Platelets from patients with diabetes mellitus have impaired ability to mediate vasodilation.

OBJECTIVES: The purpose of this study was to examine vasomotor responses mediated by platelets from patients with diabetes mellitus. BACKGROUND: Diabetes mellitus is associated with increased cardiovascular morbidity and mortality, which in part may be due to a variety of abnormalities reported in diabetic platelets. However, the effects of diabetic platelets on vasomotor tone have not been characterized. METHODS: We compared platelet-mediated vasodilation elicited by platelets isolated from 30 healthy volunteers and 29 patients with diabetes mellitus as they were perfused through a preconstricted normal rabbit carotid artery. RESULTS: Platelets from the diabetic patients mediated an impaired dilatory response in comparison with normal platelets: 2.7 +/- 2% versus 15.8 +/- 3.4% (p < 0.001) and 4.1 +/- 2.7% versus 32.7 +/- 3.3% (p < 0.001) (mean +/- SEM) increase in vessel diameter, for 5 X 10(7) and 1 X 10(8) platelets per milliliter perfused, respectively. The degree of impairment was similar for type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus. Normal platelets incubated in high D-glucose concentrations lost their ability to mediate dilation in a concentration-dependent and time-dependent manner. This was not true for incubation of normal platelets in high concentrations of L-glucose or insulin. However, there was not a significant correlation between glucose control in the diabetic patients and the ability of their platelets to mediate vasodilation. CONCLUSIONS: Platelets from patients with diabetes mellitus have an impaired ability to mediate vasodilation. This impairment appears to be mediated by high glucose concentration. Further work is needed to elucidate the mechanisms for this abnormality in diabetic platelets.

Cyclosporine impairs the ability of human platelets to mediate vasodilation.

Cyclosporine causes various platelet abnormalities. Whether it affects the ability of platelets to mediate vasodilation is unknown. Platelets were isolated from healthy volunteers and 13 heart transplant patients on cyclosporine. When perfused through preconstricted normal rabbit carotid arteries, activated platelets from transplant patients failed to cause vasorelaxation, whereas normal platelets produced significant vasodilation (-4.0 +/- 1.9% versus 30 +/- 3% [P < .0001] change in vessel diameter, respectively). When normal platelets were exposed to cyclosporine in vitro, they lost their ability to cause vasodilation in a dose- and time-dependent fashion. However, when activated and perfused through quiescent, N omega-nitro-L-arginine-pretreated arteries, platelets from transplant patients and normal platelets caused similar degrees of vasoconstriction. The amount of adenosine triphosphate in the supernatant from activated cyclosporine-exposed and control platelets was similar (1.7 +/- 0.4 versus 1.5 +/- 0.3 mumol/L [P = NS], respectively). However, concomitant perfusion of activated platelets from transplant patients impaired acetylcholine-mediated, endothelium-dependent vasodilation but perfusion of normal platelets did not. Although cyclosporine-exposed platelets showed an impaired ability to produce vasorelaxation, supernatant from the same platelets caused near normal vasodilation. Human platelets exposed to cyclosporine have an impaired ability to mediated vasodilation. This is not due to increased platelet-mediated vasoconstriction or a decrease in the release of platelet-derived nucleotides but rather to a short-acting compound released by cyclosporine-exposed platelets that interferes with endothelium-dependent vasodilation.

Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation.

1. The aim of this study was to examine the mechanism of impaired platelet-mediated endothelium-dependent vasodilation in diabetes. Exposure of human platelets to high glucose in vivo or in vitro impairs their ability to cause endothelium-dependent vasodilation. While previous data suggest that the mechanism for this involves increased activity of the cyclo-oxygenase pathway, the signal transduction pathway mediating this effect is unknown. 2. Platelets from diabetic patients as well as normal platelets and normal platelets exposed to high glucose concentrations were used to determine the role of the polyol pathway, diacylglycerol (DAG) production, protein kinase C (PKC) activity and phospholipase A2 (PLA2) activity on vasodilation in rabbit carotid arteries. 3. We found that two aldose-reductase inhibitors, tolrestat and sorbinil, caused only a modest improvement in the impairment of vasodilation by glucose exposed platelets. However, sorbitol and fructose could not be detected in the platelets, at either normal or hyperglycaemic conditions. We found that incubation in 17 mM glucose caused a significant increase in DAG levels in platelets. Furthermore, the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) caused significant impairment of platelet-mediated vasodilation. The PKC inhibitors calphostin C and H7 as well as inhibitors of PLA2 activity normalized the ability of platelets from diabetic patients to cause vasodilation and prevented glucose-induced impairment of platelet-mediated vasodilation in vitro. 4. These results suggest that the impairment of platelet-mediated vasodilation caused by high glucose concentrations is mediated by increased DAG levels and stimulation of PKC and PLA2 activity.

Diabetic human platelets release a substance that inhibits platelet-mediated vasodilation.

This study was performed to investigate the mechanism for impaired vasodilation in response to activated diabetic human platelets. As observed previously, diabetic platelets failed to cause vasorelaxation, whereas normal platelets produced normal vasodilation. However, when activated and perfused through quiescent, NG-nitro-L-arginine-pretreated arteries, diabetic and normal platelets caused similar degrees of vasoconstriction. Inhibition of serotonergic and thromboxane A2 receptors in preconstricted normal arteries also failed to improve vasodilatory responses to diabetic platelets. The amount of ADP released into the supernatant from activated diabetic and normal platelets was similar. Concomitant perfusion of activated diabetic platelets impaired vasodilation produced by abluminally applied acetylcholine but perfusion of normal platelets did not. Whereas activated diabetic platelets failed to produce vasodilation, supernatant from the same platelets caused normal vasorelaxation. Dimethylthiourea and Tiron, intracellular free radical scavengers, normalized the vasodilatory response to diabetic platelets, whereas superoxide dismutase, catalase, and mannitol did not. We conclude that the impaired vasorelaxation in response to activated diabetic platelets is caused by an unidentified, short-acting, platelet-derived substance(s) that interferes with the normal dilatory response.

Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits.

The endothelium-derived relaxing factor is rapidly inactivated by superoxide radicals, and atherosclerotic vessels generate excess radical species. We tested the hypothesis that an imbalance between intrinsic superoxide dismutase (SOD) activity and the generation of superoxide radicals in atherosclerotic arteries may result in augmented inactivation of endothelium-derived relaxing factor. Vascular SOD was increased in normal and cholesterol-fed (1% cholesterol for 4 months) rabbits approximately twofold by treatment with polyethylene-glycolated SOD (PEG-SOD; 41,000 units/kg/day i.m.) for 1 week. Aortic rings from these animals and nontreated control and atherosclerotic rabbits subsequently were studied in organ chambers. Endothelium-dependent relaxations to acetylcholine and the calcium ionophore A23187 were improved by PEG-SOD in atherosclerotic but not in normal rabbits. PEG-SOD pretreatment did not alter endothelium-independent relaxations to nitroprusside. Thus, treatment with PEG-SOD can partially restore impaired endothelium-dependent relaxation of atherosclerotic arteries. We conclude that generation of oxygen-derived radicals likely contributes to endothelial dysfunction of atherosclerotic arteries.