EET enhances renal function in obese mice resulting in restoration of HO-1-Mfn1/2 signaling, and decrease in hypertension through inhibition of sodium chloride co-transporter.

Background: We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on renal and adipose tissue function, in addition to its vasodilatory action; it increases insulin sensitivity and inhibits inflammation. In an examination of the signaling mechanisms by which EET reduces renal and peri-renal fat function, we hypothesized that EET ameliorates obesity-induced renal dysfunction by improving sodium excretion, reducing the sodium-chloride cotransporter NCC, lowering blood pressure, and enhancing mitochondrial and thermogenic gene levels in PGC-1α dependent mice.

Methods: EET-agonist treatment normalized glucose metabolism, renal ENaC and NCC protein expression, urinary sodium excretion and blood pressure in obese (db/db) mice.

Cardiovascular responses to intranasal neuropeptide Y in single prolonged stress rodent model of post-traumatic stress disorder.

Delivery of neuropeptide Y (NPY) to the brain by intranasal administration shows promise as non-invasive means for preventing or treating PTSD symptoms. Here, radiotelemetry and echocardiography were used to determine effects of intranasal NPY on cardiovascular functions in absence and presence of stress. Male adult Sprague Dawley rats were implanted with radiotelemetric probes, and subjected to single prolonged stress (SPS), followed by intranasal vehicle (V) or NPY (150μg) under conditions shown to prevent development of many of the behavioral neuroendocrine and biochemical impairments.

Pharmacological manipulation of arachidonic acid-epoxygenase results in divergent effects on renal damage.

Kidney damage is markedly accelerated by high-salt (HS) intake in stroke-prone spontaneously hypertensive rats (SHRSP). Epoxyeicosatrienoic acids (EETs) are epoxygenase products of arachidonic acid which possess vasodepressor, natriuretic, and anti-inflammatory activities. We examined whether up-regulation (clofibrate) or inhibition [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH)] of epoxygenase would alter systolic blood pressure (SBP) and/or renal pathology in SHRSP on HS intake (1% NaCl drinking solution).

Tumor necrosis factor-alpha induces renal cyclooxygenase-2 expression in response to hypercalcemia.

The effect of tumor necrosis factor-alpha (TNF) on cyclooxygenase-2 (COX-2) expression in the renal outer medulla (OM) was determined in a model of dihydrotachysterol (DHT)-induced hypercalcemia. Increases in serum calcium and water intake were observed during ingestion of a DHT-containing diet in both wild type (WT) and TNF deficient mice (TNF(-/-)). Polyuria and a decrease in body weight were observed in response to DHT treatment in WT and TNF(-/-) mice.

Tumor necrosis factor-alpha is an endogenous inhibitor of Na+-K+-2Cl- cotransporter (NKCC2) isoform A in the thick ascending limb.

The effects of TNF gene deletion on renal Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) expression and activity were determined. Outer medulla from TNF(-/-) mice exhibited a twofold increase in total NKCC2 protein expression compared with wild-type (WT) mice. This increase was not observed in TNF(-/-) mice treated with recombinant human TNF (hTNF) for 7 days.

Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats.

Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity (V(max)) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP).

TNFR1-deficient mice display altered blood pressure and renal responses to ANG II infusion.

The hypothesis that TNF receptor 1-deficient (TNFR1(-/-)) mice display blood pressure (BP) and renal functional responses that differ from wild-type (WT) mice was tested in an angiotensin II (ANG II)-dependent model of hypertension. Basal systolic BP (SBP), mean arterial pressure, diastolic BP, heart rate (HR), and pulse pressure were similar in WT and TNFR1(-/-) mice. Infusion of ANG II for 7 days elevated SBP to a greater extent in TNFR1(-/-) compared with WT mice; pulse pressure was also elevated in TNFR1(-/-).

Inhibition of the adenosine2A receptor-epoxyeicosatrienoic acid pathway renders Dahl salt-resistant rats hypertensive.

Adenosine-induced renovasodilation in Dahl rats is mediated via activation of adenosine(2A) receptors (A(2A)Rs) and stimulation of epoxyeicosatrienoic acid (EET) synthesis. Unlike Dahl salt-resistant rats, salt-sensitive rats exhibit an inability to upregulate the A(2A)R-EET pathway with salt loading; therefore, we examined the effect of in vivo inhibition of the A(2A)R-EET pathway on blood pressure and the natriuretic response to salt-loading in Dahl salt-resistant rats. N-Methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 20 mg/kg per day), an epoxygenase inhibitor, or ZM241385 (ZM; 5 mg/kg per day), an A(2A)R antagonist, was given daily as an IV bolus dose for 3 days before and after placing rats on high salt intake (2% saline).

