Impairment of vascular and platelet levels of nitric oxide and cyclic guanosine‐3′,5′‐monophosphate in cyclosporin A‐induced hypertensive rats

Abstract

The therapeutic use of the immunosuppressive agent cyclosporin A (CsA) is associated with arterial hypertension and increased risk of thromboembolism. Impaired endothelium-mediated relaxation is one of the main hypotheses explaining the CsA-induced vascular hyper-reactivity. Since nitric oxide (NO) modulates both vascular and platelet activity, we studied the effects of CsA on the levels of arterial and platelet NO as well as 3',5'-cyclic guanosine monophosphate (cGMP) levels which are influenced by NO. An animal model of CsA-induced hypertension was used. Wistar rats were treated with a clinically relevant, oral dose of 5 mg/kg CsA, daily, for 4 weeks. CsA increased both systolic and diastolic blood pressures compared to non-treated rats (P < 0.01). Nitrite, a NO metabolite, decreased in the entire aorta wall (30%, P < 0.05) and in the aorta wall without the endothelial layer (70 %, P < 0.05) in CsA-treated vs. control groups. cGMP content was also decreased in the CsA-treated group (67%, P < 0.01) vs. control. Taken together, these results suggest a defect on the endothelial NO generation, acceleration of breakdown and/or consumption of NO, as well as marked alterations directly on cGMP metabolism. Conversely, platelet nitrite and cGMP content significantly increased in the CsA-treated rats, which was also observed in in vitro studies of platelet nitrite release following CsA treatment. This suggests a platelet self-regulation mechanism against CsA-induced platelet hyper-reactivity, which, in turn, could compensate vascular impairment.

Oxidative Stress in Cyclosporine-Induced Hypertension: Evidence of Beneficial Effects or Tolerance Development With Nitrate Therapy

“…7,8,24 The reduction in aortic cNOS activity might be better explained by an effect on its complex enzymatic profile rather than by a reduction of L-arginine content or consumption, since previous studies have demonstrated that L-arginine supplementation was unable to prevent CsA-induced HT. 19,25 Thus, an effect on the enzymatic cofactors of cNOS may not be excluded, as already documented in other pathophysiological conditions.…”

“…5,6 Previous studies from our group, as well as from others, have shown a disequilibrium in the nitric oxide (NO)/cyclic guanosine-3=,5=-monophosphate (cGMP) system, which may contribute to the vascular hyperreactivity. 7,8 The NO system is essential to the relaxation of vascular smooth muscles cells (VSMC) and plays a pathophysiological role in reactive oxygen or nitrogen species (ROS) generation. 9 In addition, oxidative stress could also have a key role in CsA-associated cardiovascular toxicity.…”

Effect of preventive and regressive isosorbide 5-mononitrate treatment on catecholamine levels in plasma, platelets, adrenals, left ventricle and aorta in cyclosporin A-induced hypertensive rats

“…We have previously reported that CsA administration is associated with a decrease of NO-cGMP contents (Santiago et al, 2003), that might be corrected by previous Is-5-Mn treatment . From the present data, it is reliable to consider that the CsA influence on left ventricle NE and E and aorta NE contents might have a NO deficiency dependency.…”

“…Nitric oxide (NO) participates in the blood pressure control (Das and Kumar, 1995) and a pivotal role for a NO-cGMP (cyclic guanosine-3V,5V-monophosphate) pathway impairment has been gaining substantial attention during the last years (Marumo et al, 1995;Oriji and Keiser, 1998). However, despite widely studied, its contribution for the CsA-induced vascular dysfunction and hypertension, as well as the possible benefits of l-arginine supplementation (the most tested therapeutic intervention), remains incompletely elucidated (O'Neil et al, 1991;Stroes et al, 1997;Lassila et al, 2001;Santiago et al, 2003;El-Mas et al, 2004). In previous studies from our group, while l-arginine administration has shown inefficacy in preventing CsA-induced hypertension , the preliminary results with a different NO donor drug, the organic nitrate isosorbide 5-mononitrate (Is-5-Mn), have demonstrated promising results .…”

Dual Effect of Nitrate Therapy for Cyclosporine-Induced Hypertension on Vascular and Platelet Morphofunctional Markers; An Animal Model

“…8,9 During the last years several experimental and clinical studies, including some from our institute, have indicated a cardiovascular dysfunction in nitric oxide (NO) production as one important cause for the reduced relaxation leading to vascular hyperreactivity and increased peripheral resistance. 10,11 NO is the main endotheliumderived relaxing factor. Through its conversion to cyclic guanosine-3=, 5=-monophosphate (cGMP), it exerts vasodilatation, inhibition of vascular smooth muscle cell (VSMC) growth, and platelet inactivation, thus playing a pivotal role in cardiovascular physiology and pathophysiology, namely, arterial HT, atherosclerosis, and thrombosis.…”