Kazuya Ichiki

Increased Soluble Form of P-Selectin in Patients With Unstable Angina

BACKGROUND P-selectin in platelets and endothelial cells mediates adhesive interaction with leukocytes to form thrombi. The purpose of the present study was to investigate the plasma levels of P-selectin in patients with unstable angina and in those with stable effort angina of different pathophysiologies. METHODS AND RESULTS Plasma P-selectin levels were determined by a monoclonal antibody-based enzyme immunoassay on plasma samples taken from 12 patients with unstable angina, 11 patients with stable effort angina, and 15 healthy volunteers. Patients with unstable angina had angina at rest associated with ECG changes. In patients with unstable angina, plasma P-selectin levels within 1 hour (361 +/- 90 ng/mL) and at 3 hours (282 +/- 56 ng/mL) after angina were significantly (P < .05) higher than those in volunteers (177 +/- 31 ng/mL). Plasma P-selectin levels at 5 hours after attack (242 +/- 46 ng/mL) did not differ from those in volunteers. Although patients with stable effort angina developed angina with ST-segment depressions by treadmill exercise, their plasma P-selectin levels did not change (before, 178 +/- 45; immediately after, 186 +/- 36; and 1 hour after the exercise, 179 +/- 34 ng/mL). CONCLUSIONS Plasma P-selectin levels after angina increased significantly in patients with unstable angina but did not in patients with stable effort angina. These findings may contribute to understanding of the pathophysiology of the acute coronary syndrome of unstable angina.

Long-term Smoking Impairs Platelet-Derived Nitric Oxide Release

BACKGROUND Long-term smoking impairs endothelium-dependent vasodilation, which is mediated by nitric oxide (NO). However, it is unknown whether long-term smoking impairs the platelet-derived NO release, which regulates platelet aggregation. METHODS AND RESULTS Platelet-derived electrical current induced by collagen was measured with an NO-selective electrode in 12 smokers and 11 nonsmokers. Collagen-induced intraplatelet cGMP and platelet aggregation was measured in smokers and nonsmokers. S-nitroso-N-acetyl-dl-penicillamine, a direct NO donor, dose dependently increased in electrical current (r = .99). Collagen induced platelet aggregation and dose dependently increased electrical current (r = .94). Collagen-induced electrical current and cGMP were significantly augmented by L-arginine, a precursor of NO, and attenuated by NG-monomethyl-L-arginine, an inhibitor of NO synthesis. Significant correlation was found between collagen-induced electrical current and cGMP (r = .73). These findings indicate that the change in electrical current reflects the NO release through the L-arginine-NO pathway in platelets. Collagen-induced electrical current (6.7 versus 13.8 pA; P < .001) and cGMP (1.2 versus 3.0 pmol/10(9) platelets; P < .005) were significantly lower in smokers than in nonsmokers. Although L-arginine increased cGMP levels in both smokers and nonsmokers, the level was still lower in smokers than in nonsmokers. The inhibitory effect of L-arginine on collagen-induced platelet aggregation was significantly lower in smokers than in nonsmokers (P < .05). CONCLUSIONS These findings provide evidence that platelet-derived NO release is significantly impaired in long-term smokers, resulting in the augmentation of platelet aggregability.

Platelet-Derived Nitric Oxide and Coronary Risk Factors

Platelet aggregation is inhibited through a negative feedback mechanism by the L-arginine/nitric oxide (NO) pathway found in platelets themselves. We have shown that long-term smoking impairs the bioactivity of platelet-derived NO (PDNO), resulting in an increased platelet aggregability. However, little is known about the relation between other coronary risk factors and PDNO release. Accordingly, this study was undertaken to examine whether other coronary risk factors are related to the impairment of PDNO bioactivity. We measured collagen-induced PDNO release with an NO-selective electrode in 61 subjects (mean age 47 years, range 24 to 74 years) who underwent complete physical and laboratory examinations. There was a significant inverse correlation between PDNO release and the number of coronary risk factors (r=-0.61, P<0. 001). Univariate analysis showed a significant inverse correlation between PDNO release and age (r=-0.33, P<0.01), mean arterial pressure (r=-0.40, P<0.002), total cholesterol level (r=-0.31, P<0. 02), and LDL-cholesterol level (r=-0.33, P<0.02). PDNO release was significantly lower in long-term smokers than in nonsmokers (P<0. 001). With multiple stepwise regression analysis, PDNO release correlated significantly and independently (r(2)=0.51), with smoking (F=37.8), age (F=7.1), and mean arterial pressure (F=5.1). Thus, we demonstrated that coronary risk factors are associated with an impairment of PDNO release by human platelets. Our findings may contribute to the understanding of the pathophysiological link between coronary risk factors and atherothrombotic disease.