Dysregulation of extracellular adenosine levels by vascular smooth muscle cells from spontaneously hypertensive rats.
-The objective of this investigation was to determine whether the regulation of extracellular adenosine levels by smooth muscle cells (SMCs) from conduit arteries (aorta) and resistance microvessels (renal arterioles) is different in spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto (WKY) rats. Basal extracellular adenosine levels were decreased in cultured aortic and arteriolar SHR SMCs, and the increase in extracellular adenosine levels induced by stimulation of the cAMP-adenosine pathway was less in aortic and arteriolar SHR SMCs. Extracellular adenosine levels were lower in SHR SMCs, however, even when the cAMP-adenosine pathway was inhibited with 3-isobutyl-1-methylxanthine. Inhibition of adenosine kinase with iodotubercidin and inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl) adenine increased extracellular adenosine; however, only inhibition of adenosine deaminase equalized extracellular adenosine levels in SHR versus WKY SMCs. Membrane-disrupted SHR SMCs metabolized exogenous adenosine faster than WKY SMCs did, and this difference was abolished by inhibition of adenosine deaminase but not adenosine kinase. SHR SMCs demonstrated a greater proliferative response than WKY SMCs. This enhanced proliferative response was not blocked by adenosine per se or inhibition of adenosine kinase but was blocked by inhibition of adenosine deaminase and by 2-chloroadenosine (adenosine deaminase-resistant adenosine analogue). We conclude that dysregulation of extracellular adenosine levels exists in SHR SMCs, that this dysregulation is not due to a defect in the cAMP-adenosine pathway but rather to enhanced activity of adenosine deaminase, and that the dysregulation of extracellular adenosine mediates the enhanced proliferative response of SHR SMCs.
Dubey
R
R
Departmentof Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich, Zurich,Switzerland. rag@fhk.usz.ch
Mi
Z
Z
Gillespie
D G
DG
Jackson
E K
EK
D000241:Adenosine / Q000032:analysis*; D000818:Animals; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D014471:Umbilical Veins / Q000737:chemistry*
D000241:Adenosine