Coronary endothelial dysfunction and impaired microcirculation response to atrial natriuretic peptide in hyperinsulinemia.

Endothelial dysfunction occurs in hyperinsulinemia (HI). Coronary microcirculation responses to vasoactive agents are examined in 57 patients with angiographically normal coronary arteries. Patients were divided into 2 groups, 37 with normoinsulinemia (NI) and 20 with HI based on results of a 75-g oral glucose tolerance test. Epicardial artery vasoactivity in response to acetylcholine chloride is measured to assess endothelial function. Coronary microcirculation function is evaluated by intracoronary administration of 50 microg of adenosine triphosphate, 1 mg of isosorbide dinitrate, and 0.05 mg/kg of atrial natriuretic peptide. Epicardial artery vasoconstriction in response to 100 microg of acetylcholine is mildly reduced in HI (P = .04). Coronary flow reserve in response to adenosine triphosphate in NI is similar to that in HI. In NI, the resting mean (SD) peak velocity in response to isosorbide dinitrate (40.7 [10.9] cm/s) vs atrial natriuretic peptide (39.6 [10.9] cm/s) is similar. In contrast, the resting mean (SD) peak velocity in response to atrial natriuretic peptide (31.3 [9.3] cm/s) vs isosorbide dinitrate (43.5 [10.0] cm/s) in HI is statistically significantly blunted (P < .001). Atrial natriuretic peptide may have a pathologic effect on coronary microcirculation even in mild endothelial dysfunction among patients with HI.

Examination of the microcirculation damage in smokers versus nonsmokers with vasospastic angina pectoris.

Endothelial dysfunction is considered one of the mechanisms underlying vasospastic angina pectoris (VSA). It is also known that smokers have abnormalities in endothelial dysfunction. Although smoking is a major risk factor for coronary artery disease, microvascular abnormalities have not been well shown. We investigated clinical characteristics and coronary reactivity with adenosine triphosphate in smokers with VSA. Twenty-two consecutive patients whose coronary spasm was documented in the left anterior descending (LAD) coronary artery with acetylcholine were enrolled. Coronary blood flow responses were also evaluated by intracoronary Doppler flow velocity recordings in the LAD coronary artery. Average peak velocities (APVs) were measured at baseline and intracoronary administration of adenosine triphosphate (50 microg) in 11 smokers (age 60+/-9 years; 8 men) and 11 nonsmokers (age 61+/-10 years, 5 men). Coronary flow reserve (CFR) was calculated by the ratio of baseline to hyperemic APV. Multivessel spasm was demonstrated in 6 smokers and only 2 nonsmokers (p<0.05). APV at rest in smokers (13.4+/-3.0 cm/s) was similar to that in nonsmokers (13.5+/-2.9 cm/s). However, CFR in smokers (2.6+/-0.7) was significantly lower than in nonsmokers (3.4+/-0.8; p<0.05). In conclusion, multivessel spasm was demonstrated in smokers in clinical settings, and microcirculation damage is prominent in smokers with VSA.

P-selectin expression, but not GPIIb/IIIa activation, is enhanced in the inflammatory stage of Takayasu's arteritis.

BACKGROUND: Inflammation and thrombosis are closely related processes, but the association between disease activity and thrombogenicity in Takayasu's arteritis (TA) is poorly understood. To investigate the link between platelet activation and disease activity, flow cytometric analyses of platelet P-selectin and activated GPIIb/IIIa expression were performed in patients with TA. METHODS AND RESULTS: Twenty-two patients with TA, classified into active (Group A, n = 9) and inactive (Group I, n = 13) according to blood-derived inflammatory markers, and 14 healthy age- and gender-matched controls (Group C) were studied. Compared with Group C, the mean fluorescence intensity of P-selectin in response to 0.1-10 micromol/L of ADP was significantly upregulated in Group A, but not in Group I. No differences in platelet GPIIb/IIIa expression in stimulated platelets were seen among the 3 groups. Standard platelet aggregation studies revealed that disease activity did not influence platelet aggregation by ADP. CONCLUSIONS: P-selectin expression, but not activated GPIIb/IIIa, is enhanced in ADP-activated platelets from patients in the inflammatory stage of TA. P-selectin may play a significant role in the inflammatory and thrombotic responses associated with intractable TA, presumably by inducing platelet-leukocyte interactions.

Perindopril augments ecto-ATP diphosphohydrolase activity and enhances endothelial anti-platelet function in human umbilical vein endothelial cells.

