Article de synthese traitant de la pharmacologie de l'oxyde nitrique, du facteur EDRF et du GMP cyclique dans les vaisseaux sanguins et les thrombocytes, de l'isolation et de l'identification du facteur EDRF comme de l'oxyde nitrique, et de la formation, de la liberation et du metabolisme de l'endothelium derived NO (EDNO)

Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein.

Increased vascular constriction has been observed at the site of atherosclerotic lesions, suggesting an association between atherosclerosis and altered vascular tone. While atherosclerosis may increase sensitivity to exogenous vasoconstrictors, little is known about the response of normal and atherosclerotic coronary arteries to an exogenous stimulus that excites the sympathetic nervous system. Therefore, we studied the response to cold pressor test (CPT) using quantitative angiography and Doppler flow velocity measurements in eight patients with angiographically normal coronary arteries (group I), nine patients with mild coronary atherosclerosis (less than 50% diameter narrowing) (group II), and 13 patients with advanced coronary stenoses (greater than 50% diameter narrowing) (group III). In 31 segments of angiographically smooth arteries in group I, the CPT produced vasodilation from a control mean diameter of 2.68 +/- 0.09 (mean +/- SE) to 2.99 +/- 0.09 mm at peak CPT (p less than 0.001), a 12 +/- 1% increase in diameter. In group II, 27 irregular segments constricted to peak CPT from a mean control diameter of 1.82 +/- 0.12 to 1.66 +/- 0.12 mm (p less than .001), a 9 +/- 1% decrease, while 10 smooth segments dilated from a mean control diameter of 1.98 +/- 0.11 mm to 2.34 +/- 0.15 mm (p less than .01), a 19 +/- 2% increase in diameter. Likewise, in group III, the 17 stenotic segments constricted from 1.16 +/- 0.09 to 0.89 +/- 0.09 mm (p less than .001), a 24 +/- 6% decrease; the irregular segments also constricted from 2.44 +/- 0.11 to 2.22 +/- 0.12 mm (p = .002), a 10 +/- 2% decrease. In contrast, two smooth segments dilated from 2.98 to 3.23 mm (mean), an 8% increase in diameter. Coronary blood flow increased 65 +/- 4% (mean) during CPT in group I, it increased 15 +/- 6% in group II, and it decreased 39 +/- 8% in group III. The vasodilator response in four normal patients was partly inhibited by the administration of intracoronary propranolol (17 +/- 3% increase during control, 10 +/- 2% increase after propranolol, 41% less dilation; p = .002). We conclude that the response of normal coronary arteries to the CPT test is dilation, in part related to beta-adrenoreceptor stimulation and possibly flow-mediated endothelial dilation or alpha 2-adrenergic activity. The paradoxical vasoconstrictor response induced by atherosclerosis may represent altered catecholamine sensitivity and/or a defect in endothelial vasodilator function. The presence of atherosclerosis impairs vasodilator responses and thus may contribute to the pathogenesis of myocardial ischemia.

Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test.

We studied the effects of hypercholesterolemia on vascular responsiveness in different arteries isolated from rabbits: control groups of rabbits and groups receiving the atherogenic diet consisted of eight animals each. In the arteries, 16 weeks of cholesterol-rich (0.3%) diet evoked intimal lesions which were more pronounced than those noted after 8 weeks of hypercholesterolemia; the aortic arch was affected significantly more by the lesions than the abdominal aorta and the pulmonary artery. Segments of the arteries were mounted in organ chambers for isometric tension recording or for measurement of the endothelium-derived relaxant factor. Contractions caused by acetylcholine and prostaglandin F2 alpha were not altered by the hypercholesterolemia; those evoked by serotonin were moderately augmented only in the aortic arch of hypercholesterolemic rabbits. As the degree of intimal lesion formation increased, the contractions to norepinephrine and clonidine were progressively inhibited. The endothelium-independent relaxations to nitroglycerin were inhibited in only the most severely affected arteries; the endothelium-dependent relaxations to acetylcholine and adenosine triphosphate were progressively inhibited as the degree of fatty streak formation augmented. Thus, in the aortic arch, the relaxations to 3 X 10(-6) M acetylcholine, expressed as percent of the initial contraction, decreased from 86.7 +/- 3.3% in control tissues to 16.3 +/- 8.6% in the 16-week hypercholesterolemic vessels; in the abdominal aortas these relaxations averaged 93.5 +/- 2.2% in control vessels and 72.0 +/- 6.9% in the hypercholesterolemic tissues. The acetylcholine-induced release of endothelium-derived relaxant factor from the abdominal aorta was not significantly affected by the hypercholesterolemia. We conclude from these studies that in arteries obtained from hypercholesterolemic rabbits: the contractions caused by serotonergic mechanisms tend to be augmented, while those to alpha-adrenergic activation are decreased, the endothelium-independent relaxations are modified only in the more severely affected arteries, and the endothelium-dependent relaxations are progressively inhibited as the degree of fatty streak formation augments, probably because a step subsequent to the release of endothelium-derived relaxant factor is altered.

Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits.

Detailed formal protocol with illustrations and extensive bibliography. Note: Some information has been redacted in the publicly-available version due to privacy issues. For questions, contact archives@utsouthwestern.edu.

Coronary-artery spasm.

We established the incidence of coronary artery spasm provoked by 0.4 mg of methergine in 1089 consecutive patients undergoing coronary angiography. The test was performed after routine coronary arteriography. Subjects included patients with angina, both typical and atypical, patients who had recently had myocardial infarction and patients with either valvular disease or congestive cardiomyopathy. Patients with spontaneous spasm, left main narrowing or severe three-vessel disease were excluded. One hundred thirty-four patients experienced focal spasm. Focal spasm was uncommon in patients with atypical precordial pain (1.2%), angina of effort (4.3%), valvular disease (1.95%) or cardiomyopathy (0%). It occurred most often in patients with angina at rest and less often in patients with angina both at rest and induced by exercise. Spasm was provoked in 20% of patients with recent transmural infarction, but in only 6.2% of patients studied later after infarction. Spasm was superimposed on fixed atherosclerotic lesions in 60% of the patients. No serious complications were encountered. Although the patients who underwent provocation tests in this study are not representative of all patients with coronary artery disease, spasm occurred in 20% of patients who experienced a coronary event and in 15% of patients who complained of chest pain.

Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography.

Ergonovine maleate (Ergotrate) was given to 57 patients undergoing coronary arteriography for investigation of angina occurring at rest or without provocation when routine study showed normal arteries or insufficient occlusive disease to explain their symptoms. This provocative test induced coronary arterial spasm in 13 patients, 10 of whom had definite Prinzmetal's angina. The spasm was easily reversed with sublingually administered nitroglycerin. The spasm was occlusive or nearly occlusive in nine patients, and there was associated reproduction of the chest pain and S-T elevation similar to the spontaneous episodes. One patient with Prinzmetal's angina had S-T depression rather than elevation in association with the chest pain. The other three patients without Prinzmetal's angina had focal narrowing without coronary occlusion, reproduction of the chest pain or electrocardiographic changes. Of the 44 patients who did not demonstrate coronary spasm in response to ergonovine, 29 had normal coronary arteries and 15 had various degrees of atherosclerotic occlusive disease. We conclude that cautious administration of ergonovine maleate during coronary arteriography can be safely used to elicit coronary spasm in some patients who have insufficient fixed occlusive disease to explain their symptoms.

Robert A. Quint

Papers

Provocation of coronary spasm with ergonovine maleate: New test with results in 57 patients undergoing coronary arteriography☆