calcimycin and Coronary-Vasospasm

Morphological and functional modifications occurring in Langendorff rabbit heart preparations perfused with purified human leukocytes (PMNL), as an organ model of sulfidopeptide-leukotrienes (sLT) transcellular biosynthesis, were studied. Coronary perfusion pressure (CPP), monitored as an index of coronary vasospasm, increased by 295% after challenge with the Ca(2+)-ionophore A-23187 (0.5 micromol/L) for 30', accompanied by a significant formation of sLT. Increase in CPP was prevented by PMNL pretreatment with the 5-lipoxygenase inhibitor MK-886 (1 micromol/L) or by heart pretreatment with LTD4-receptor antagonist SKF 104353, indicating a pivotal role of PMNL-derived 5-lipoxygenase (5-LO) products in the observed functional modifications. Similar effects were obtained using granulocyte macrophage-colony stimulating factor-primed PMNL challenged with the tripeptide n-formyl-methionyl-leucyl-phenylalanine. Scanning electron microscopy (SEM) of coronary arteries showed craters on the vessel luminal surface, PMNL adhering to endothelial cells (EC), increased number of microvilli on EC, presence of nonviable, desquamating, fusiform EC. SEM and transmission electron microscopy of myocardial microvessels, showed presence of perivascular and intermuscle edema, presence of activated PMNL and decreased number of patent microvessels. These morphological alterations were significantly blunted by MK-886 or SKF 104353. These data provide evidence of close interaction between PMNL and myocardial EC, resulting in enhanced sLT formation via transcellular biosynthesis, originating from transfer of PMNL-derived LTA4 to EC. These potent proinflammatory autacoids are responsible for coronary vasospasm and the morphological alternations observed.

Topics: Animals; Calcimycin; Cell Adhesion; Coronary Vasospasm; Coronary Vessels; Dicarboxylic Acids; Endothelium, Vascular; Granulocyte-Macrophage Colony-Stimulating Factor; Indoles; Ionophores; Leukotriene Antagonists; Leukotrienes; Lipoxygenase Inhibitors; Membrane Proteins; Microcirculation; Microscopy, Electron, Scanning; Myocardium; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Perfusion; Rabbits; Receptors, Leukotriene; Vasoconstriction

The effects of hemostatic substances on the vascular tone in porcine coronary arteries and the influence of low density lipoprotein on tension were investigated. Thrombin induced a marked concentration-dependent relaxation in prostaglandin F2 alpha-precontracted strips with intact endothelium, whereas it produced a modest constriction in endothelium-denuded arteries. Methylene blue abolished the relaxation, but indomethacin did not affect it significantly. An exposure of the intact strips to low density lipoprotein resulted in a marked inhibition of the relaxation to thrombin but did not interfere with vasodilation by sodium nitroprusside. The inhibition by low density lipoprotein was reversed completely by washing. In contrast, high density lipoprotein lacked such inhibitory effects. Adenosine diphosphate, calcium ionophore A23187, and platelet-activating factor also produced relaxation in the intact strips. An exposure of the strips to low density lipoprotein almost abolished relaxation to these substances. The inhibition was also reversible. Heat treatment or acid treatment of low density lipoprotein resulted in a complete loss of the inhibitory effects, but diisopropyl fluorophosphate treatment did not alter the effect. It is concluded that low density lipoprotein may play a new pathological role in promotion of coronary vasospasm through rapid and reversible inhibition in endothelium-dependent relaxation to hemostatic substances.

Topics: Acids; Adenosine Diphosphate; Animals; Calcimycin; Coronary Vasospasm; Coronary Vessels; Endothelium, Vascular; Female; Hot Temperature; In Vitro Techniques; Lipoproteins, LDL; Male; Muscle Relaxation; Nitric Oxide; Platelet Activating Factor; Swine; Thrombin; Thrombosis

Mechanism of coronary spasm was examined regarding endothelium-related relaxation and contraction produced by smooth muscle cells of spastic vessels isolated from Göttingen miniature pigs. In these pigs, coronary artery spasm was documented angiographically in vivo three months after endothelial denudation, and spastic and control segments of the coronary artery were suspended in organ chambers at their optimal length for generating tension. Applications of KCl (118 mM), acetylcholine(10(-9) to 10(-4) M), and PGF2 alpha (10(-8) to 3 X 10(-5) M) produced similar tension, at the respective doses, in both the spastic and control coronary arteries. During increasing concentrations of histamine (10(-8) to 3 X 10(-4) M; n = 14) and serotonin (10(-9) to 10(-5) M; n = 13), the maximum tension of the spastic vessel was 136 +/- 6 and 97 +/- 4%, respectively, of the tension produced by 118 mM KCl. That is significantly larger than seen in the control vessels: 98 +/- 4 and 74 +/- 4%, respectively. The ED50 to histamine and serotonin was also significantly less in the spastic vessels. After mechanical removal of the endothelium, the tension generated during the cumulative administration of histamine (n = 8) but not serotonin (n = 8) was larger in the spastic than the control vessels, thereby suggesting the presence of augmented responses of the smooth muscle to histamine in the spastic vessels. The increase in maximum tension after mechanical denudation was greater in the control than the spastic vessels in cases of histamine and serotonin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calcimycin; Coronary Vasospasm; Dinoprost; Disease Models, Animal; Endothelium, Vascular; Histamine; Ketanserin; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Prostaglandins F; Serotonin; Swine; Swine, Miniature