l-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats

Abstract

Nitric oxide (NO) is essential for normal function of the cardiovascular system. This study has determined whether chronic administration of l-arginine, the biological precursor of NO, attenuates the development of structural and functional changes in hearts and blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Uninephrectomized rats treated with DOCA (25 mg every 4th day sc) and 1% NaCl in the drinking water for 4 wk were treated with l-arginine (5% in food, 3.4 ± 0.3 g·kg body wt−1·day−1). Changes in cardiovascular structure and function were determined by echocardiography, microelectrode studies, histology, and studies in isolated hearts and thoracic aortic rings. DOCA-salt hypertensive rats developed hypertension, left ventricular hypertrophy with increased left ventricular wall thickness and decreased ventricular internal diameter, increased inflammatory cell infiltration, increased ventricular interstitial and perivascular collagen deposition, increased passive diastolic stiffness, prolonged action potential duration, increased oxidative stress, and inability to increase purine efflux in response to an increased workload. l-Arginine markedly attenuated or prevented these changes and also normalized the reduced efficacy of norepinephrine and acetylcholine in isolated thoracic aortic rings of DOCA-salt hypertensive rats. This study suggests that a functional NO deficit in blood vessels and heart due to decreased NO synthase activity or increased release of reactive oxygen species such as superoxide may be a key change initiating many aspects of the cardiovascular impairment observed in DOCA-salt hypertensive rats. These changes can be prevented or attenuated by administration of l-arginine.

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

“…6 In this model, structural changes lead to the development of left ventricular hypertrophy characterized by increased wall thickness, thickening of the small arteriolar coronaries, increased interstitial and perivascular collagen deposition, and elevated oxidative stress. 6 Accordingly, the high levels of 8-isoprostane alongside increased NF-B, AP-1, AP-2, and JNK observed in DOCAhypertensive rats may act in concert with elevated TGF-␤ 1 , fibronectin, and collagen-1 to accentuate the oxidative and fibrotic destruction of cardiac tissues. [3][4][5]7 Interestingly, upregulating the HO system abated these destructive factors and attenuated cardiac lesions, whereas the HO inhibitor, CrMP, exacerbated cardiac hypertrophy.…”

“…6 There are 2 types of cardiac fibrosis, reactive (interstitial/perivascular) and reparative (scarring followed by necrosis), 25 which manifest in DOCA hypertension. Because inflammation stimulates fibrosis, 6 the concomitant attenuation of NF-B, AP-1, and AP-2 alongside the reduction of collagen deposition/collagen-1 in hemin-treated animals may attenuate the infiltration of inflammatory cells/mediators into interstitial and scarred tissue. Because cardiac fibrosis is difficult to study in human patients, other than its therapeutic relevance, our findings may have diagnostic implications, because the DOCA-salt model displays distinct fibrotic characteristics.…”

“…Because cardiac fibrosis is difficult to study in human patients, other than its therapeutic relevance, our findings may have diagnostic implications, because the DOCA-salt model displays distinct fibrotic characteristics. 6 Although the HO system is cytoprotective, 9 -11 some reports indicate that carbon monoxide may interfere with NO-induced vasodilation, 35 causing endothelium-dependent vasoconstriction. 36 These studies suggest that carbon monoxide may have a biphasic effect, and, therefore, the specific conditions under which different experiments are done may be critical to the observed effect.…”

“…1,2 In mineralocorticoid-induced hypertension, the activation of JNK, TGF-␤ (TGF-␤ 1 ) and NF-B constitutes a potent prohypertrophic/remodeling axis. [2][3][4][5] The pathophysiological role of aldosterone in cardiac damage is evident in deoxycorticosterone acetate-salt (DOCA-salt) hypertension, 6 where elevated superoxide quenches NO to form peroxynitrite and 8-isoprostane, with subsequent stimulation of endothelin-1 to potentiate oxidative injury. 7,8 Moreover, in DOCA-salt hypertension, locally produced aldosterone in cardiac tissue 3 stimulates TGF-␤ 1 , fibronectin, and collagen-1 causing fibrosis and hypertrophy.…”

“…Thus, this study unveils novel mechanisms by which the HO system alleviates cardiac damage in DOCA hypertension, a model of volume overload and human primary aldosteronism. 6 …”