Progressive Cardiac Metabolic Defects Accompany Diastolic and Severe Systolic Dysfunction in Spontaneously Hypertensive Rat Hearts.

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR).

Evidence That Binding of Cyclic GMP to the Extracellular Domain of NKA (Sodium-Potassium ATPase) Mediates Natriuresis.

Background: Extracellular renal interstitial guanosine cyclic 3',5'-monophosphate (cGMP) inhibits renal proximal tubule (RPT) sodium (Na) reabsorption via Src (Src family kinase) activation. Through which target extracellular cGMP acts to induce natriuresis is unknown. We hypothesized that cGMP binds to the extracellular α1-subunit of NKA (sodium-potassium ATPase) on RPT basolateral membranes to inhibit Na transport similar to ouabain-a cardiotonic steroid.

Renal AT Receptors Mediate Natriuresis via Protein Phosphatase PP2A.

Background: How signals from activated angiotensin type-2 receptors (ATR) mediate inhibition of sodium ion (Na) reabsorption in renal proximal tubule cells is currently unknown. Protein phosphatases including PP2A (protein phosphatase 2A) have been implicated in ATR signaling in tissues other than kidney. We investigated whether inhibition of protein phosphatase PP2A reduced ATR-mediated natriuresis and evaluated changes in PP2A activity and localization after renal ATR activation in normal 4- and 10-week-old control Wistar-Kyoto rats and 4-week-old prehypertensive and 10-week-old hypertensive spontaneously hypertensive rats.

Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats.

Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding β-amino acid. β-Amino acid substitution at the proline residue of Ang III (β-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of β-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats.

Identification of a Primary Renal AT Receptor Defect in Spontaneously Hypertensive Rats.

Rationale: Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl-angiotensin II])-elicited ATR (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR).

Objective: This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired ATR signaling and renal sodium (Na) retention by utilizing the selective ATR agonist compound-21 (C-21).

Methods And Results: Female 4-week-old Wistar Kyoto and SHR rats were studied after 24-hour systemic ATR (Ang II type-1 receptor) blockade.

Ghrelin-Induced Sodium Reabsorption Is Mediated by PKA and Microtubule-Dependent EC Translocation in Female Rats.

Intrarenal ghrelin infusion activates ghrelin receptors in the kidney collecting duct (CD) to increase epithelial sodium (Na) channel (EC)-dependent Na reabsorption , but the underlying mechanisms are unknown. Seventy-two hours following uninephrectomy, 12-week-old female Sprague-Dawley rats received the following renal interstitial (RI) infusions for 1 hour after a 1-hour control: vehicle (n = 10), ghrelin (3 μg/minute; n = 8), ghrelin + phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 (0.1 μg/kg/minute; n = 7), ghrelin + protein kinase A (PKA) inhibitor adenosine 3'5'-cyclic monophosphorothioate, Rp-isomer (10 μg/kg/minute; n = 8), ghrelin + microtubule polymerization inhibitor nocodazole (0.

Defective Renal Angiotensin III and AT Receptor Signaling in Prehypertensive Spontaneously Hypertensive Rats.

Background Previous studies demonstrated that angiotensin (Ang) III , not Ang II , is the predominant endogenous agonist for Ang type-2 receptor ( AT R)-induced natriuresis in normal rats, and that hypertensive 12-week-old spontaneously hypertensive rats ( SHR ) lack natriuretic responses to Ang III . This study tested whether prehypertensive SHR already have defective Ang III -induced natriuresis and determined possible mechanisms. Methods and Results Female and male normotensive 4-week-old SHR and Wistar Kyoto rats were studied after 24-hour systemic AT R blockade.

The Dopamine D Receptor and Angiotensin II Type-2 Receptor are Required for Inhibition of Sodium Transport Through a Protein Phosphatase 2A Pathway.

Activation of the renal DR (dopamine D-like receptor) or ATR (angiotensin II type-2 receptor), individually or both, simultaneously, is necessary in the normal regulation of renal sodium (Na) transport and blood pressure. However, little is known regarding the precise mechanism of this interaction. Pharmacological stimulation, membrane biotinylation, and cell surface immunofluorescence were used to study the effect of the DR/ATR interaction in human renal proximal tubule cells.

