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The present study was performed to determine the effects of neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (COX-2) inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible ANG II-dependent malignant hypertension [strain name: TGR(CyplalRen2)]. Male Cyplal-Ren2 rats (n = 7) were fed a normal diet containing indole-3-carbinol (I3C; 0.3%) for 6-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were assessed in pentobarbital sodium-anesthetized Cyplal-Ren2 rats before and during intravenous infusion of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 1 mg/h). In hypertensive Cyplal-Ren2 rats, L-SMTC increased MAP from 169 [+ or -] 3 to 188 [+ or -] 4 mmHg (P < 0.01), which was a smaller increase than in noninduced rats (124 [+ or -] 9 to 149 [+ or -] 9 mmHg, P < 0.01, n = 5). Additionally, L-SMTC decreased renal plasma flow (RPF) to a similar extent (-34 [+ or -] 13 vs. -35 [+ or -] 12%) in the hypertensive and normotensive rats (4.1 [+ or -] 0.2 to 2.7 [+ or -] 0.5 and 3.1 [+ or -] 0.3 to 2.0 [+ or -] 0.3 ml x [min.sup-1] x [g.sup.-1], respectively, P < 0.01) but did not alter glomerular filtration rate (GFR) in either group. In additional experiments, administration of the COX-2 inhibitor, nimesulide (3 mg/kg iv), during simultaneous infusion of L-SMTC decreased MAP in both hypertensive and noninduced rats (182 [+ or -] 2 to 170 [+ or -] 3 mmHg and 153 [+ or -] 3 to 140 [+ or -] 3 mmHg, respectively, P < 0.01). Nimesulide also decreased RPF (1.9 [+ or -] 0.2 to 0.8 [+ or -] 0.1 ml x [min.sup.-1] x [g.sup.-1], P < 0.01) and GFR (0.9 [+ or -] 0.1 to 0.4 [+ or -] 0.1 ml x [min.sup.-1] x [g.sup.-1], P < 0.01) in hypertensive rats but did not alter RPF or GFR in noninduced rats. The present findings demonstrate that both nNOS-derived NO and COX-2 metabolites exert pronounced renal vasodilator influences in hypertensive Cyplal-Ren2 rats. The data also indicate that the renal vasodilator effects of COX-2-derived prostanoids in hypertensive Cyplal-Ren2 rats are not dependent on nNOS activity. kidney; nimesulide; S-methyl-L-thiocitrulline; renal hemodynamics; renin-angiotensin system; glomerular filtration rate; renal plasma flow

The contribution of elevated aldosterone to the pathogenesis of malignant, ANG II-dependent hypertension remains uncertain. Therefore, we examined whether chronic mineralocorticoid receptor blockade attenuates the development of malignant hypertension in transgenic rats (TGRs) with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Systolic blood pressure (SBP) was measured by radiotelemetry in male TGRs in three groups: 1) control (n = 9), 2) hypertensives (HT; n = 8), and 3) hypertensives + spironolactone (11 mg x [kg.sup.-1] x day sc; HTS; n = 8). Malignant hypertension was induced with dietary indole-3-carbinol (0.3%) for 10 days. Metabolic measurements were taken at the beginning of the study and at day's 2 and 9. HT exhibited elevated SBP (125 [+ or -] 3 vs. 187 [+ or -] 5 mmHg), plasma renin activity (5 [+ or -] 1 vs. 29 [+ or -] 10 ng ANG I x [ml.sup.-1] x [h.sup.-1]), plasma ANG II (175 [+ or -] 39 vs. 611 [+ or -] 74 fmol/ml), and plasma aldosterone (0.31 [+ or -] 0.04 vs. 5.42 [+ or -] 1.02 nmol/l). Urinary aldosterone excretion increased 5.5-fold by day 2 and an additional 90% by day 9. HT was associated with a 1.8-fold increase in proteinuria by day 9 that was alleviated by treatment with spironolactone (25 [+ or -] 5 vs. 13 [+ or -] 3 mg/day), suggesting that aldosterone contributes to the renal damage observed in malignant hypertension. Urinary Na+ excretion was decreased 76% on day 2, despite a sixfold increase in urinary aldosterone excretion. Decrease in urinary [Na.sup.+] excretion on day 2 in HT suggests that [Na.sup.+] reabsorption was increased in response to the increase in aldosterone; however, the lack of a change in SBP between HT and HTS suggests that mechanisms independent of aldosterone stimulation make a greater contribution to the maintenance of elevated arterial pressure in malignant hypertension in Cyp1a1-Ren2 transgenic rats. angiotensin II; eplerenone; pressure natriuresis; spironolactone

