Adenosine receptors, cyclic AMP accumulation, and DNA‐synthesis in aortic smooth muscle cell cultures of adult and neonatal rats

Abstract

The effects of two adenosine analogs on cyclic AMP (cAMP) accumulation and DNA synthesis were studied in cultured smooth muscle cells (SMCs) isolated from adult and neonatal rat arteries. N-ethylcarboxamido adenosine (NECA) dose-dependently increased intracellular cAMP levels and appeared to be more potent in adult than in neonatal SMCs. R-phenylisopropyl adenosine (R-PIA), in nanomolar concentrations, counteracted the increase in cAMP evoked by 10 microM forskolin in adult but not in neonatal SMCs, indicating that the enhanced "A2" response seen in adult SMCs was not due to a lack of "A1" receptors in these cultures. Binding experiments performed using the adenosine antagonist XAC did not reveal any differences in the number or affinity of the adenosine receptors between neonatal and adult SMCs. This indicates effects presumably on the G-protein level. A high capacity to spontaneously synthesize DNA and a weak response to platelet-derived growth factor (PDGF) were seen in the neonatal SMCs. Furthermore, NECA had no effect on PDGF-induced DNA synthesis in these cells. In contrast, adult SMCs presented a low rate of spontaneous DNA synthesis and a marked proliferative response to PDGF, which was inhibited by NECA. This inhibition paralleled the increase in cAMP elicited by NECA. Our findings suggest that neonatal and adult SMCs differ both in their response to growth factors and growth inhibitors.

Ending Restenosis: Inhibition of Vascular Smooth Muscle Cell Proliferation by cAMP

“…In searching for physiological cAMP elevating agents, early studies identified the metabolite adenosine as a potent inhibitor of VSMC proliferation [53,54,55,56]. Treatment of VSMC in vitro with adenosine or stable adenosine analogues potently inhibited serum mitogen-induced proliferation.…”

A 2B Receptors Mediate Antimitogenesis in Vascular Smooth Muscle Cells

“…1,2 Although the standard view is that A 1 and A 2A receptors are the most important with regard to adenosine-mediated cardioprotection, indirect evidence suggests that adenosine inhibits vascular SMC growth via activation of A 2 and more specifically A 2B receptors. [2][3][4][5][6] However, the inference that A 2B receptors mediate the growth-inhibiting effects of adenosine is weak because to date researchers do not have available agonists or antagonists selective for A 2B receptors. Moreover, recent data suggest that in contrast to SMCs, A 2 receptors induce growth in vascular endothelial cells 7,8 and stimulate mitogen-activated protein (MAP) kinase activity in several cell types.…”