Kinetics and persistence of cardiovascular and locomotor effects of immobilization stress and influence of ACTH treatment.

Stress triggers crucial responses, including elevated blood pressure and heart rate (HR), to handle the emergency and restore homeostasis. However, continuation of these effects following cessation of the stress is implicated with many stress-related disorders. Here, we examine the kinetics and persistence of cardiovascular and locomotor responses to single and repeated immobilization stress (IMO), with and without prior treatment with adrenocorticotropic hormone (ACTH).

Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension.

In stroke-prone spontaneously hypertensive rats (SHRSP) end-organ damage is markedly accelerated by high-salt (HS) intake. Since epoxyeicosatrienoic acids (EETs) possess vasodepressor and natriuretic activities, we examined whether a soluble epoxide hydrolase (sEH) inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), to inhibit the metabolism of EETs, would protect against pathologic changes in SHRSP. Seven-week-old male SHRSP were treated as follows: normal salt (NS), NS + AUDA, HS and HS + AUDA.

Aldosterone, but not angiotensin II, increases profibrotic factors in kidney of adrenalectomized stroke-prone spontaneously hypertensive rats.

An increase in angiotensin II (ANG II) under conditions of high salt intake can result in renal damage. The extent to which ANG II does this directly or by way of stimulating aldosterone (Aldo) secretion is a subject of some debate. In the present study, we sought to determine the separate effects of Aldo and ANG II on the expression of plasminogen activator inhibitor-1 (PAI-1) and other factors related to renal fibrosis in the stroke-prone spontaneously hypertensive rat (SHRSP).

Direct inhibition of renin as a cardiovascular pharmacotherapy: focus on aliskiren.

The important role of renin-angiotensin-aldosterone system blockade in the treatment of systemic hypertension, heart failure, diabetic kidney disease, and atherogenesis has been clearly established. The theoretical therapeutic advantages for inhibiting the detrimental effects of the renin-angiotensin system at its most upstream point have served as the impetus for the development of renin inhibitors. The advent of aliskiren, the first in a novel class of orally active, nonpeptide, highly specific, human renin inhibitors, provides a new modality in the armamentarium of renin-angiotensin system antagonists.

Increase in heme oxygenase-1 levels ameliorates renovascular hypertension.

Background: The heme oxygenase system (HO-1 and HO-2) catalyzes the conversion of heme to free iron, carbon monoxide (CO), a vasodepressor, and biliverdin, which is further converted to bilirubin, an antioxidant. HO-1 induction has been shown to suppress arachidonic acid metabolism by cytochrome P450 (CYP450) monooxygenases and cyclooxygenases (COX), and to decrease blood pressure in spontaneously hypertensive rats (SHR). The Goldblatt 2K1C model is a model of renovascular hypertension in which there is increased expression of COX-2 in the macula densa and increased renin release from the juxtaglomerular apparatus of the clipped kidney.

Effect of aldosterone and MR blockade on the brain and the kidney.

The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-I converting enzyme (ACE) inhibitors and angiotensin II (Ang II) subtype-1 (AT(1)) receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur whereby aldosterone levels return to, or exceed, baseline levels. The classical effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance.

Male gender and not the severity of hypertension is associated with end-organ damage in aged stroke-prone spontaneously hypertensive rats.

Background: It is well-known that gender affects the progression of kidney failure. Male patients exhibit faster development of age-dependent renal disease than do women. In the present study, we examined arterial blood pressure (BP), proteinuria, and end-organ damage in male and female retired breeders from our colony of stroke-prone spontaneously hypertensive rats (SHRSP).

Stress triggered rise in plasma aldosterone is lessened by chronic nicotine infusion.

The ability of nicotine infusion to modulate plasma aldosterone levels in response to different stressors was investigated. Sprague-Dawley rats given nicotine (5 mg/kg/day) or saline for 14 days were subjected to stress. Baseline plasma aldosterone (86+/-17 pmol/l) was unaffected by nicotine.

Aldosterone and aldosterone antagonism in systemic hypertension.

Aldosterone mediates both water and electrolyte balance by acting on the renal mineralocorticoid receptors. Recent experimental studies have also documented the presence of these receptors in other body organs, including the brain, blood vessels, and heart, suggesting that aldosterone plays a larger role in normal physiologic function and in cardiovascular diseases such as systemic hypertension and congestive heart failure (CHF). The nonspecific aldosterone inhibitor spironolactone, and the selective aldosterone inhibitor eplerenone, are both approved for clinical use in treating patients with hypertension and/or symptomatic CHF.