Transgenic rats with inducible ANG II-dependent malignant hypertension [TGR(Cyp1a1-Ren2)] were generated by inserting the mouse Ren2 renin gene into the genome of the rat. The present study was performed to assess renal morphological changes occurring during the development of ANG II-dependent malignant hypertension in these rats. Male Cyplal-Ren2 rats (n = 10) were fed normal rat food containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension. Rats induced with I3C had higher mean arterial pressures (173 [+ or -] 9 vs. 112 [+ or -] 11 mmHg, P < 0.01) than noninduced normotensive rats (n = 9). Glomerular damage was evaluated by determination of the glomerulosclerosis index (GSI) in tissue sections stained with periodic acid-Schiff. Kidneys of hypertensive rats had a higher GSI than normotensive rats (21.3 [+ or -] 5.6 vs. 3.5 [+ or -] 1.31 units). Quantitative analysis of macrophage ED-1-positive cells and proliferating cell nuclear antigen using immunohistochemistry demonstrated increased macrophage numbers in the renal interstitium (106.4 [+ or -] 11.4 vs. 58.7 [+ or -] 5.0 cells/[mm.sup.2]) and increased proliferating cell number in cortical tubules (37.8 [+ or -] 5.7 vs. 24.2 [+ or -] 2.1 cells/mm2), renal cortical vessels (2.2 [+ or -] 0.5 vs. 0.13 [+ or -] 0.07 cells/vessel), and the cortical interstitium (33.6 [+ or -] 5.7 vs. 4.2 [+ or -] 1.4 cells/[mm.sup.2]) of hypertensive rat kidneys. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyplal-Ren2 rats are characterized by inflammation and cellular proliferation in cortical vessels and tubulointerstitium. kidney; glomerulosclerosis; renal injury; immunohistochemistry; renin-angiotensin system; renal pathology; peptide hormones doi:10.1152/ajprenal.00469.2006

The present study was performed to determine the effects of cyclooxygenase (COX)-1 and COX-2 inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats (n = 7) were fed a normal diet containing the aryl hydrocarbon, indole-3-carbinol (I3C; 0.3%), for 6-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats during control conditions, following administration of the COX-2 inhibitor nimesulide (3 mg/kg iv), and following administration of the nonspecific COX inhibitor meclofenamate (5 mg/kg iv). Rats induced with I3C had higher MAP than noninduced rats (n = 7; 188 [+ or -] 6 vs. 136 [+ or -] 4 mmHg, P < 0.01). There was no difference in renal plasma flow (RPF) or glomerular filtration rate (GFR) between induced and non-induced rats. Nimesulide elicited a larger decrease in MAP in hypertensive rats (188 [+ or -] 6 to 140 [+ or -] 8 mmHg, P < 0.01) than in normotensive rats (136 [+ or -] 4 to 113 [+ or -] 8 mmHg, P < 0.01). Additionally, nimesulide decreased GFR (0.9 [+ or -] 0.13 to 0.44 [+ or -] 0.05 ml x [min.sup.-1] x [g.sup.-1], P < 0.05) and RPF (2.79 [+ or -] 0.27 to 1.35 [+ or -] 0.14 ml x [min.sup.-1] x [g.sup.-1], P < 0.05) in hypertensive rats but did not alter GFR or RPF in normotensive rats. Meclofenamate further decreased MAP in hypertensive rats (to 115 [+ or -] 10 mmHg, P < 0.05) but did not decrease MAP in normotensive rats. Meclofenamate did not alter GFR or RPF in either group. These findings demonstrate that COX-1- and COX-2-derived prostanoids contribute importantly to the development of malignant hypertension in Cyplal-Ren2 transgenic rats. The data also indicate that COX-2-derived vasodilatory metabolites play an important role in the maintenance of RPF and GFR following induction of malignant hypertension in Cyp1a1-Ren2 transgenic rats. renal hemodynamics; nimesulide; meclofenamate; kidney; renin-angiotensin system; glomerular filtration rate; renal plasma flow doi:10.1152/ajprenal.00032.2006

