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Role of endothelin-1 in cardiac and vascular dysfunction in streptozotocin-diabetic rats : effects of chronic endothelin receptor blockade Arikawa, Emi

Abstract

The present thesis examined the role of endothelin-1 (ET-1), a potent 21-aminoacid vasoconstrictor-mitogen, in diabetic cardiovascular complications. Our previous data showed that diabetic rats exhibited impaired isolated working heart performance, which was ameliorated by chronic treatment with bosentan, a mixed ET[sub A]/ ET[sub B] receptor blocker. Accordingly, an activated endothelin system may be involved in diabetic cardiomyopathy. Using streptozotocin (STZ)-induced diabetic rats, a rodent model of Type 1 diabetes, we examined the effects of long-term treatment with ET receptor antagonists on both the cardiac and vascular systems. The primary observations from our studies are that STZ-induced diabetes resulted in cardiac and vascular dysfunction in association with an up-regulation of the expression of the local ET system (i.e. ET-1 and its receptors). Chronic ET receptor blockade with bosentan improved functional cardiac performance and corrected vascular hyper-reactivity to vasoconstrictors in STZ-diabetic rats. These data suggest that exaggerated ET-1 production and/or action may play a role in the development of cardiovascular dysfunction in diabetes. In the diabetic heart, the cardioprotective effects of bosentan were shown to require the blockade of ET[sub B] receptors, since selective ET[sub A] receptor antagonism with ABT-627 did not provide significant improvement in diabetic rat heart function. Moreover, bosentan may improve diabetic cardiac function by blocking the increase in ET-1-evoked coronary vasoconstriction in diabetes. In the vasculature, while chronic bosentan treatment equally ameliorated the hyper-responsiveness to vasoconstrictors in superior mesenteric arteries (SMA) and renal arteries (RA) from diabetic rats, the underlying mechanisms for this effect appear to be tissue-specific. In SMA, the enhanced vasoconstrictor responses in diabetes seem to be related to an increase in ET[sub A] receptor-activated thromboxane (Tx) synthesis/release in diabetic vascular endothelium, and bosentan may act by blocking the activation of the ET[sub A] receptor and/or normalizing the increased expression of the receptor. In RA, however, the beneficial effects of bosentan treatment on the diabetic vasoconstrictor responses are unlikely to be due to an effect on Tx synthesis, but rather, may be exerted through normalization of the vascular responses to TxA2 . Results presented in this thesis, therefore, provide evidence for a role of ET-1 in cardiovascular dysfunction in diabetes.

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