Chronic dietary supplementation with ?-arginine inhibits platelet aggregation and thromboxane A2 synthesis in hypercholesterolaemic rabbits in vivo

Abstract

Objectives: L-arginine exerts anti-atherosclerotic effects in hypercholesterolaemic rabbits via modulating endogenous NO production. We investigated whether L-arginine inhibits thromboxane formation in vivo and platelet aggregation ex vivo in this animal model. Ž . Ž Methods: The urinary excretion rates of 2,3-dinor-6-keto-PGF major urinary metabolite of PGI and 2,3-dinor-TXB major urinary . N s 4 for 12 weeks. Urine samples were collected in weekly intervals. At the end of the study period platelet aggregation ex vivo and endothelium-dependent and -independent vascular function of isolated aortic rings in vitro was assessed. Results: Urinary 2,3-dinor-TXB 2 Ž . Ž excretion significantly increased in the cholesterol group p -0.05 , and endogenous NO formation measured as urinary nitrate . Ž . Ž . excretion decreased p -0.05 . Both parameters were significantly correlated with each other R s 0.48, p -0.01 . L-arginine partly restored urinary nitrate excretion and significantly reduced TXA production to values even below those in the control group 2 Ž . p -0.001 . Urinary 2,3-dinor-6-keto-PGF excretion increased in early hypercholesterolaemia and returned to control values in the 1a second half of the study period. The early increase in urinary 2,3-dinor-6-keto-PGF excretion was attenuated by L-arginine. Platelet 1a aggregation was significantly enhanced in cholesterol-fed rabbits and attenuated by dietary L-arginine. L-arginine also improved the impaired endothelium-dependent relaxations to ADP, and normalized the vasoconstrictor effects of 5-HT in isolated aortic rings. Conclusions: Cholesterol-feeding enhances platelet aggregation and TXA formation, and stimulates platelet-endothelial cell interaction 2 in rabbits. These effects are probably due to impaired NO elaboration, as indicated by decreased urinary nitrate excretion. Chronic dietary supplementation with L-arginine elevates systemic NO elaboration and significantly increases the PGI rTXA ratio. It thus beneficially 2 2 influences the homeostasis between vasodilator and vasoconstrictor prostanoids in vivo. q 1998 Elsevier Science B.V.

Investigations on the Significance of Inductable Cyclooxygenase in Atherogenesis in Cholesterol-Fed Rabbits

“…To further understand this mechanism, we recommend future studies with larger collectives, the use of special metabolic cages and the immediate analysis of the urine samples. As expected the total concentration of cholesterol in the 3 cholesterol-fed collectives/ groups was highly significant higher than in the healthy control like in other studies too [25] (Figure 4). Within the collective of the healthy control a significant reduction in values was shown from week 0 to week 12, which could not be demonstrated in the other study collectives.…”

“…This phenomenon could not be explained by our study. The constant PGE-2 and PGE-MUM values in the healthy control group and the considerable fluctuation and dispersion of the values in the other 3 groups may enable the finding of a causal influence of a cholesterol diet like other studies were able to [25] (Figures 2 and 3). The fluctuation of the other parameters measured in the urine make this seem unlikely.…”

“…Within the collective of the healthy control a significant reduction in values was shown from week 0 to week 12, which could not be demonstrated in the other study collectives. This only confirms the triggering of atheroscleroris by feeding rabbits with a cholesterol diet [1,25], but does not explain the reduction of atherosclerosis through the COX inhibitor Celecoxib. The triglyceride values lead us to certain indications for the cause of the reduction in atherosclerosis-all 3 study collectives that were fed with cholesterol showed highly significant higher values than the healthy control.…”

“…The rabbits were kept in single cages at specific-pathogen-free-standard. The used protocol for the rabbit model of atherosclerosis is based on the one developed by Bode-Böger et al [25]. 48 male White New Zealand rabbits bred by Charles River with body weight between 1.7 and 2.7 kg at the beginning of the tests were studied for 12 weeks after a fourteen day period of adaptation with feeding standard pellets (Ssniff KH, company Ssniff Soest) ad libitum.…”

Clot dissolution is better with ultrasound assisted thrombolysis for fresh clots with higher cholesterol content

“…Altogether, it seems that fresh thrombi with higher cholesterol levels have high thrombolysis efficiencies in tPA and ultrasound exposure. Cholesterol has an affinity to fibrinogen and gets incorporated in the fibrin threads [9]. Cholesterol content in the fibrin threads may increase the pore size of fibrin threads or influence better interaction with enzyme tPA.…”