The present study was performed to evaluate tubuloglomerular feedback responses in transgenic rats [TGR(CypalalRen2)] with inducible malignant hypertension and to determine the degree to which feedback responsiveness is modulated by ANG II in these rats. Male Cyp1a1-Ren2 rats were fed a normal diet containing the aryl hydrocarbon indole-3-carbinol (I3C; 0.3%), for 5-6 days to stimulate expression of the Cyp1a1-Ren2 transgene and, thereby, to induce malignant hypertension. Stop-flow pressure (SFP) feedback responses to a late proximal perfusion rate of 40 nl/min were assessed in pentobarbital sodium-anesthetized rats during control conditions and after administration of the A[T.sub.1] receptor antagonist candesartan (0.1 mg/kg iv). Rats induced with I3C (n = 6) exhibited elevated mean arterial pressure and increased maximal SFP feedback responses compared with noninduced rats (n = 4; 163 [+ or -] 4 vs. 130 [+ or -] 2 mmHg, P < 0.01 and 16.3 [+ or -] 1.4 vs. 11.7 [+ or -] 0.5 mmHg, P < 0.05, respectively). Systemic candesartan decreased arterial pressure (to 98 [+ or -] 7 and to 101 [+ or -] 5 mmHg, respectively, P < 0.001) and attenuated SFP feedback responses (to 2.0 [+ or -] 0.4 and to 3.3 [+ or -] 0.9 mmHg, respectively, P < 0.01) in both hypertensive and normotensive rats. In additional experiments, peritubular capillary infusion of [10.sup.-3] M candesartan did not alter arterial pressure but attenuated feedback responses in both hypertensive (19.3 [+ or -] 1.4 to 8.8 [+ or -] 0.9 mmHg, P < 0.01, n = 9) and normotensive Cyp1a1-Ren2 rats (9.0 [+ or -] 0.8 to 4.7 [+ or -] 0.6 mmHg, P < 0.01, n = 7). The present findings indicate that Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension exhibit augmented tubuloglomerular feedback responses. The data also show that A[T.sub.1] receptor activation by ANG II contributes to the enhanced feedback responsiveness in Cyp1a1-Ren2 rats with malignant hypertension. renal micropuncture; kidney; renal hemodynamics; A[T.sub.1] receptors; blood pressure

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(Cypla1-Ren2)]. Malignant hypertension was induced in male Cypla1-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 Cypla1-Ren2 rats before and during intravenous infusion of the superoxide dismutase mimetic tempol (100 [micro]mol/h). Basal MAP and renal vascular resistance (RVR) were elevated in rats induced with indole-3-carbinol compared with noninduced rats (n = 5) (184 [+ or -] 4 vs. 127 [+ or -] 3 mmHg, P < 0.01, and 29 [+ or -] 2 vs. 21 [+ or -] 1 mmHg x [ml.sup.-1] x min x g, P < 0.01, respectively). Hypertensive rats had elevated excretion of urinary 8-isoprostane compared with normotensive rats (41 [+ or -] 4 vs. 13 [+ or -] 6 pg x [min.sup.-1] x [g.sup.-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 [+ or -] 4 to 151 [+ or -] 4 mmHg, P < 0.01) and RVR (29 [+ or -] 2 to 25 [+ or -] 2 mmHg x [ml.sup.-1] x min x g, P < 0.05) in hypertensive but not in normotensive Cypla1-Ren2 rats. In addition, tempol administration decreased urinary excretion of 8-isoprostane (41 [+ or -] 4 to 25 [+ or -] 4 pg x [min.sup.-1] x [g.sup.-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 Cypla1-Ren2 rats with malignant hypertension. tempol; kidney; renin-angiotensin system; GFR; peptide hormones

Transient exposure to ANG II results in the development of salt-sensitive hypertension in rats. This study was performed to determine whether a transient hypertensive episode can induce salt-sensitive hypertension in transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name TGR(Cyplal-Ren2)]. Systolic blood pressures were measured in conscious male Cyplal-Ren2 rats (n = 6) during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.15%, wt/wt), for 14 days. Systolic pressure increased from 135 [+ or -] 5 to 233 [+ or -] 7 mmHg by day 14. I3C administration was terminated and blood pressure returned to normal levels (137 [+ or -] 5 mmHg) within 10 days. Subsequently, the rats were placed on a high-salt diet (8% NaCl) for 10 days. Systolic pressure increased by 34 [+ or -] 2 mmHg throughout 10 days of the high-salt diet. Neither glomerular filtration rate nor renal plasma flow was altered in Cyplal-Ren2 rats with salt-sensitive hypertension. In a separate group of male Cyplal-Ren2 rats (n = 6) transiently induced with 0.15% I3C for 14 days, administration of the superoxide dismutase mimetic tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, 2 mM) attenuated the increase in systolic pressure induced by high salt. Systolic pressure increased by only 11 [+ or -] 1 mmHg throughout 8 days of a high-salt diet and tempol administration. Thus transient induction of ANG II-dependent hypertension via activation of the Cypl a l-Ren2 transgene induces salt-sensitive hypertension in these transgenic rats. The attenuation by tempol of the high salt-induced blood pressure elevation indicates that ANG II-induced production of superoxide anion contributes to the development of salt-sensitive hypertension after transient induction of ANG II-dependent hypertension. tempol; superoxide anion; kidney; sodium excretion; renal hemodynamics

