Abstract-We recently reported that the activation of nuclear factor-B (NF-B) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]

Since its discovery, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. Plasma concentrations of endothelin-1 are low and its release by endothelial cells is polarized towards the basolateral side, suggesting that it is a paracrine factor and not a hormone. Consequently, the effect of injected endothelin-1 may not reflect the effect of endogenous endothelin-1. In contrast, blockade of the action of endogenous endothelin-1 using receptor antagonists should be a valuable means of investigating its physiological and pathological effects. We report here evidence for the pathophysiological role of endothelin-1 as brought by the first synthetic orally active nonpeptide antagonist of endothelin receptors, Ro 46-2005.

This study indicates that clazosentan reduces the frequency and severity of cerebral vasospasm following severe aneurysmal SAH with the incidence and severity of adverse events comparable to that of placebo.

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Abstract-Hypertension and kidney damage in the double transgenic rat (dTGR) harboring both human renin and human angiotensinogen genes are dependent on the human components of the renin angiotensin system. We tested the hypothesis that monocyte infiltration and increased adhesion molecule expression are involved in the pathogenesis of kidney damage in dTGR. We also evaluated the effects of long-term angiotensin-converting enzyme (ACE) inhibition, AT 1 blockade, and human renin inhibition on monocyte recruitment and inflammatory response in dTGR. Systolic blood pressure and 24-hour albuminuria were markedly increased in 7-week-old dTGR as compared with age-matched normotensive Sprague Dawley rats. We found a significant monocyte/macrophage infiltration in the renal perivascular space and increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the interstitium, intima, and adventitia of the small renal vessels. ␣ L ␤ 2 integrin and ␣ 4 ␤ 1 integrin, the corresponding ligands for ICAM-1 and VCAM-1, were also found on infiltrating monocytes/macrophages. The expression of plasminogen activator inhibitor-1 and fibronectin in the kidneys of dTGR were increased and distributed similarly to ICAM-1. In 4-week-old dTGR, long-term treatment with ACE inhibition (cilazapril), AT 1 receptor blockade (valsartan), and human renin inhibition (RO 65-7219) (each drug 10 mg/kg by gavage once a day for 3 weeks) completely prevented the development of albuminuria. However, only cilazapril and valsartan were able to decrease blood pressure to normotensive levels. Interestingly, the drugs were all equally effective in preventing monocyte/macrophage infiltration and the overexpression of adhesion molecules, plasminogen activator inhibitor-1, and fibronectin in the kidney. Our findings indicate that angiotensin II causes monocyte recruitment and vascular inflammatory response in the kidney by blood pressure-dependent and blood pressure-independent mechanisms. ACE inhibition, AT 1 receptor blockade, and human renin inhibition all prevent monocyte/macrophage infiltration and increased adhesion molecule expression in the kidneys of dTGR. Key Words: angiotensin II Ⅲ intercellular adhesion molecule-1 Ⅲ vascular cell adhesion molecule-1 Ⅲ plasminogen activator inhibitor-1 Ⅲ fibronectin Ⅲ renin H ypertension is a major risk factor for renal injury. However, the mechanisms underlying the development and progression of hypertension-induced kidney damage are incompletely understood. There is growing evidence that vascular inflammatory responses and interstitial accumulation of extracellular matrix proteins are involved in the pathogenesis. 1,2 Moreover, both experimental and clinical studies revealed that angiotensin II (Ang II), the key effector of the local and circulating renin-angiotensin system (RAS), plays a central role in the pathogenesis of hypertensioninduced end-organ damage (for reviews see References 3 and 4). The mechanisms of Ang II-induced hypertension and renal damage are...

