u-0126 and candesartan

Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal-regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with N(G)-nitro-l-arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal-regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal-regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal-regulated kinase 1/2 activation by angiotensin II.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Benzimidazoles; Biphenyl Compounds; Blood Flow Velocity; Blotting, Western; Butadienes; Cyclic N-Oxides; Extracellular Signal-Regulated MAP Kinases; Hydralazine; Male; Mesenteric Arteries; Mice; Mice, Knockout; Microscopy, Confocal; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Nitriles; Perindopril; Rats; Rats, Wistar; Reactive Oxygen Species; Spin Labels; Tetrazoles; Vascular Resistance; Vasodilator Agents

The fat cell hormone leptin is known to be implicated in the pathogenesis of hypertension and cardiovascular disease. Here we tested whether angiotensin (Ang) II is involved in the control of leptin release from human adipocytes.. Leptin secretion was assessed from in vitro differentiated human adipocytes by radioimmunoassay. Western blot experiments were used to test for the signaling pathway activated by Ang II.. Ang II increased leptin secretion into the culture medium in a dose- and time-dependent fashion. At 10(-5) M Ang II, the leptin concentration in the medium was increased at 24 hours by 500+/-222% compared with control cultures (p<0.05). This effect was also seen at the mRNA level. Similar effects were seen after exposure of fat cells to Ang III and Ang IV. Preincubation of fat cells with candesartan, an angiotensin II type 1 receptor antagonist, or the extracellular-signal-regulated kinases 1 and 2 inhibitor UO126 completely abolished the effect of Ang II on leptin production. The peroxisome proliferator-activated receptor-gamma agonist troglitazone modestly attenuated leptin release.. In conclusion, Ang II and its metabolites stimulated leptin production in human adipocytes. This effect is mediated through an extracellular-signal-regulated kinases 1 and 2-dependent pathway and includes the angiotensin II type 1 receptor subtype.

Topics: Adipocytes; Adult; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Blotting, Western; Butadienes; Cells, Cultured; Chromans; Drug Interactions; Extracellular Signal-Regulated MAP Kinases; Female; Fibrinolytic Agents; Humans; Leptin; MAP Kinase Signaling System; Nitriles; Protein Kinase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazoles; Thiazolidinediones; Troglitazone