REGULATION OF KININ-INDUCED CONTRACTION AND DNA-SYNTHESIS BY INFLAMMATORY CYTOKINES IN THE SMOOTH-MUSCLE OF THE RABBIT AORTA

1 In rabbit aortic rings, the contractile response to kinins is mediat ed by the B-1 receptors for kinins; the response is upregulated from a n initial null level in a time- and protein synthesis-dependent manner . Incubation (3 h) with human recombinant interleukin-1 beta (IL-1 bet a) selectively amplified the contractile response to the B-1 receptor agonist Sar-[D-Phe(8)]des-Arg(9)-BK, while it did not affect the contr actile effect of other agents (angiotensin II, endothelin-1, phenyleph rine). 2 Oncostatin M (OSM), but not macrophage migration- inhibitory factor (MIF), increased the contractile response to the B-1 receptor a gonist, des-Arg(9)-bradykinin (des-Arg(9)-BK). 3 Cultured smooth muscl e cells-derived from the rabbit aorta exhibit a significant des-Arg(9) -BK-induced increase in [H-3] thymidine incorporation if pretreated wi th a cyclo;oxygenase inhibitor (diclofenac) and concomitantly treated with the cytokines IL-1 or OSM. Angiotensin II, endothelin-1 or phenyl ephrine, alone or in the presence of IL-1 beta, exerted little effect on DNA synthesis in these cells. 4 The pharmacological characterizatio n of the mitogenic response to kinins using a set of agonist and antag onist analogues is consistent with mediation by B-1 receptors. Des-Arg (9)-BK-induced DNA synthesis is suppressed by prostaglandin E(2) by a prostacyclin mimetic (iloprost), by the Ser/Thr protein kinase inhibit or, H-7, and by a tyrosine kinase inhibitor (i.e. an erbstatin analogu e).5 B-1 receptor-mediated responses and their capacity to be regulate d by cytokines, are retained in rabbit aortic smooth:muscle cells. Suc h responses could be relevant to tissue repair mechanisms and hypertro phic medial responses to injury in arteries.