A THERAPEUTIC DOSAGE OF AMLODIPINE PREVENTS VASCULAR HYPOREACTIVITY INDUCED IN RATS BY LIPOPOLYSACCHARIDE

The aim of this work was to investigate whether treatment with the 1,4 -dihydropyridine Ca2+ antagonist amlodipine could affect the vascular hyporesponsiveness induced by cytokines. Endotoxemia was induced by Sa lmonella typhosa lipopolysaccharide (LPS) injection (4 mg kg(-1), i.p. ). In endothelium-denuded rings of thoracic aorta from untreated rats, contractile response to noradrenaline was decreased after LPS injecti on, this effect was partially overcome by the addition of N-omega-nitr o-L-arginine (L-NNA, 100 mu M) into the bathing solution. In amlodipin e-pretreated rats (15 mg kg(-1) day(-1), orally, for one week), the ef fect of LPS was lower than in untreated ones and it was completely rev ersed by L-NNA. The relaxation of the noradrenaline-induced tone evoke d by L-arginine (10 mu M) in aortae of LPS-injected rats was reduced i n amlodipine-pretreated rats. Amlodipine-treatment reduced both the LP S-induced Ca2+-indcpendent NOS activity in homogenates of heart and th e expression of iNOS mRNA in aortae of LPS-injected rats. However, the vascular hyporeactivity induced by exposing aortae to interleukin-1 b eta in vitro was not influenced by amlodipine (10 nM). Amlodipine (10 mu M) also did not affect the production of nitrite in primary aortic smooth muscle cell culture challenged by LPS although nitrite producti on in macrophage culture challenged with LPS was significantly inhibit ed. The results show that rat pretreatment with amlodipine prevented t he decrease of vascular responsiveness induced by LPS, an effect that may be at least paltry related to reduction of in vivo NOS induction. The weak effect of amlodipine on the in vitro NOS induction indicates that the protective action in endotoxemia did not result from a short term interaction with L-type Ca2+ channels in vascular smooth muscle. Alternative mechanisms are discussed.