◽

A. Miyatake ◽

Y. Hayashida ◽

Y. Aki ◽

S. Kimura ◽

...

Keyword(s):

Receptor Antagonist ◽

Inhibitory Action ◽

Sympathetic Nerve Activity ◽

Stimulatory Action ◽

Renal Sympathetic Nerve Activity ◽

Conscious Rats ◽

V2 Receptor ◽

Regulation Of Blood Pressure ◽

Renal Sympathetic

Hypotensive hemorrhage decreases heart rate (HR) and renal sympathetic nerve activity (RSNA). Hemorrhage is a potent stimulus for arginine vasopressin (AVP) release; therefore, AVP may contribute to such inhibitory action of HR and RSNA during hemorrhage. We evaluated the roles of vasopressin on the regulation of blood pressure (BP), HR, and RSNA during hemorrhage using nonpeptide and selective V1- and V2-receptor antagonists (OPC-21268 and OPC-31260) in conscious rats. After hemorrhage (20 ml/kg body wt) BP decreased by 62 +/- 10 mmHg along with bradycardia (-110 +/- 15 beats/min) and renal sympathoinhibition (-50 +/- 8). Pretreatment of V1-receptor antagonist (5 mg/kg iv) did not affect the initial fall of BP but attenuated subsequent BP recovery. Bradycardic and renal sympathoinhibitory responses following hemorrhage were abolished (-14 +/- 24 beats/min and -7 +/- 9) by V1-receptor antagonist. Pretreatment of V2-receptor antagonist (1 mg/kg iv) did not affect the response of BP; however, it did slightly strengthen bradycardia and prolong renal sympathoinhibition. Hemorrhage increased the plasma AVP concentration more than 50-fold. These results indicate that when the plasma concentration of AVP is extremely high during hemorrhage, vasopressin via V1 receptor contributes to BP recovery by the peripheral vasoconstriction and exerts an inhibitory action on RSNA, and vasopressin via V2 receptor exerts opposite stimulatory action on RSNA.

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Renal Effects of S18886 (Terutroban), a TP Receptor Antagonist, in an Experimental Model of Type 2 Diabetes

Diabetes ◽

10.2337/db06-1136 ◽

2007 ◽

Vol 56 (4) ◽

pp. 968-974 ◽

Cited By ~ 27

Author(s):

K. Sebekova ◽

T. Eifert ◽

A. Klassen ◽

A. Heidland ◽

K. Amann

Keyword(s):

Type 2 Diabetes ◽

Receptor Antagonist ◽

Experimental Model ◽

Renal Effects ◽

Tp Receptor

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The Mineralocorticoid Receptor Antagonist Eplerenone Suppress Interstitial Fibrosis in Subcutaneous Adipose Tissue in Type 2 Diabetes Patients

10.2337/figshare.13050743.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Marie Louise Johansen ◽

Jaime Ibarrola ◽

Amaya Fernández-Celis ◽

Morten Schou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Receptor Antagonist ◽

Subcutaneous Adipose Tissue ◽

Mineralocorticoid Receptor ◽

Prostaglandin D2 ◽

Type I ◽

Mineralocorticoid Receptor Antagonist ◽

Subcutaneous Adipose

Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association between the MR, fibrosis and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present sub-study including 30 participants was prespecified as part of the Mineralocorticoid Receptor Antagonist in type 2 Diabetes (MIRAD) trial, randomizing patients to either high dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examinations and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen type I and VI, and the profibrotic factor α-smooth muscle actin, as compared to placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase–associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusions, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.

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