Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries.

Rationale: Vascular wall stretch is the major stimulus for the myogenic response of small arteries to pressure. The molecular mechanisms are elusive, but recent findings suggest that G protein-coupled receptors can elicit a stretch response.

Objective: To determine whether angiotensin II type 1 receptors (AT1R) in vascular smooth muscle cells exert mechanosensitivity and identify the downstream ion channel mediators of myogenic vasoconstriction.

Interaction between P450 eicosanoids and nitric oxide in the control of arterial tone in mice.

Objective: Epoxyeicosatrienoic acids (EETs) serve as endothelial-derived hyperpolarizing factors (EDHF), but may also affect vascular function by other mechanisms. We identified a novel interaction between EETs and endothelial NO release using soluble epoxide hydrolase (sEH) -/- and +/+ mice.

Methods And Results: EDHF responses to acetylcholine in pressurized isolated mesenteric arteries were neither affected by the sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), nor by sEH gene deletion.

Antioxidant U74389G improves glycerol-induced acute renal failure without affecting PPARgamma gene.

Oxygen metabolites play an important role in the pathogenesis of myoglobinuric acute renal failure (ARF). Previously, we have reported a down regulation of peroxisome proliferator activated receptor gamma (PPARgamma) in glycerol-induced ARF, and the induction of PPARgamma has been shown to provide renal protection. In this study, we determined the protective influence of U74389G, a hydroxyl radical scavenger in myoglobinuric ARF, and its association with PPARgamma-mediated renal protection in the rat.

The vasodilator 17,18-epoxyeicosatetraenoic acid targets the pore-forming BK alpha channel subunit in rodents.

17,18-Epoxyeicosatetraenoic acid (17,18-EETeTr) stimulates vascular large-conductance K(+) (BK) channels. BK channels are composed of the pore-forming BK alpha and auxiliary BK beta1 subunits that confer an increased sensitivity for changes in membrane potential and calcium to BK channels. Ryanodine-sensitive calcium-release channels (RyR3) in the sarcoplasmic reticulum (SR) control the process.

Regulator of G protein signalling 2 ameliorates angiotensin II-induced hypertension in mice.

Angiotensin II (Ang II) activates signalling pathways predominantly through the G-protein-coupled Ang II type 1 receptor (AT(1)R). The regulator of G protein signalling 2 (RGS2) is a negative G protein regulator. We hypothesized that RGS2 deletion changes blood pressure regulation by increasing the response to Ang II.

Ciglitazone, a peroxisome proliferator-activated receptor gamma inducer, ameliorates renal preglomerular production and activity of angiotensin II and thromboxane A2 in glycerol-induced acute renal failure.

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor, modulates vascular responses to angiotensin II (AII) or thromboxane A(2) (TxA(2)) via regulation of their gene/receptor. Increased vasoconstriction and deteriorating renal function in glycerol-induced acute renal failure (ARF) may be attributed to down-regulation of PPARgamma. In this study, we investigated the effect of ciglitazone (CG), a PPARgamma inducer, on AII and TxA(2) production and activity in glycerol-induced ARF.

Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation.

AA (arachidonic acid) hydroxylation to 20-HETE (20-hydroxyeicosatetraenoic acid) influences renal vascular and tubular function. To identify the CYP (cytochrome P450) isoforms catalysing this reaction in the mouse kidney, we analysed the substrate specificity of Cyp4a10, 4a12a, 4a12b and 4a14 and determined sex- and strain-specific expressions. All recombinant enzymes showed high lauric acid hydroxylase activities.

Nitric oxide/cytochrome P450 interactions in cyclosporin A-induced effects in the rat.

Introduction: The present study evaluated the contribution of 20-hydroxyeicosatetraenoic acid (20-HETE) and its interaction with nitric oxide (NO) in cyclosporin A-induced nephrotoxicity and hypertension.

Methods And Results: The treatment of rats with cyclosporin A (25 mg/kg) for 7 days increased the renal microsomal conversion of arachidonic acid (AA) to 20-HETE (93 +/- 6%, P < 0.05), increased systolic blood pressure (SBP), reduced the urinary excretion of nitrite (53 +/- 8%, P < 0.

Alteration in endothelin receptor sub-type responsiveness and in the endothelin-TXA(2) mimetic U46619 interaction, in type-2 hypertensive diabetic Zucker rats.

Background: Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates.

Endothelin-like action of Pausinystalia yohimbe aqueous extract on vascular and renal regional hemodynamics in Sprague Dawley rats.

The bark of the African tree Pausinystalia yohimbe has been used as a food additive with aphrodisiac and penile erection enhancing properties. The effect of an aqueous extract of P. yohimbe (CCD-X) on renal circulation was assessed in order to test the hypothesis that it possesses additional effects on nitric oxide production and/or endothelin-1 (ET-1)-like actions.

Chronic endopeptidase inhibition in DOCA-salt hypertension: mechanism of cardiovascular protection.

These studies examined the interactions of neutral endopeptidase (NEP), endothelin-1 (ET-1), and nitric oxide (NO) in deoxycorticosterone acetate (DOCA)-induced hypertension. Male Sprague-Dawley rats (n = 35) were uninephrectomized (UNx) or uninephrectomized and treated with DOCA (25 mg pellet implanted subcutaneously). Candoxatril (30 mg/kg day(-1)), a NEP inhibitor, was given orally for 3 weeks in UNx or DOCA rats.