Metabolic Changes in Spontaneously Hypertensive Rat Hearts Precede Cardiac Dysfunction and Left Ventricular Hypertrophy.

Background Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats.

Intrarenal ghrelin receptor inhibition ameliorates angiotensin II-dependent hypertension in rats.

The intrarenal ghrelin receptor (GR) is localized to collecting duct (CD) cells, where it increases epithelial Na channel (αEC)-dependent sodium reabsorption in rodents. We hypothesized that chronic GR inhibition with intrarenal GR siRNA lowers blood pressure (BP) in angiotensin II-dependent hypertension via reductions in αEC-dependent sodium reabsorption. Uninephrectomized Sprague-Dawley rats ( n = 121) received subcutaneous osmotic pumps for chronic systemic delivery of angiotensin II or vehicle (5% dextrose in water).

Sodium bicarbonate cotransporter NBCe2 gene variants increase sodium and bicarbonate transport in human renal proximal tubule cells.

Rationale: Salt sensitivity of blood pressure affects >30% of the hypertensive and >15% of the normotensive population. Variants of the electrogenic sodium bicarbonate cotransporter NBCe2 gene, SLC4A5, are associated with increased blood pressure in several ethnic groups. SLC4A5 variants are also highly associated with salt sensitivity, independent of hypertension.

AT2 Receptor Activation Prevents Sodium Retention and Reduces Blood Pressure in Angiotensin II-Dependent Hypertension.

Rationale: Compound 21 (C-21) is a highly selective nonpeptide angiotensin AT2 receptor (AT2R) agonist.

Objective: To test the hypothesis that chronic AT2R activation with C-21 induces natriuresis via an action at the renal proximal tubule (RPT) and lowers blood pressure (BP) in experimental angiotensin II (Ang II)-dependent hypertension.

Methods And Results: In rats, Ang II infusion increased both sodium (Na(+)) retention and BP on day 1, and BP remained elevated throughout the 7-day infusion period.

The sodium-bicarbonate cotransporter NBCe2 (slc4a5) expressed in human renal proximal tubules shows increased apical expression under high-salt conditions.

The electrogenic sodium bicarbonate cotransporter (NBCe2) is encoded by SLC4A5, variants of which have been associated with salt sensitivity of blood pressure, which affects 25% of the adult population. NBCe2 is thought to mediate sodium bicarbonate cotransport primarily in the renal collecting duct, but NBCe2 mRNA is also found in the rodent renal proximal tubule (RPT). The protein expression or function of NBCe2 has not been demonstrated in the human RPT.

AT₂ receptor activation induces natriuresis and lowers blood pressure.

Rationale: Compound 21 (C-21) is a highly selective nonpeptide AT2 receptor (AT2R) agonist.

Objective: To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure in Sprague-Dawley rats and mice.

Methods And Results: In rats, AT2R activation with intravenous C-21 increased urinary sodium excretion by 10-fold (P<0.

Intrarenal ghrelin receptor antagonism prevents high-fat diet-induced hypertension in male rats.

Excess weight gain contributes up to 65% of the risk of primary hypertension, and the increase in blood pressure in response to high-fat diet (HFD) is preceded by significant increases in renal tubular sodium (Na(+)) reabsorption. In normal rats, intrarenal ghrelin infusion increases distal nephron-dependent Na(+) reabsorption via activation of the intrarenal ghrelin receptor (GHSR). This study focusses on the role of intrarenal GHSR-mediated Na(+) reabsorption in HFD-induced hypertension.

Intrarenal ghrelin receptors regulate ENaC-dependent sodium reabsorption by a cAMP-dependent pathway.

The main distal nephron segment sodium transporters are the distal tubule chlorothiazide-sensitive sodium chloride cotransporter (NCC) and the collecting duct amiloride-sensitive epithelial sodium channel (ENaC). The infusion of ghrelin into the renal interstitium stimulates distal nephron-dependent sodium reabsorption in normal rats, but the mechanism is unknown. Here we localize renal ghrelin receptors (GR) to the cortical collecting duct (CCD).

Intrarenal angiotensin III is the predominant agonist for proximal tubule angiotensin type 2 receptors.

