dinoprost and Hypertension--Malignant

We have shown recently that fasudil, a Rho-kinase inhibitor, has renoprotective effects in salt-sensitive hypertensive rats. We hypothesized that activation of Rho-kinase is involved in the pathogenesis of glomerulosclerosis in malignant hypertensive rats. To test this hypothesis, we studied the following 4 groups: control Wistar-Kyoto rats, untreated deoxycorticosterone-acetate salt spontaneously hypertensive rats (DOCA-SHR), low-dose fasudil-treated DOCA-SHR, and high-dose fasudil-treated DOCA-SHR. After 3 weeks of treatment, the effects of fasudil were examined. DOCA-SHR was characterized by increased blood pressure (BP); increased kidney weight; decreased renal function; increased proteinuria; abnormal histological findings; increased monocyte/macrophage infiltration; increased urinary 8-isoprostran levels; increased gene expression of collagen I, collagen III, transforming growth factor-beta, and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits (p40phox, p47phox, and p67phox); and decreased gene expression of endothelial NO synthase (eNOS) in the renal cortex as compared with Wistar-Kyoto rats. Long-term high-dose fasudil treatment significantly improved renal function and histological findings without changing BP, as compared with untreated DOCA-SHR. Interestingly, long-term fasudil treatment significantly decreased monocyte/macrophage infiltration and urinary 8-isoprostran excretion, in association with decreased mRNA levels of transforming growth factor-beta, collagen I, collagen III, and NADPH oxidase subunits (p40phox, p47phox, and p67phox), and increased mRNA levels of eNOS in the renal cortex. Long-term low-dose fasudil treatment tended to improve these variables slightly but did not affect most of them significantly. Our results suggest that long-term fasudil treatment provides renoprotective effects independent of BP-lowering activity. These renoprotective effects are associated with inhibition of extracellular matrix gene expression, monocyte/macrophage infiltration, oxidative stress, and upregulation of eNOS gene expression.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Desoxycorticosterone; Dinoprost; Dose-Response Relationship, Drug; Drug Administration Schedule; Ectodysplasins; Gene Expression; Hypertension, Malignant; Immunohistochemistry; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Cortex; Membrane Proteins; NADP; Nitric Oxide Synthase Type III; Protein Isoforms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; rho-Associated Kinases; Tumor Necrosis Factors

Superoxide anion contributes to the pathogenesis of various forms of hypertension, but its role in the development of malignant hypertension remains unclear. The present study was performed to determine the influence of superoxide anion on blood pressure and renal hemodynamics in transgenic rats with inducible malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Malignant hypertension was induced in male Cyp1a1-Ren2 rats (n = 6) through dietary administration of the aryl hydrocarbon, indole-3-carbinol (0.3%) for 7-9 days. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats before and during intravenous infusion of the superoxide dismutase mimetic tempol (100 mumol/h). Basal MAP and renal vascular resistance (RVR) were elevated in rats induced with indole-3-carbinol compared with noninduced rats (n = 5) (184 +/- 4 vs. 127 +/- 3 mmHg, P < 0.01, and 29 +/- 2 vs. 21 +/- 1 mmHg.ml(-1).min.g, P < 0.01, respectively). Hypertensive rats had elevated excretion of urinary 8-isoprostane compared with normotensive rats (41 +/- 4 vs. 13 +/- 6 pg.min(-1).g(-1), P < 0.01). There were no differences in renal plasma flow and glomerular filtration rate between groups. Systemic administration of tempol decreased MAP (184 +/- 4 to 151 +/- 4 mmHg, P < 0.01) and RVR (29 +/- 2 to 25 +/- 2 mmHg.ml(-1).min.g, P < 0.05) in hypertensive but not in normotensive Cyp1a1-Ren2 rats. In addition, tempol administration decreased urinary excretion of 8-isoprostane (41 +/- 4 to 25 +/- 4 pg.min(-1).g(-1), P < 0.05). Renal plasma flow and glomerular filtration rate remained unaltered during tempol administration in both groups. The administration of the nitric oxide synthase inhibitor nitro-l-arginine attenuated the decrease in MAP and RVR in response to tempol. These findings indicate that superoxide anion contributes to the elevated RVR and increased arterial blood pressure, by a mechanism that is at least in part nitric oxide dependent, in Cyp1a1-Ren2 rats with malignant hypertension.

Topics: Animals; Animals, Genetically Modified; Blood Pressure; Cyclic N-Oxides; Cytochrome P-450 CYP1A1; Dinoprost; Enzyme Inhibitors; Glomerular Filtration Rate; Hemodynamics; Hypertension, Malignant; Kidney Function Tests; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxidants; Rats; Renal Circulation; Renin; Spin Labels; Superoxides; Transgenes; Vascular Resistance

With radioimmunoassay, daily urinary levels of prostaglandins E2 and F2 alpha (PGE2, FGF2 alpha were measured in 45 patients with hypertensive disease, 13 patients with chronic diffuse glomerulonephritis and 14 healthy persons. A progressive reduction in urinary PGE2 excretion was found to accompany the occurrence of labile arterial hypertension (AH), its stabilization, and development of malignant AH in patients with hypertensive disease or chronic diffuse glomerulonephritis. When labile AH developed, urinary PGF2 alpha excretion was increased, but when AH stabilized, its excretion became increased up to the baseline level. The specific features of malignant AH are significantly higher urinary PGF2 alpha and sharply greater PGF2 alpha/PGE2 coefficient. The identified abnormal metabolism of renal prostaglandins may contribute to the stabilization of blood pressure at a high level and to the development of malignant AH.

Topics: Circadian Rhythm; Dinoprost; Dinoprostone; Glomerulonephritis; Humans; Hypertension; Hypertension, Malignant; Reference Values