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Ann Thorac Surg 2000;69:1986-1987
© 2000 The Society of Thoracic Surgeons
a Division of Cardiology, Faculty of Medicine, The University of Calgary,, Calgary, AB T2N 2T9, Canada
b Division of Cardiac Surgery, Faculty of Medicine, The University of Calgary,, Calgary, AB T2N 2T9, Canada
e-mail: sverma{at}med.ucalgary.ca
To the Editor
The pharmacology of coronary artery bypass grafts has attracted much attention over the past decade. Specifically, in vitro organ bath experiments aimed at assessing vascular reactivity and endothelial function are routinely performed to examine the mechanisms of vessel contraction and uncover strategies and targets for pharmacologic intervention. We commend Rosenfeldt and associates [1] for presenting with such clarity the enormous body of data on the pharmacology of bypass conduits. The review provides clinicians and basic scientists with a logical paradigm when examining vascular reactivity of bypass conduits. Here, we take the opportunity to discuss two issues of current interest in regard to the pharmacology and endothelial function of bypass conduits: endothelin (ET) and tetrahydrobiopterin (BH4). We also introduce a new hypothesis regarding "vascular insulin resistance" and bypass conduit reactivity.
Endothelin-1 (ET-1) is the most potent vasoconstrictor known and is believed to play an important role in the pathogenesis and clinical course of a number of cardiovascular and cerebrovascular disorders. As highlighted by Rosenfeldt and coauthors [1], a growing body of evidence suggests that this endothelium-derived vasoconstrictor may play an important role in mediating perioperative graft vasospasm. In both arterial and venous conduits, ET-1 evokes potent and protracted contractile responses and potentiates the effects of other vasoconstrictors. Plasma ET-1 levels rise during cardiac surgical procedures, and increased internal mammary artery ET-1 content has been suggested to modulate perioperative graft flow in these patients [2].
These data raise the obvious question regarding the potential for ET-receptor blockade as a target for improving acute vasospasm. Although studies using ET antagonists have been conducted in arterial and venous grafts, most of these studies (in internal mammary arteries) have focused on the ability of such agents to counter the vasoconstrictive responses evoked by graded doses of ET-1 [3]. Endothelial function, assessed by acetylcholine-induced relaxation (in the presence of ET-receptor blockade), is not well documented. Mechanistically, ET-receptor blockers may improve vascular reactivity through antagonism of ET-1 action on vascular smooth muscle ET receptors, improvement in nitric oxide (NO)–mediated vasodilation (by release of tonic inhibition of ET-1 on NO production and release), or a combination of these. In this regard, we [4] recently demonstrated endothelial protective effects of ET-receptor blockers on acetylcholine-mediated (and hence NO–mediated) vasorelaxation in human internal mammary arteries and saphenous veins. Thus, it appears that in addition to blocking ET-1–induced contraction, these compounds may also serve to improve endothelial function and NO production and release.
Rosenfeldt and colleagues [1] raise another interesting point regarding targeting endothelial NO synthase in bypass conduits. Modulation of NO synthase by the addition of BH4 is an area of current interest to vascular biologists. BH4 is an absolute cofactor required for NO synthase activation and production of NO. We have recently examined the effects of this cofactor on endothelial function in bypass conduits and noted a twofold improvement in acetylcholine-mediated relaxation in saphenous veins after the addition of BH4 (unpublished observations). These data support the suggestion of Rosenfeldt and coauthors [1] that targeting endothelial NO synthase might improve NO production.
We propose a role for "vascular insulin resistance" as a potential mechanism of diminished endothelial function in bypass conduits. The vasodilative actions of insulin are well documented; these effects are NO dependent, occur at physiologic doses, and are linked to whole-body glucose disposal [5]. Importantly, in states of insulin resistance (diabetes, obesity, hypertension), the vascular effects of insulin are blunted, thus predisposing the patient for endothelial dysfunction and increased vascular tone [5]. Given the number of bypass patients with insulin-resistant conditions such as diabetes, obesity, and hypertension, it is tempting to speculate that diminished endothelial function may be due to resistance to the vasodilative actions of insulin. Diminished insulin-mediated vasodilation could directly impair NO release, indirectly tip the balance in favor of endothelium-derived vasoconstrictors such as ET-1 and thromboxane, or both of these effects. We are currently testing this hypothesis.
In summary, we congratulate Rosenfeldt and associates [1] for an excellent review of the subject and highlight the role of ET-receptor blockade and BH4 as potential targets for improving endothelial function. Because endothelial dysfunction is believed to predispose the vascular smooth muscle to increased tone, decreased vasomotion, altered reactivity, changes in structure or geometry, enhanced platelet adhesion, and eventual atherosclerosis or graft failure, elucidating the mechanisms of endothelial dysfunction in bypass conduits may serve to counter vasospasm, promote thromboresistance, and impede atherosclerosis.
References
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