Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia.

In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator NO and harmful superoxide free radicals. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering the membrane association of these molecules, statins affect intracellular positioning and hence activity of a multitude of substances. These include eNOS(endothelial NO synthase), which produces NO (inhibited by Rho), and NADPH oxidase, which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of NO while decreasing superoxide production. A total of 40 hypercholesterolaemic patients were randomized to treatment with either atorvastatin or placebo; 20 normolipidaemic patients were also studied. Platelet nitrite, NO and superoxide were examined as was the cellular distribution of the GTPases Rho and Rac at baseline and after 8 weeks of treatment.Following atorvastatin therapy, platelet NO was increased (3.2 pmol/10(8) platelets) and superoxide output was attenuated [-3.4 pmol min(-1) (10(8) platelets)(-1)] when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets, implying reduced activity. In conclusion, the results of the present study show altered NO/superoxide production following statin therapy. A potential mechanism for this is the change in the distribution of intracellular GTPases, which was considered to be secondary to decreases in isoprenoid intermediates, suggesting that the activity of the former had been affected by atorvastatin.

NAD(P)H-dependent superoxide production in platelets: the role of angiotensin II and protein kinase C.

OBJECTIVES: Vascular NAD(P)H oxidase represents a major source for excessive superoxide production in hypertension. Angiotensin II (AngII) can activate NAD(P)H oxidase via the angiotensin II type 1 (AT1) receptor and protein kinase C (PKC). Platelets possess AT1 receptors and all the components of the NAD(P)H oxidase system. We employed this tissue model to explore mechanisms involved in AngII-mediated superoxide production. DESIGN AND METHODS: Platelet suspensions from hypertensive patients' blood were activated with AngII or phorbol 12-myristate 13-acetate (PMA). Inhibitors of NAD(P)H oxidase, PKC, and the AT1 receptor were employed to study their effects on superoxide production. RESULTS: Superoxide production was stimulated by AngII and PMA and attenuated by AT1 receptor antagonists (mean percentage reduction 80.2%, P<0.01) and inhibitors of PKC (mean reduction 94.8%, P<0.001) and NAD(P)H oxidase (mean reduction 100%, P< 0.001). CONCLUSIONS: AngII stimulates platelet superoxide production through activation of vascular NAD(P)H oxidase via the AT1 receptor and PKC.

Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure.

BACKGROUND: Impaired endothelium-dependent and independent vasodilator responses in chronic heart failure (CHF) have been well described. Previous studies involved younger patients and omitted medications prior to study. AIMS: We explored if new therapeutic interventions would restore vasodilator responses in typical patients with chronic heart failure. METHODS AND RESULTS: 24 patients and 15 controls were recruited, patients were maintained on their usual medications. Forearm blood flow responses were measured by venous occlusion plethysmography in response to incremental doses of sodium nitroprusside (SNP) (6, 9 and 12 nmol/min), acetylcholine (ACH) (120, 180 and 240 nmol/min), angiotensin II (AII) (1, 10 and 100 nmol/min) and N(g)-Nitro-L-arginine methyl ester (L-NAME) (1, 2 and 4 nmol/min) infused into the non-dominant brachial artery. FBF responses to SNP were impaired in patients compared with controls (13.7(9.9,17.4) vs. 24.8(18.6,30.9)) arbitrary units, P<0.001). Similarly FBF responses to ACH were reduced in patients compared with controls (7.5(4.2,10.9) vs. 24.8(16.4,33.2)) arbitrary units, P<0.001. Decreased FBF was noted in response to AII and L-NAME but was significant only for AII and did not differ between groups. CONCLUSIONS: In elderly patients with CHF, endothelium-dependent and independent vasodilator responses were blunted compared with controls. Defects in nitric oxide bioavailability and smooth muscle responsiveness are not reversed by modern medical management of the heart failure syndrome.