Effects of Picotamide on Release of Endothelin-1,Thromboxane,and Prostacycline After Treadmill Stress in Patients with Peripheral Artery Disease

Abstract

To assess the effects of picotamide, an antithromboxane receptor and antithromboxane synthase drug, on vascular function and endothelin-1 release, 20 patients with peripheral arterial disease, without hypertension or diabetes mellitus, receiving placebo and pico tamide (900 mg/day) were studied. The modifications of vascular parameters were evaluated by arterial distensibility index and postischemic hyperemia test (postischemic perfusion index and recovery time). Endothelin-1, prostacycline, and thromboxane B₂ were determined under resting conditions and after treadmill test. Picotamide treatment caused a decrease of resting thromboxane B₂ and endothelin-1 concentrations, produced an improvement of the vascular function as seen by the increase of vascular parameters reported, and attenuated the ischemic treadmill-induced increase of thromboxane B₂, but not of endothelin-1. These data confirm that the picotamide improved vascular flow by the reduction of thromboxane-mediated effects, reduced resting endothelin-1 levels, but did not attenuate endothelin-1 concentrations induced by the treadmill stress.

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References

Antiplatelet Trialist Collaboration : Secondary prevention of vascular disease by prolonged antiplatelet treatment Br Med J 296:320-321, 1988.

Moncada S. , Vane JR : Arachidonic acid and the interaction between platelets and blood vessel walls N Engl J Med 300:1142-1147, 1979 .

Vane JR : Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs Nature New Biol 231:232-235, 1971.

Gresele P. , Deckmyn H. , Arnout J., et al : Characterization of N,N bis (3 Picolyl)-4-Methoxyisopthalamide (Picotamide) as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets Thromb Haemost 61:479-484, 1989.

Neri Serneri GG , Gensini GF , Poggesi U. : The role of extraplatelet thromboxane A 2 in unstable angina investigated with a dual thromboxane A2 inhibitor: Importance of activated monocytes Coron Artery Dis 5:137-145, 1994.

Neirotti M. , Molaschi M. , Ponzetto M., et al : Hemodynamic, hemorrheologic, and hemocoagulative changes after treatment with picotamide in patients affected by peripheral arterial disease (PAD) of the lower limbs Angiology 45:137-141, 1994.

Balsano F. , Violi F. , and the ADEP Group : Effect of picotamide on the clinical progression of peripheral vascular disease. A double-blind placebo-controlled study Circulation 87:1563-1569, 1997.

Yanagisa MA , Kurihara H. , Kimura S., et al : A novel potent vasoconstrictor peptide produced by vascular endothelial cells Nature 322:411-415, 1988.

Lerman A. , Edwars BS , Hallet JW, et al : Circulation and tissue endothelin immunoreactivity in advance atherosclerosis N Engl J Med 325:997-1003, 1991.

10.

DeNucci A. , Thomas R. , D'Orleans-Juste P., et al : Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor. Proc Natl Acad Sci USA 85:9797-9800, 1988.

11.

Hirata Y. , Takagi Y. , Fucuda Y., et al : Endothelin is a potent mitogen for rat vascular smooth muscle cells Atherosclerosis 78:225-228, 1989.

12.

Wright CD , Cody W. , Dunbar JB, et al : Characterization of the chemotactic activity of endothelins and peptide fragments for human neutrophils FASEB J 5:A637, 1991 .

13.

Goto K. , Kasuya Y. , Matsuki N., et al : Endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca 2+ channel in vascular smooth muscle Proc Natl Acad Sci USA 86:3915-3918, 1989.

14.

Hieda HS , Gomez Sanches CE : Hypoxia increases endothelin release in bovine endothelial cells in culture but epinephrine, norepinephrine, serotonin, histamine and angiotensin II do not Life Sci 47: 247-251, 1990.