Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted due to the development of nitrate tolerance. With initiation of nitroglycerin therapy one can detect neurohormonal activation and signs for intravascular volume expansion. These so called pseudotolerance mechanisms may compromise nitroglycerin's vasodilatory effects. Long-term treatment with nitroglycerin is also associated with a decreased responsiveness of the vasculature to nitroglycerin's vasorelaxant potency suggesting changes in intrinsic mechanisms of the tolerant vasculature itself may also contribute to tolerance. More recent experimental work defined new mechanisms of tolerance such as increased vascular superoxide production and increased sensitivity to vasoconstrictors secondary to an activation of the intracellular second messenger protein kinase C. As potential superoxide producing enzymes, the NADPH oxidase and the nitric oxide synthase have been identified. Nitroglycerin-induced stimulation of oxygen-derived free radicals together with NO derived from nitroglycerin may lead to the formation of peroxynitrite, which may be responsible for the development of tolerance as well as for the development of cross tolerance to endothelium-dependent vasodilators. The oxidative stress concept of tolerance and cross tolerance may explain why radical scavengers such as vitamin C or substances which reduce oxidative stress, such as ACE-inhibitors, AT1 receptor blockers or folic acid, are able to beneficially influence both tolerance and nitroglycerin-induced endothelial dysfunction. New aspects concerning the role of oxidative stress in nitrate tolerance and nitrate induced endothelial dysfunction and the consequences for the NO/cyclicGMP downstream target, the cGMP-dependent protein kinase will be discussed.
 ...
PMID:Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies. 1237 19

The menopause is associated with an increased incidence of atherosclerotic disease. Estrogen deficiency causes AT1 receptor overexpression which is involved in the development of vascular dysfunction. The effect of a 6 week-treatment with the AT1 receptor antagonist candesartan (16 mg/d) on endothelium-dependent vasorelaxation was compared to the treatment with placebo or the calcium channel antagonist felodipine (5 mg/d) in 29 postmenopausal women in the absence or presence of hormone replacement therapy (HRT) in a prospective, double-blind, randomized cross-over study. Endothelial function was assessed by measurement of forearm blood flow (FBF) by venous occlusion plethysmography. FBF during reactive hyperemia was significantly improved by candesartan in patients without HRT (hyperemic peak flow and area under the FBF curve), whereas felodipine and placebo exerted no effect. In patients with HRT, no treatment regimen showed a significant effect on endothelial function. Nitroglycerin-induced vasorelaxation and basal FBF were not significantly altered in all groups. AT1 receptor antagonism improves vascular function in postmenopausal women without HRT. Thus, AT1 receptor blockade may resemble an efficient approach for the prevention of vascular dysfunction in estrogen-deficient women.
 ...
PMID:AT1 receptor antagonism improves endothelial dysfunction in postmenopausal women. 1592 66