A study was conducted on the peripheral and renal vascular responsiveness to angiotensin II (ANG II) in hypertensive transgenic rats (TGR). The mean arterial blood pressure and renal blood flow responses were measured in hypertensive TGR and age-matched transgene-negative control rats. The findings demonstrated that hypertensive TGR exhibited heightened peripheral and renal vascular responsiveness to ANG II, which increased vascular resistance, thereby leading to hypertension in TGR.

A study on the proximal tubular fluid, kidney and plasma levels of angiotensin II in hypertensive ren-2 transgenic rats (TGR) was conducted using in vivo micropuncture experiments. Results of the experiments revealed that proximal tubular fluid of hypertensive TGR contained nanomolar concentrations of angiotensin II (ANG II). Furthermore, proximal tubular fluid, plasma and kidney ANG II levels in anesthetized TGR are not suppressed.

Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in neonatal rats that have received intravenous injections of HOE-140, a bradykinin B2 receptor antagonist, to determine the role of B2 receptors in developmental changes in neonatal rat renal hemodynamics. The results show that bradykinin acting on B2 receptors is not the main mediator of the maturational increase in RBF and GFR. It was also discovered that the vasodilator effect of bradykinin on the developing rat kidney is antagonized by angiotensin II, which exerts its effects via AT1 receptors.

The levels of angiotensin II (ANG II) in proximal tubule fluid and the possible sources of ANG II were examined. Experiments were conducted to determine ANG II concentrations in free-flow samples of proximal tubular fluid by an ANG II radioimmunoassay procedure and in vivo microperfusion. The compartmentalization of intrarenal ANG II and the interdependent regulation of plasma and intrarenal ANG II levels were established.

Studies were conducted to examine the influence of activation of ATP-sensitive P2 purinoceptors on glomerular pressure, as determined from proximal tubule stop-flow pressure (SFP) assessments, and on the size of optimal tubuloglomerular feedback-intervened decrease in SFP. When adenosine receptor is obstructed, ATP can enhance preglomerular vascular resistance. Extracellular ATP functioning through particular P2 purinoceptors could be involved in the modulation of tubuloglomerular feedback responsiveness.

In angiotensin II (ANG II)-dependent hypertension, there is an angiotensin type 1 receptordependent amplification mechanism enhancing intrarenal angiotensinogen (AGT) formation and secretion in the tubular fluid. To evaluate the role of increased arterial pressure, AGT mRNA, protein expression, and urinary AGT (uAGT) excretion and tissue injury were assessed in both kidneys of two-kidney, one-clip Sprague-Dawley hypertensive rats subjected to left renal arterial clipping (0.25-mm gap). By 18-21 days, systolic arterial pressure increased to 180 ± 3 mmHg, and uAGT increased. Water intake, body weights, 24-h urine volumes, and sodium excretion were similar. In separate measurements of renal function in anesthetized rats, renal plasma flow and glomerular filtration rate were similar in clipped and nonclipped kidneys and not different from those in sham rats, indicating that the perfusion pressure to the clipped kidneys remained within the autoregulatory range. The nonclipped kidneys exhibited increased urine flow and sodium excretion. The uAGT excretion was significantly greater in nonclipped kidneys compared with clipped and sham kidneys. AGT mRNA was 2.15-fold greater in the nonclipped kidneys compared with sham (1.0 ± 0.1) or clipped (0.98 ± 0.15) kidneys. AGT protein levels were also greater in the nonclipped kidneys. The nonclipped kidneys exhibited greater glomerular expansion and immune cell infiltration, medullary fibrosis, and cellular proliferation than the clipped kidneys. Because both kidneys have elevated ANG II levels, the greater tissue injury in the nonclipped kidneys indicates that an increased arterial pressure synergizes with increased intrarenal ANG II to stimulate AGT production and exert greater renal injury. [ABSTRACT FROM AUTHOR]