In angiotensin type 1 receptor-blocked rats, renal interstitial (RI) administration of des-aspartyl(1)-angiotensin II (Ang III) but not angiotensin II induces natriuresis via activation of angiotensin type 2 receptors. In the present study, renal function was documented during systemic angiotensin type 1 receptor blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion, fractional sodium, and lithium excretion.

Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis.

Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D.

A nonpeptide angiotensin II type 2 receptor agonist does not attenuate postmyocardial infarction left ventricular remodeling in mice.

Cardiac overexpression of the angiotensin II type 2 receptor (AT2 R) attenuates left ventricular (LV) remodeling after myocardial infarction (MI) in transgenic mice. We hypothesized that a novel nonpeptide AT2 R agonist, compound 21 (C21), would attenuate post-MI LV remodeling. Fifty-nine mice were studied for 28 days after 1-hour surgical occlusion-reperfusion of the left anterior descending coronary artery.

Role of SRC family kinase in extracellular renal cyclic guanosine 3',5'-monophosphate- and pressure-induced natriuresis.

cGMP functions as an extracellular (paracrine) messenger acting at the renal proximal tubule and is an important modulator of pressure-natriuresis (P-N). The signaling pathway activated by cGMP in the tubule cell basolateral membrane remains unknown. We hypothesized that renal interstitial microinfusion of cGMP (50 nmol/kg per minute) or P-N would be accompanied by increased renal protein levels of phospho-Src (Tyr 416) and that the natriuresis would be decreased by Src inhibition.

The observable pressure of light in dielectric fluids.

By considering a perfect reflector submerged in a dielectric fluid, we show that the Minkowski formulation describes the optical momentum transfer to submerged objects. This result is required by global energy conservation, regardless of the phase of the reflected wave. While the electromagnetic pressure on a submerged reflector can vary with phase of the mirror reflection coefficient between twice the Abraham momentum and twice the Minkowski momentum, the Minkowski momentum is always restored due to the additional pressure on the dielectric surface.

Inhibition of renal caveolin-1 reduces natriuresis and produces hypertension in sodium-loaded rats.

Renal dopamine receptor function and ion transport inhibition are impaired in essential hypertension. We recently reported that caveolin-1 (CAV1) and lipid rafts are necessary for normal D(1)-like receptor-dependent internalization of Na-K-ATPase in human proximal tubule cells. We now hypothesize that CAV1 is necessary for the regulation of urine sodium (Na(+)) excretion (U(Na)V) and mean arterial blood pressure (MAP) in vivo.

Intrarenal ghrelin infusion stimulates distal nephron-dependent sodium reabsorption in normal rats.

Ghrelin is a 28-amino acid peptide hormone that exerts powerful orexigenic effects. Ghrelin receptor expression has been reported in the kidney, but the role of ghrelin in the kidney is unknown. The present studies confirmed ghrelin receptor mRNA expression in the kidneys of normal Sprague Dawley rats (n=6) using reverse transcription polymerase chain reaction (PCR) and sequencing of the 588-bp PCR product.

Optical force on a cylindrical cloak under arbitrary wave illumination.

The optical force distribution in the cylindrical cloak under arbitrary incident waves is presented. We show that on the inner surface of the cloak both the induced surface currents and polarization charges interact with the waves and give opposite radiation pressure onto the inner surface. The Lorentz force in the cloak can contribute to change the trajectory of the rays, while in some cases it may only reflect the rays having a tendency to decrease the total energy it carries.

Intrarenal aminopeptidase N inhibition restores defective angiontesin II type 2-mediated natriuresis in spontaneously hypertensive rats.

The preferred ligand of angiotensin (Ang) II type 2 (AT(2)R)-mediated natriuresis is Ang III. The major enzyme responsible for the metabolism of Ang III is aminopeptidase N, which is selectively inhibited by compound PC-18. In this study, urine sodium excretion rates (U(Na)V), fractional excretion of sodium, fractional excretion of lithium, glomerular filtration rate, and mean arterial pressures were studied in prehypertensive and hypertensive spontaneously hypertensive rats (SHRs) and compared with age-matched Wistar-Kyoto rats (WKYs).