Abstract-Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II-induced cardiac injury. We administered spironolactone (SPIRO; 20 mg · kg, valsartan (VAL; 10 mg · kg Ϫ1 · d Ϫ1 ), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-␤ 1 , and the transcription factors AP-1 and nuclear factor (NF)-B. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-␤ 1 were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-B were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-B, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II-induced cardiac damage. Key Words: angiotensin Ⅲ nuclear factors Ⅲ receptors, mineralocorticoid Ⅲ spironolactone I n a recent study, patients with heart failure after myocardial infarction exhibited a 30% reduced mortality rates with mineralocorticoid receptor blockade compared with control subjects. 1 A direct relationship has been shown between death and serum aldosterone concentrations in heart failure patients. 2 After myocardial infarction, the renin-angiotensin-aldosterone system contributes to cardiac remodeling; local tissue angiotensin (Ang) II and aldosterone are increased. 3,4 The effects of aldosterone on the kidney are well recognized; however, less appreciated are the facts that aldosterone also induces collagen, fibronectin, and laminin and contributes directly to fibrosis. 5-7 Vascular smooth muscle and endothelial cells respond to aldosterone with increased ITP, [Ca 2ϩ ] i , and protein kinase C activity, as well as with ion channel activation. Aldosterone-induced genes include the G protein K-Ras and several serum glucocorticoid kinase proteins. 8 Furthermore, genes important for cell cycle progression, such as c-myc, c-fos, and c-jun, are upregulated by aldosterone. 8 Aldosterone-induced cardiac fibrosis can be prevented with spironolactone (SPIRO), as well as with Ang II type 1 receptor (AT 1 ) blockade. 9 We investigated the effect of SPIRO in rats harboring the human renin and angiotensinogen genes (dTGR). They produce Ang II locally and develop hypertension and severe end-organ damage. 10 M...

Background-An activated endothelin (ET) system may be of pathophysiological relevance in human heart failure. We characterized the functional effects of ET-1, ET receptors, and ET-1 peptide concentration in left ventricular myocardium from 10 nonfailing hearts (NF) and 27 hearts in end-stage failure due to idiopathic dilative cardiomyopathy (DCM).

Abstract-The blood pressure-independent effects of angiotensin II (Ang II) were examined in double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes, in which the end-organ damage is due to the human components of the renin angiotensin system. Triple-drug therapy (hydralazine 80 mg/L, reserpine 5 mg/L, and hydrochlorothiazide 25 mg/L in drinking water) was started immediately after weaning. Triple-drug therapy normalized blood pressure and coronary resistance, only partially prevented cardiac hypertrophy, and had no effect on ratio of renal weight to body weight. Although triple-drug therapy delayed the onset of renal damage, severe albuminuria nevertheless occurred. Semiquantitative scoring of ED-1-positive and MIB-5-positive (nuclear cell proliferation-associated antigen Ki-67) cells showed profound perivascular monocyte/macrophage infiltration and cell proliferation in kidneys and hearts of untreated dTGR. Triple-drug therapy had only a minimal effect on local inflammatory response or vascular cell proliferation. In contrast, a novel orally active human renin inhibitor (HRI), 30 mg/kg by gavage for 4 weeks, normalized blood pressure and coronary resistance and also prevented cardiac hypertrophy and albuminuria. ED-1-positive cells and MIB-5-positive cells were decreased by HRI in hearts and kidneys almost to levels observed in normotensive Sprague-Dawley rats. The renoprotective effects of HRI were at least in part due to improved renal hemodynamics and distal tubular function, since HRI shifted renal pressure-diuresis/natriuresis curves leftward by Ϸ35 mm Hg, increased glomerular filtration rate and renal blood flow, and shifted the fractional water and sodium excretion curves leftward. In untreated dTGR, plasma Ang II was increased by 400% and renal Ang II level was increased by 300% compared with Sprague-Dawley rats. HRI decreased plasma human renin activity by 95% and normalized Ang II levels in both plasma and kidney compared with triple-drug therapy. Our findings indicate that in dTGR harboring human renin and angiotensinogen genes, Ang II causes end-organ damage and promotes inflammatory response and cellular growth largely independent of blood pressure. (Hypertension. 2000;35:587-594.)Key Words: renin Ⅲ angiotensinogen Ⅲ angiotensin II Ⅲ albuminuria Ⅲ cell proliferation Ⅲ natriuresis A sscher and Anson 1 demonstrated a vascular permeability factor causing arterial necrosis in malignant hypertension. Subsequently, other investigators reported similar findings and presented evidence that angiotensin II (Ang II) was responsible. [2][3][4] More recent studies indicated that Ang II can be synthesized not only in the blood compartment but also locally in the tissues. 5 Furthermore, alternative pathways to the angiotensin-converting enzyme may exist for local Ang II generation. 6,7 Ang II acts as a direct trophic factor for smooth muscle cells and cardiac myocytes in vitro. 8,9 The effects are mediated through the AT 1 receptor and involve activation of signal transduction pathways...