Adenosine inhibitory effect on enhanced growth of aortic smooth muscle cells from streptozotocin-induced diabetic rats.
1. There is evidence to suggest that adenosine may regulate arterial smooth muscle cell (SMC) growth and proliferation, which is a key event in atherogenesis. This regulation may be mediated via adenylate cyclase. As diabetes is a known risk factor for atherosclerosis, we investigated the growth of aortic SMC from diabetic rats in primary culture and their sensitivity to adenosine and to adenylate cyclase activity. 2. Diabetes was induced with streptozotocin (STZ, 66 mg kg-1, i.p.) Aortic SMC primary cultures were prepared from STZ-diabetic and age-matched rats 5 weeks after the STZ injection. 3. SMC from STZ-diabetic rats grew faster and reached greater densities at confluence than those from non-diabetic animals. 4. Adenosine inhibited growth in both control and diabetic SMC. However, cells from STZ-diabetic rats were apparently more sensitive to adenosine. 5. Direct activation of adenylate cyclase by forskolin induced a dose-dependent growth inhibition, similar in both groups of cells. 6. Cholera toxin, an activator of stimulatory GTP-binding protein (Gs), induced a similar growth inhibitory response in non-diabetic and diabetic SMC. Pertussis toxin (PTX), an inactivator of inhibitory GTP-binding protein (Gi), did not itself affect SMC growth. However, PTX increased dose-dependently the growth inhibition induced by adenosine in SMC from non-diabetic rats but not in SMC from diabetic rats. 7. These findings suggest a functional abnormality in Gi activity in SMC from diabetic rats, that would explain the increased sensitivity to the nucleoside. This impaired inhibitory pathway may reflect changes in the growth regulation of SMC in experimental diabetic states.
Parés-Herbuté
N
N
Department of Metabolism, Lapeyronie Hospital, Montpellier, France.
Hillaire-Buys
D
D
Etienne
P
P
Gross
R
R
Loubatières-Mariani
M M
MM
Monnier
L
L
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors
D013311:Streptozocin; D000241:Adenosine