Vascular Smooth Muscle Cells (VSMC) Proliferation of Streptozotocin-Diabetic Animals Induced by Diadenosine Polyphosphates

E. J. Verspohl; J. Hagemann; M. Lempka

doi:10.1055/s-2004-817823

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2004; 112(3): 142-147
DOI: 10.1055/s-2004-817823

Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

Vascular Smooth Muscle Cells (VSMC) Proliferation of Streptozotocin-Diabetic Animals Induced by Diadenosine Polyphosphates

E. J. Verspohl¹ , J. Hagemann¹ , M. Lempka¹

¹Institute of Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, University of Münster, Münster, Germany

Abstract

Specific binding sites for diadenosine polyphosphates (Ap₄A, Ap₅A, Ap₆A) exist in VSMC (cultured vascular smooth muscle cells). These compounds may regulate VSMC growth and proliferation which is a key event in atherogenesis. Since diabetes is a known risk factor for atherosclerosis, the proliferation of VSMC from normoglycemic (control) and hyperglycemic (diabetic) rats were compared and the possibly involved receptors for diadenosine polyphosphates inducing this effect were investigated. Diabetes was induced by streptozotocin (66 mg/kg i.p.) and VSMC were prepared from rat aorta (primary culture). (³H)thymidine incorporation was a measure of cell proliferation. For all diadenosine polyphosphates tested a stimulatory effect was observed as a bell-shaped concentration-response curve and a maximum effect at 10 µM (physiological concentration). Ap₆A has the most prominent effect (247.8 ± 33.2 % increase over basal). In VSMC of diabetic rats the effects were even more prominent (Ap₅A: 430.1 ± 62.7 %). ATP (a degradation product of Ap₆A) is able to increase the maximum effect of 10 µM Ap₆A. UTP (P2Y₂ agonist) exhibits a weaker proliferation. 1 µM suramin (P2 receptor antagonist) shifts the concentration response curve of ATP and of Ap₆A to the right. In contrast, 10 µM PPADS (P2 X receptor antagonist) has no effect. There is no difference between VSMC of normal and diabetic rats in this respect. ADP, AMP, and adenosine exhibit a dual proliferative effect. The effect of either of these 3 compounds is much higher in VSMC of diabetic rats than of controls. 2MeSATP (P2Y₁ agonist) and α,β-Methylen-ATP (P2X agonist) were not effective in VSMC of both normoglycemic and diabetic rats. In conclusion: The proliferative effect of diadenosine polyphosphates and some degradation products is more pronounced in VSMC of diabetic than of normal rats. Ap₆A acts maximally by itself and not by its degradation product ATP. Adenosine receptors or an unknown P2Y_ApxA receptor may be involved in proliferative effects, but not P2X and P2Y₁ receptors irrespective of a diabetic situation.

Key words

Diadenosine polyphosphates - VSMC - proliferation - streptozotocin-diabetic animals

Full Text

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Dr. E. J. Verspohl

Department of Pharmacology · Institute of Pharmaceutical and Medicinal Chemistry

Hittorfstraße 58 - 62

48149 Münster

Germany

Phone: + 492518333339

Fax: + 49 25 18 33 21 44

Email: verspoh@uni-muenster.de