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It has been shown that endothelium-derived relaxing factor (EDRF) may inhibit platelet aggregation in vitro through activation of platelet-soluble guanylate cyclase. To assess whether EDRF may also affect platelet function in vivo, intravascular platelet aggregation was initiated by placing an external constrictor around endothelially injured rabbit carotid arteries. Carotid blood flow velocity was measured continuously by a Doppler flow probe placed proximal to the constrictor. After placement of the constrictor, cyclic flow reductions (CFRs), due to recurrent platelet aggregation, developed at the site of the stenosis. After CFRs were observed for 30 minutes, a solution of authentic nitric oxide (NO, n = 10) was infused into the carotid artery via a small catheter placed proximally to the stenosis. Before infusion of NO, CFR frequency averaged 18.3 +/- 2.9 cycles per hour, and CFR severity (lowest carotid blood flow as percentage of baseline values) was 6 +/- 1%. NO completely inhibited CFRs in all animals, as shown by the normal and constant pattern of carotid blood How (CFR frequency, 0 cycles per hour, p

Background. Serotonin is released after the aggregation of platelets, a phenomenon that may occur after coronary angioplasty. We sought to determine whether serotonin is released into the coronary circulation during coronary angioplasty and to assess whether serotonin can affect coronary-artery tone during angioplasty. Methods. Blood samples were drawn from the ascending aorta and the coronary sinus of eight patients scheduled to undergo angioplasty of the left anterior descending or circumflex coronary artery. Samples were obtained before angioplasty and after each balloon dilation. The dimensions of arterial segments distal to the site of dilation were measured angiographically before angioplasty and 5 and 15 minutes after the last dilation in these eight patients and in seven similar patients; the latter group was treated with ketanserin, a serotonin(2)-receptor antagonist, before angioplasty. Results. Before the eight patients underwent angioplasty, their mean (+/-SE) plasma serotonin level in the aorta was 2.5+/-0.7 ng per milliliter and that in the coronary sinus was 2.3+/-0.6 ng per milliliter (P = 0.34). The seretonin level in plasma from the coronary sinus rose significantly, to 31.5+/-13.5, 17.6+/-5.3, and 29.1+/-8.1 ng per milliliter after the first, second, and third dilations, respectively (P = 0.014 for the comparison with preoperative levels). In contrast, the serotonin level in plasma from the ascending aorta did not change. The cross-sectional area of the coronary artery was significantly reduced 5 and 15 minutes after the last dilation (from a preoperative value of 3.7+/-0.5 mm(2) to 2.7+/-0.4 mm(2) 15 minutes after the last dilation; P = 0.011). This vasoconstriction was significantly blunted in the seven patients who received ketanserin (from 3.7+/-0.5 mm(2) before angioplasty to 3.9+/-0.4 mm(2) after 15 minutes) (P = 0.017 for comparison with the eight patients who did not receive ketanserin). Conclusions. Serotonin is released into the coronary circulation during angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction distal to the dilated site. The vasoconstriction is attenuated by ketanserin, a serotonin(2)-receptor antagonist.

It has been suggested that activation of tissue phospholipases may contribute to the development of ischemic cell injury. In the present study we sought to assess whether administration of the phospholipase inhibitor quinacrine would reduce the extent of myocardial necrosis after coronary artery occlusion. In open-chest, anesthetized dogs the left anterior descending coronary artery was ligated, and technetium-99-labeled albumin microspheres were injected into the left atrium to measure the area at risk. The animals were then randomly divided into a control group (n = 8) and a group receiving quinacrine (5 mg/kg intravenous bolus followed by a 40 micrograms/kg/min infusion for 6 hours; n = 9). The animals were killed 6 hours after occlusion, and the infarcted area was delineated by triphenyltetrazolium chloride staining. The extent of the risk region was similar in the two groups (32.3 +/- 2.1% of the left ventricle in control dogs and 34.2 +/- 3.4% in quinacrine-treated dogs). Infarct size was 86.4 +/- 8.8% of the risk region in control animals, whereas in treated dogs it averaged 62.3 +/- 6.4% of the risk region (p = 0.05). No differences were found in heart rate, arterial pressure, and rate-pressure product between the two groups. Thus administration of the phospholipase inhibitor quinacrine reduced the extent of myocardial necrosis in a model of fixed coronary artery occlusion. Preservation of membrane phospholipids, reduced formation of lipoxygenase metabolites, or both may mediate this phenomenon.

Background. Studies in animals have shown that serotonin constricts coronary arteries if the endothelium is damaged, but in vitro studies have revealed a vasodilating effect on isolated coronary segments with an intact endothelium. To investigate the effect of serotonin in humans, we studied coronary-artery cross-sectional area and blood flow before and after the infusion of serotonin in seven patients with angiographically normal coronary arteries and in seven with coronary artery disease. Methods. We measured the cross-sectional area of the coronary artery by quantitative angiography and coronary blood flow with an intracoronary Doppler catheter. Measurements were obtained at base line and during intracoronary infusions of serotonin (0.1, 1, and 10-mu-g per kilogram of body weight per minute, for two minutes). We repeated the measurements after an infusion of ketanserin, an antagonist of serotonin receptors that is thought to block the effect of serotonin on receptors in the arterial wall but not in the endothelium. Results. In patients with normal coronary arteries, the highest dose of serotonin increased cross-sectional area by 52 percent (P < 0.001) and blood flow by 58 percent (P < 0.01). The effect was significantly potentiated by administration of ketanserin. In patients with coronary-artery atherosclerosis, serotonin reduced cross-sectional area by 64 percent (P < 0.001) and blood flow by 59 percent (P < 0.001). Ketanserin prevented this effect. Conclusions. Serotonin has a vasodilating effect on normal human coronary arteries; when the endothelium is damaged, as in coronary artery disease, serotonin has a direct, unopposed vasoconstricting effect. When considered with other evidence, these data suggest that platelet-derived factors such as serotonin may have a role in certain acute coronary ischemic syndromes.