Nitric oxide-epoxygenase interactions and arachidonate-induced dilation of rat renal microvessels.

Nitric oxide (NO) is an inhibitor of hemoproteins including cytochrome P-450 enzymes. This study tested the hypothesis that NO inhibits cytochrome P-450 epoxygenase-dependent vascular responses in kidneys. In rat renal pressurized microvessels, arachidonic acid (AA, 0.

Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat.

20-Hydroxyeicosatetraenoic acid (20-HETE), a major renal eicosanoid, regulates renal function and contributes to renal responses following withdrawal of nitric oxide (NO). However, the role of 20-HETE-synthesizing isoforms in renal function resulting from NO inhibition is unknown. The present study evaluated the role of cytochrome (CYP)4A1, -4A2 and -4A3 isoforms on renal function in the presence and absence of NO.

Gender difference in vascular and platelet reactivity to thromboxane A(2)-mimetic U46619 and to endothelial dependent vasodilation in Zucker fatty (hypertensive, hyperinsulinemic) diabetic rats.

We examined the hypothesis that gender differences exist in platelet and vascular reactivity in type-2 diabetes mellitus, using Zucker fatty diabetic rats of both sexes and their lean littermates. Type-2 diabetes is characterized by excessive platelet production of TXA(2), which is thrombogenic. Testosterone up-regulates platelet TXA(2) receptors and the aggregation response to thromboxane mimetics.

Renal cytochrome p450 oxygenases and preglomerular vascular response to arachidonic acid and endothelin-1 following ischemia/reperfusion.

This study tested the hypothesis that cytochrome P450 (P450) metabolites of arachidonic acid (AA) contribute to the vascular changes in ischemia/reperfusion (I/R) injury in the rat. In this study, P450-dependent omega-hydroxylase-mediated vascular reactivity of the rat renal interlobular and arcuate vessels [preglomerular vessels (PGMV)] was measured in left kidneys subjected to I/R. Clipping the left renal artery and vein for 30 min followed by reperfusion (I/R) for 3, 6, and 24 h markedly reduced renal microsomal omega-hydroxylase-mediated conversion of [(14)C]AA to 20-hydroxyeicosatetraenoic acid (HETE) that amounted to 34, 37, and 58% of the control enzyme activity, respectively.

Interactions of the renin-angiotensin system and alpha-1 adrenoceptors on renal hemodynamics in healthy and acute renal failure rats: the role of nitric oxide.

The renin-angiotensin (RAS) and the alpha1 sympathetic nervous system (SNS) interact at different levels in cardiovascular regulation. Concurrent use of angiotensin-converting enzyme (ACE) inhibitors and alpha1 receptor antagonists result in a synergistic antihypertensive action and is of wide utility in cardiovascular therapy. We examined the impact of concurrent inhibition of RAS (captopril or losartan) and the SNS (prazosin) before and after acute nitric oxide (NO) synthase inhibition with L-nitro-L-arginine methyl ester (L-NAME) on renal cortical perfusion (RCF) and blood pressure (MAP) in healthy and acute ischemic renal failure (ARF) rats (n = 6).

Role of NO and cytochrome P-450-derived eicosanoids in ET-1-induced changes in intrarenal hemodynamics in rats.

Endothelin-1 (ET-1) produces potent renal effects that we have previously shown to be dependent on cytochrome P-450 (CYP450) metabolites of aracidonic acid (24) This study evaluated the role of these metabolites in the effects produced by ET-1 on renal blood flow (RBF), cortical blood flow (CBF), medullary blood flow (MBF), and mean arterial blood pressure (MBP). ET-1 (20-200 pmol/kg) increased MBP, renal vascular resistance (RVR), and MBF but reduced CBF and RBF in a dose-dependent manner. The decreases in CBF and RBF, and increases in MBP and RVR were blunted by BMS-182874, an ET(A) receptor antagonist or BQ-788, an ET(B) receptor antagonist.

Cytochrome P450 omega/omega-1 hydroxylase-derived eicosanoids contribute to endothelin(A) and endothelin(B) receptor-mediated vasoconstriction to endothelin-1 in the rat preglomerular arteriole.

The preglomerular arteriole of the rat was used to evaluate the contribution of cytochrome P450-derived eicosanoids to the vasoconstrictor effect of endothelin (ET)-1 and to determine the receptors mediating the response. ET-1 (4 x 10(-11) to 2 x 10(-9) M) produced dose-dependent reductions in the intraluminal diameter of the renal arteriole ranging from 25 +/- 8 to 142 +/- 16 micrometer. BMS182874 [(5-dimethylamino)-N-(3, 4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; 3 microM], an ET(A) receptor antagonist, or BQ788 (N-cis-2, 6-dimethyl-piperidino-carbonyl-L-gamma-methylleucyl-D-1-methoxy carbonyl-tryptophanyl-D-norleucine; 1 microM), an ET(B) receptor antagonist, attenuated ET-1 vasoconstriction by 59 +/- 4 and 50 +/- 10%, respectively.