Asymmetrical Dimethylarginine, an Endogenous Nitric Oxide Synthase Inhibitor, in Experimental Hypertension

Abstract

Nc,NG-dimethyl-L-argmme (ADMA) IS an endogenously synthesized mtnc oxide (NO) synthase mhibltor which has potent pressor/vasoconstnctor effects Dimethylargmmase metabolizes ADMA to L-citrullme and plays a key role m deterrmmng the m VIVO levels of ADMA To mvestlgate the role of ADMA m the pathogenesls of hypertension, we measured 24-hour urinary excretion of ADMA (UADMA) and nitrate/nitrite (NOx) m Dahl salt-sensitive hypertensive rats and spontaneously hypertensive rats (SHR) In Dahl salt-resistant rats, high-salt &et (8% NaCI) did not increase blood pressure and increased urinary NOx (P< 01) wlthout changes in UADMA cornpaled with lowsalt diet (0 3% NaCI) In contrast, m Dahl salt-sensitive rats, hlghsalt diet Increased blood pressure (P< Ol), did not change urinary NOx excretion, and Increased UADMA (P< 01) There was a slgmficant (Y= 65, P< 01) correlation between UADMA and the level of blood pressure m Dahl salt-sensltlve rats Plasma levels of NOx and ADMA and renal chmethylargmmase content were comparable among them These results may suggest that m Dahl salt-resistant rats, blood pressure 1s kept constant during high-salt intake, possibly due to the compensatory increased production of NO, and that m Dahl salt-sensitive rats, high-salt intake increases the production of ADMA, attenuates the compensatory Increase\ m NO, and increases blood pressure These results also suggest that the systemic production of ADMA 19 not dependent on renal dlmethylargmmase SHR had significantly greater urinary NOx excretion (P< 05) and smaller UADMA than Wlstar-Kyoto rats nously have suggested that the NO production 1s preserved m SHR * Furthermore, recent evidence demonstrated the increased but not decreased production of NO m the heart9.10 and aorta" of SHR The synthesis of NO can be inhibited experimentally by some analogues of argmme mcludmg L-NMMA and ADMA), both of which have equally potent vasoconstnctor and pressor actions 12 Acute admmlstratlon of ADMA into guinea pigsI and rats'4 causes blood pressure elevation partly via elevation of total peripheral resistance I4 In humans, mtra-arterial admmlstratlon of ADMA lowers forearm blood flow 1~15 Although both L-NMMA and ADMA are synthesized I6 and metabolized I7 endogenously, the plasma concentration of dlmethylargmme 1s ten times greater than that of L-NMMA 13 Since studies m ammals suggest that the kidney may be mvolved m the excretion lx and metabolism 1Y.*O of ADMA, abnormalities of the ADMA production or ehmmatlon have been reported m human kidney diseases 13 21 Although recent evidence demonstrated high accumulation of ADMA m plasma from hypercholesterolexmc ammals**J3 and m balloon-injured vessels,*4 the role of this endogenous NO synthase mhlbltor m the pathogenesls of hypertension has not been elucidated at all Accordmgly, we hypothesized that endogenous ADMA may play a role m salt-sensitive hypertension by competltlve inhibition of NO synthesis. To test this hypothesis, urinary and plasma ADMA and NOx were evaluated m Dahl rats on different salt intakes....

Downregulation of vascular soluble guanylate cyclase induced by high salt intake in spontaneously hypertensive rats

“…However, this dysfunction presents di erent characteristics depending on the model studied (Boulanger, 1999). In Dahl-salt sensitive rats, impaired eNOS activity (Hayakawa & Raij, 1997) and increased endogenous NOS inhibitor (Matsuoka et al, 1997) are associated with a decrease in endothelium-dependent relaxations. Furthermore, in large arteries from aged SHR, endothelium-dependent relaxations are impaired because of the concomitant augmented release of a contractile factor (LuÈ scher & Vanhoutte, 1986) and superoxide anions (Bauersachs et al, 1998).…”

“…In Dahl salt-sensitive hypertensive rats, a high salt diet has been shown to impair endothelium-dependent relaxations induced by a variety of vasodilators (LuÈ scher et al, 1987;Raij et al, 1988). This impairment is considered to be due to a decreased release of nitric oxide (NO) from the endothelium (Nava & LuÈ scher, 1995;Boegehold, 1992), which results from reduced endothelial NO synthase (eNOS) activity or increased endogenously synthesized NOS inhibitor (Hayakawa & Raij, 1997;Matsuoka et al, 1997). Similar impairment of NO synthesis and release by a high salt intake has been observed as a pathogenic factor in the development of hypertension in healthy subjects (Facchini et al, 1999) or normal Sprague-Dawley rats (Tolins & Shultz, 1994).…”

Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis

“…DDAH I predominates in tissues that express the neuronal isoform of NOS, while DDAH II distribution mainly follows endothelial NOS (Leiper et al, 1999). Dysfunction of DDAH and elevated levels of its substrate ADMA have been implicated in pathological conditions including hypertension, pre-eclampsia, renal failure and atherosclerosis (Matsuoka et al, 1997;Holden et al, 1998;Miyazaki et al, 1999). Recently, high levels of ADMA have been correlated with impaired angiogenesis in hypercholesterolemic mice (Jang et al, 2000).…”

Circulating concentrations of asymmetrical dimethyl- L -arginine are increased in women with previous gestational diabetes

“…A decreased plasma L-arginine to ADMA ratio or increased ADMA concentrations has been described in hypercholesterolemia [6,7], hypertension [8,9], arterial occlusive disease [10], chronic renal failure [11], and preeclampsia [12]. It has been suggested that alteration of the L-arginine to ADMA ratio could affect the clinical course of arteriosclerosis, which has not been seen in patients with stable angina [13].…”