Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin.

Abstract

To test the ability of regenerated endothelium to evoke endothelium-dependent relaxations, male Yorkshire pigs underwent balloon endothelial denudation of the proximal left anterior descending coronary artery. Endothelium-dependent responses were examined in vitro, in rings of coronary segments taken from the denuded area or from the proximal left circumflex coronary artery. The experiments were performed 8 days or 4 weeks after the denudation. Endothelial regrowth was confirmed by histologic examination 8 days after the denudation and by demonstrating the presence of endothelium-dependent relaxations to bradykinin; at that time aggregating platelets evoked normal endothelium-dependent responses. However, 4 weeks after the denudation, the relaxations to aggregating platelets were markedly depressed although continuous endothelial lining was present, and the endothelium-dependent responses to bradykinin, adenosine diphosphate, the Ca2+-ionophore A23187, platelet activating factor, and thrombin were unaltered. Four weeks after denudation, endothelium-dependent relaxations to serotonin were depressed. Higher concentration of serotonin induced endothelium-dependent contractions in quiescent rings with regenerated endothelium, suggesting that regenerated endothelial cells may produce endothelium-derived constricting factor(s) and release less endothelium-derived relaxing factor(s) when exposed to the monoamine. The endothelium-dependent relaxation to serotonin was not reduced by the S2-serotonergic antagonist ketanserin but prevented by the combined S1- and S2-serotonergic blocker methiothepin. The platelet-induced relaxation was due to released serotonin and adenine nucleotides in control left circumflex coronary arteries, but in left anterior descending coronary artery with regenerated endothelium, it was due solely to the latter. The platelet-induced contractions were due to activation of receptors on the smooth muscle cells. Four weeks after denudation, regenerated endothelial cells were morphologically different from native cells; they were elongated and cuboidal, and the number of the cells had increased twofold. At this state, eccentric myointimal thickening was present in the previously denuded portion. These experiments indicate that the protective role of endothelial cells against the vasoconstriction induced by aggregating platelets is depressed in the chronic regenerated state. A lack of responsiveness to serotonin appears to be the cause for the endothelial dysfunction.

Vasoconstrictor and vasodilator effects in normal and atherosclerotic conscious rabbits

“…Attempts have been made to clarify this hyperresponsiveness of arteriosclerotic vessels by experiments in vitro, but the results differed greatly depending on species and experimental conditions (Henry & Yokoyama, 1980;Godfraind & Miller, 1983;Kawachi et al, 1984;j / Ginsburg et al, 1984;Harrison et al, 1987). The defective endothelium-derived relaxing factor (EDRF) release in atherosclerotic vessels (Freiman et al, 1986;Jayakody et al, 1987a; (EDCF) or endothelin (Yanagisawa et al, 1988) as is found in hypertension or in regenerating endothelium (Luescher & Vanhoutte, 1986;Vanhoutte, 1987;Shimokawa et al, 1987 (Hof et al, 1987), for this purpose. The calcium after (continuous line) antagonist shifted the dose-response curves to NA cg 1. n = 6 for each and Phen (but not AII) more effectively to the right in atherosclerotic animals so that the pressor In summary, our experiments support the view that pressor effects of several vasoconstrictor agents are enhanced in atherosclerotic animals.…”

Effect of Platelet Activation on Coronary Collateral Blood Flow

“…Shimokawa et al 23 reported that PAF caused endothelium-dependent relaxation in isolated porcine coronary arteries at concentrations several orders of magnitude higher (IC 50 10 Ϫ4.5 mol) than used in the present study. Hu and Man 22 reported a weak biphasic response after PAF injection in an isolated rat heart preparation perfused with Krebs-Henseleit buffer.…”

“…28 A direct vasodilator effect on coronary arterial vessels has been demonstrated at PAF concentrations several orders of magnitude higher than those achieved in the present study. 23,27 Although statistically significant, the magnitude of PAF-induced collateral vasodilation during thromboxane A 2 receptor blockade was small.…”

“…Alternatively, the lack of vasodilation could reflect absence of receptors to platelet derived substances such as ADP or serotonin on the collateral vessel endothelium. Shimokawa et al 23 demonstrated that 4 weeks after balloon denudation of normal coronary arteries, vessel segments containing newly regenerated endothelium have an impaired vasodilator response to aggregating platelets. It is possible that newly developed endothelium in immature collaterals might have a similarly impaired vasodilator response to platelet aggregation.…”

Vein graft failure: current clinical practice and potential for gene therapeutics

“…49 The repaired endothelial lining is however markedly dysfunctional in part due to the arterial pressure that the vein is now subjected to. 50,51 After implantation, the vein graft, which has been subjected only to an internal pressure of 10 mm Hg in the venous circulation, is immediately subjected to the arterial pressure (100 mm Hg) as well as immediate increases in flow, longitudinal wall (shear) stress, circumferential, radial and pulsatile deformation and stress. 52 Numerous genes are upregulated in response to the altered shear stress, including adhesion molecules, 53,54 and therefore this is a substantial promoter of intimal thickening.…”