Abstract-A large body of evidence has accrued indicating that voltage-gated Ca 2ϩ channel subtypes, including L-, T-, N-, and P/Q-type, are present within renal vascular and tubular tissues, and the blockade of these Ca 2ϩ channels produces diverse actions on renal microcirculation. Because nifedipine acts exclusively on L-type Ca 2ϩ channels, the observation that nifedipine predominantly dilates afferent arterioles implicates intrarenal heterogeneity in the distribution of L-type Ca 2ϩ channels and suggests that it potentially causes glomerular hypertension. In contrast, recently developed Ca 2ϩ

Abstract-Dimethylarginie dimethylaminohydrolase (DDAH) degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) synthase inhibitor, and comprises 2 isoforms, DDAH1 and DDAH2. To investigate the in vivo role of DDAH2, we generated trangenic mice overexpressing DDAH2. The transgenic mice manifested reductions in plasma ADMA and elevations in cardiac NO levels but no changes in systemic blood pressure (SBP), compared with the wild-type mice. When infused into wild-type mice for 4 weeks, ADMA elevated SBP and caused marked medial thickening and perivascular fibrosis in coronary microvessels, which were accompanied by ACE protein upregulation and cardiac oxidative stress. The treatment with amlodipine reduced SBP but failed to ameliorate the ADMA-induced histological changes. In contrast, these changes were abolished in transgenic mice, with a reduction in plasma ADMA. In coronary artery endothelial cells, ADMA activated p38 MAP kinase and the ADMA-induced ACE upregulation was suppressed by p38 MAP kinase inhibition by SB203580. In wild-type mice, long-term treatment with angiotensin II increased plasma ADMA and cardiac oxidative stress and caused similar vascular injury. In transgenic mice, these changes were attenuated. The present study suggests that DDAH2/ADMA regulates cardiac NO levels but has modest effect on SBP in normal conditions. Under the circumstances where plasma ADMA are elevated, including angiotensin II-activated conditions, ADMA serves to contribute to the development of vascular injury and increased cardiac oxidative stress, and the overexpression of DDAH2 attenuates these abnormalities. Collectively, the DDAH2/ADMA pathway can be a novel therapeutic target for vasculopathy in the ADMA or angiotensin II-induced pathophysiological conditions. (Circ Res. 2007;101:e2-e10.)Key Words: DDAH2 Ⅲ ADMA Ⅲ angiotensin II A symmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase (NOS). Substantial evidence has been accumulated that plasma ADMA mediates the endothelial dysfunction and serves as a marker of risk for cardiovascular disease. 1-3 ADMA is degraded by the enzyme, dimethylarginine dimethylaminohydrolase (DDAH), and would subsequently affect NO metabolism. It has been demonstrated that DDAH is composed of 2 isoforms, DDAH1 and DDAH2, 4 each of which stems from different chromosomes and differs in several aspects. DDAH1 and 2 appear to have distinct tissue distributions, with DDAH1 predominating in the tissues that express nNOS and DDAH2 being coexpressed with eNOS in highly vascularized tissues. 5 Moreover, in cultured human endothelial cells, DDAH1 is uniformly distributed in the cytosol and nucleus, whereas DDAH2 is found only in the cytosol. 6 The different characteristics between these 2 isoforms suggest different physiological functions.Physiological function of DDAH1 has been elucidated by the studies using transgenic (TG) mice overexpressing DDAH1 7 and DDAH1 knockout (KO) mice. 8 In TG mice, tissue DDAH1 expression is increased and t...

Rho-kinase plays an important role in hypertension and is reported to interfere with insulin signaling through serine phosphorylation of insulin receptor substrate-1 (IRS-1) in cultured vascular smooth muscle cells. We therefore examined the role of Rho-kinase in the development of insulin resistance in Zucker obese rats. In skeletal muscles and aortic tissues of Zucker obese rats, activation of RhoA/Rho-kinase was observed. Long-term Rho-kinase inhibition by 4 wk treatment with fasudil (a Rho-kinase inhibitor) not only reduced blood pressure but corrected glucose and lipid metabolism, with improvement in serine phosphorylation of IRS-1 and insulin signaling in skeletal muscles. Direct visualization of skeletal muscle arterioles with an intravital CCD videomicroscope demonstrated that both acetylcholine- and sodium nitroprusside-induced vasodilations were blunted, which were restored by the fasudil treatment. Furthermore, both fasudil and Y-27632 prevented the serine phosphorylation of IRS-1 induced by insulin and/or tumor necrosis factor-alpha in skeletal muscle cells. Collectively, Rho-kinase is responsible for the impairment of insulin signaling and may constitute a critical mediator linking between metabolic and hemodynamic abnormalities in insulin resistance.

Peroxisome proliferator activated receptor-S S S S (PPARS S S S ) ligands increase nitric oxide (NO