OBJECTIVES: Recent clinical trials have demonstrated that angiotensin-converting enzyme inhibitors (ACEIs) reduce thrombotic events by unknown mechanisms in patients with atherosclerotic cardiovascular diseases. DESIGN: We studied the in-vitro effects of perindopril, an ACEI, on the ability of human umbilical vein endothelial cells (HUVEC) to inhibit platelet aggregation. METHODS: Platelet aggregation in the presence of HUVEC and endothelial surface expression and activities of ecto-ATP diphosphohydrolase (ecto-ADPase), CD39, were determined. The capability of HUVEC to release prostacyclin and nitric oxide (NO) was also investigated. RESULTS: Perindoprilat (an active metabolite of perindopril) significantly enhanced the surface expression and activities of ecto-ADPase and prostacyclin release, resulting in enhancement of ability to inhibit platelet aggregation by HUVEC. These effects of perindoprilat were also observed in HUVEC activated by tumour necrosis factor (TNF)-alpha, which increased the expression of intracellular adhesion molecule-1 (ICAM-1), CD54, and, despite up-regulation of prostacyclin release, attenuated endothelial anti-platelet properties by decreasing ecto-ADPase activity. Perindoprilat partially restored this capability, but failed to reduce enhanced expression of ICAM-1. By contrast, the role of NO as a platelet inhibitor appeared minimal in HUVEC. Candesartan, an angiotensin II receptor (AT(1)) blocker, did not affect endothelial anti-platelet property. CONCLUSIONS: Perindoprilat was found to augment endothelial capability to inhibit platelet aggregation by increasing ecto-ADPase activity and prostacyclin release in HUVEC. This beneficial effect of perindoprilat appeared to be preserved in the activated cells exposed to TNF-alpha, although no evidence was found to support that it could reverse the inflammation process induced by cytokines.

Smokers lack morning increase in platelet sensitivity to nitric oxide.

This study investigated whether a circadian variation is present in the sensitivity of platelets to nitric oxide (NO) and, if so, if long-term smoking modifies it. Blood samples were taken at 0:00, 6:00, 9:00, 12:00, and 18:00 from 14 nonsmokers and 10 smokers. Dose-response curves for platelet aggregation by collagen were constructed in both the presence and absence of 1.0 micro M of NOR-3, a NO donor. The antiaggregation properties of NOR-3 were quantified by the half maximal concentration (EC50) ratio in the presence of NOR-3 to that in its absence. Platelet aggregation showed a monophasic circadian rhythm, with the lowest levels at 6:00 and the highest at 18:00 in both groups. However, there was a significant (p < 0.01) upward shifting of platelet aggregation in the smokers. A circadian variation in sensitivity to NOR-3 also was demonstrated in the nonsmokers. The sensitivity was lowest at 6:00 (1.68 +/- 0.19), increased significantly at 9:00 (2.58 +/- 0.26; p < 0.01), and remained high at 12:00 (2.47 +/- 0.21; p < 0.05). In smokers, however, a circadian variation in platelet sensitivity to NOR-3 was not found. Furthermore, the sensitivity was significantly lower at 9:00 and 12:00 in smokers (1.94 +/- 0.26 and 1.76 +/- 0.13, respectively; p < 0.05 for both) than in nonsmokers. Thus, long-term smoking impairs the normal morning increase in platelet sensitivity to NO, making platelets in smokers more thrombogenic during the hazardous hours.

Opening of K(ATP) channel attenuates the increase in QT dispersion produced by the first balloon inflation during coronary angioplasty.

Increased QT dispersion predicts the occurrence of lethal ventricular arrhythmias complicating percutaneous transluminal coronary angioplasty (PTCA). Moreover, these arrhythmias occur more frequently at the first balloon inflation. Activation of the K(ATP) channel may influence QT dispersion and ventricular arrhythmias during coronary angioplasty, so 40 consecutive patients with stable angina were randomized to receive 3 mg/h of nicorandil infusion or placebo and QT dispersion and the incidence of ventricular ectopy were investigated before and throughout PTCA. There were no significant differences in QT dispersion at baseline between the nicorandil group (42+/-8 ms) and placebo (42+/-12ms). At the first balloon inflation, the QT dispersion in the nicorandil group (51+/-13 ms) was significantly less than that observed with placebo (76+/-16ms, p<0.001). However, the QT dispersion at the second inflation was similar in both groups (nicorandil: 45+/-12ms; placebo: 52+/-14ms). Ventricular ectopy was observed in 1 patient receiving nicorandil and 5 patients in the placebo group during the first inflation, and none in the nicorandil and 1 patient in the placebo group during the second balloon inflation. Activation of the K(ATP) channel may inhibit the development of ventricular arrhythmias during PTCA, particularly at the first balloon inflation.

Acute vigorous exercise primes enhanced NO release in human platelets.

Activation of platelets by acute vigorous exercise has been demonstrated by various parameters, including an increase in agonist-induced platelet [Ca2+]i levels. However, direct evidence is lacking regarding how acute exercise affects platelet-derived NO. Twenty-three healthy male non-smokers (21-59 years) underwent a symptom-limited treadmill exercise test. Washed platelets were prepared from blood samples obtained before and immediately after exercise. All subjects completed at least Bruce stage 2 and were each negative for ischemia. With a low dose (2 microg/ml) of collagen, NO release from washed platelets, detected by the NO-selective microelectrode, was significantly increased after exercise (pmols/10(8) platelets, before: 0.64+/-0.11, after: 1.03+/-0.18; P<0.005) without changes in aggregation ability. This enhanced NO release was accompanied by increased platelet [Ca2+]i levels (before: 232+/-25, after: 296+/-37; P<0.01). With a high dose (5 or 10 microg/ml) of collagen, NO release and aggregation were both modestly, but significantly, enhanced after exercise. The exercise-induced enhancement of platelet NO release in response to collagen was also suggested by increase in platelet cyclic guanosine monophosphate accumulation and augmenting effect of N(G)-monomethyl-L-arginine on platelet aggregation. In summary, acute strenuous exercise primes enhanced NO release and may play a protective role against exercise-induced activation of platelets in normal subjects.