Advertisement

Abnormalities of endothelium-dependent responses in mesenteric arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats are improved by chronic treatment with thromboxane A2 synthase inhibitor

      Abstract

      Thromboxane A2 (TXA2) is thought to contribute to the development of diabetic complications. We tested the hypothesis that the impaired endothelial function seen in Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a type 2 diabetic model) might be improved by chronic treatment with ozagrel, a TXA2 synthase inhibitor. In mesenteric arteries from OLETF rats (40–46 weeks old) [vs. those from age-matched Long-Evans Tokushima Otsuka (LETO) rats]: (1) ACh-induced endothelium-dependent relaxation, NO-mediated relaxation, and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation were all reduced; (2) ACh-induced cyclooxygenase-dependent contraction was enhanced; (3) endothelium-derived contracting factor (EDCF)-mediated contraction was enhanced; (4) ACh-stimulated nitrite production was reduced but the nitrate/nitrite ratio was increased; and (5) ACh-stimulated production of TXA2 was increased. Chronic treatment with ozagrel (100 mg/kg/day for 4 weeks, starting when they were 36–42 weeks of age) partly corrected the above abnormalities. These results suggest that ozagrel has normalizing effects on endothelial functions in OLETF mesenteric arteries, at least partly by increasing endothelium-derived relaxing factors (i.e., NO and EDHF) signaling and reducing EDCF signaling.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Rask-Madsen C.
        • King G.L.
        Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes.
        Nat Clin Pract Endocrinol Metab. 2007; 3: 46-56
        • Matsumoto T.
        • Kobayashi T.
        • Wachi H.
        • Seyama Y.
        • Kamata K.
        Vascular NAD(P)H oxidase mediates endothelial dysfunction in basilar arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats.
        Atherosclerosis. 2007; 192: 15-24
        • Cohen R.A.
        Role of nitric oxide in diabetic complications.
        Am J Ther. 2005; 12: 499-502
        • Feletou M.
        • Vanhoutte P.M.
        Endothelial dysfunction: a multifaceted disorder (The Wiggers Award Lecture).
        Am J Physiol Heart Circ Physiol. 2006; 291: H985-H1002
        • Pieper G.M.
        Review of alterations in endothelial nitric oxide production in diabetes: protective role of arginine on endothelial dysfunction.
        Hypertension. 1998; 31: 1047-1060
        • Vanhoutte P.M.
        • Feletou M.
        • Taddei S.
        Endothelium-dependent contractions in hypertension.
        Br J Pharmacol. 2005; 144: 449-458
        • Sellers M.M.
        • Stallone J.N.
        Sympathy for the devil: the role of thromboxane in the regulation of vascular tone and blood pressure.
        Am J Physiol Heart Circ Physiol. 2008; 294: H1978-H1986
        • Galipeau D.
        • Arikawa E.
        • Sekirov I.
        • McNeill J.H.
        Chronic thromboxane synthase inhibition prevents fructose-induced hypertension.
        Hypertension. 2001; 38: 872-876
        • Zuccollo A.
        • Shi C.
        • Mastroianni R.
        • et al.
        The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus.
        Circulation. 2005; 112: 3001-3008
        • Dogne J.M.
        • Hanson J.
        • Pratico D.
        Thromboxane, prostacyclin and isoprostanes: therapeutic targets in atherogenesis.
        Trends Pharmacol Sci. 2005; 26: 639-644
        • Kawano K.
        • Hirashima T.
        • Mori S.
        • Saitoh Y.
        • Kurosumi M.
        • Natori T.
        Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain.
        Diabetes. 1992; 41: 1422-1428
        • Matsumoto T.
        • Kakami M.
        • Noguchi E.
        • Kobayashi T.
        • Kamata K.
        Imbalance between endothelium-derived relaxing and contracting factors in mesenteric arteries from aged OLETF rats, a model of Type 2 diabetes.
        Am J Physiol Heart Circ Physiol. 2007; 293: H1480-H1490
        • Matsumoto T.
        • Kobayashi T.
        • Kamata K.
        Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats.
        Am J Physiol Heart Circ Physiol. 2003; 285: H283-H291
        • Matsumoto T.
        • Noguchi E.
        • Ishida K.
        • Kobayashi T.
        • Yamada N.
        • Kamata K.
        Metformin normalizes endothelial function by suppressing vasoconstrictor prostanoids in mesenteric arteries from OLETF rats, a model of Type 2 diabetes.
        Am J Physiol Heart Circ Physiol. 2008; 295: H1165-H1176
        • Kobayashi T.
        • Kamata K.
        Effect of chronic insulin treatment on NO production and endothelium-dependent relaxation in aortae from established STZ-induced diabetic rats.
        Atherosclerosis. 2001; 155: 313-321
        • Okumura M.
        • Imanishi M.
        • Okamura M.
        • et al.
        Role of thromboxane A2 from glomerular thrombi in nephropathy with type 2 diabetic rats.
        Life Sci. 2003; 72: 2695-2705
        • Matsuo Y.
        • Kihara T.
        • Ikeda M.
        • Ninomiya M.
        • Onodera H.
        • Kogure K.
        Role of platelet-activating factor and thromboxane A2 in radical production during ischemia and reperfusion of the rat brain.
        Brain Res. 1996; 19: 296-302
        • Matsumoto T.
        • Kobayashi T.
        • Kamata K.
        Mechanisms underlying the impaired EDHF-type relaxation response in mesenteric arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats.
        Eur J Pharmacol. 2006; 538: 132-140
        • Ashton A.W.
        • Yokota R.
        • John G.
        • et al.
        Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A(2).
        J Biol Chem. 1999; 274: 35562-35570
        • Crane G.J.
        • Garland C.J.
        Thromboxane receptor stimulation associated with loss of SKCa activity and reduced EDHF responses in the rat isolated mesenteric artery.
        Br J Pharmacol. 2004; 142: 43-50
        • Michel F.S.
        • Man G.S.
        • Man R.Y.
        • Vanhoutte P.M.
        Hypertension and the absence of EDHF-mediated responses favor endothelium-dependent contractions in renal arteries of the rat.
        Br J Pharmacol. 2008; 155: 217-226
        • Sowers J.R.
        Insulin resistance and hypertension.
        Am J Physiol Heart Circ Physiol. 2004; 286: H1597-H1602
      1. Luksha L, Agewall S, Kublickiene K. Endothelium-derived hyperpolarizing factor in vascular physiology and cardiovascular disease. Atherosclerosis; in press.