temocaprilat and olmesartan

Advanced glycation end products (AGE) and a receptor for AGE (RAGE) play a key role in diabetic vascular complications. Matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. The renin-angiotensin system (RAS) is crucial for NADPH oxidase-dependent redox signaling pathways in the vascular wall. We investigated the effects of RAS blockade on AGE-triggered signaling pathways and its downstream events, including MMP-9 and apoptosis.. We used cultured rabbit aortic smooth muscle cells (SMCs), which were stimulated with AGE in the presence or absence of temocaprilat or olmesartan.. Angiotensin converting enzyme (ACE) mRNA levels were increased 4 to 6 hours after adding AGE. AGE induced Rac1 and p47(phox) membrane translocation, reactive oxygen species (ROS) generation and NF-kappaB phosphorylation within 15 minutes, and various molecular expressions after 18 hours, which were attenuated by RAS blockade by temocaprilat or olmesartan. AGE-induced RAGE expression, as well as other molecules, including membrane type 1-MMP (MT1-MMP), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), was NADPH oxidase signaling-dependent and blunted by temocaprilat and olmesartan. The parameters of plaque instability, including MMP-9 expression and activity, and apoptosis were up-regulated by AGE, which was markedly attenuated by temocaprilat or olmesartan. Using isolated human monocyte culture, AGE-induced ROS generation and molecular expression were also attenuated by RAS blockade.. The present study shows that AGE-triggered NADPH oxidase signaling pathways, including MMP-9 and apoptosis, were attenuated by RAS blockade, which may be an attractive strategy for treating plaque instability in diabetic vascular complications.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aorta; Cells, Cultured; Diabetic Angiopathies; Glycation End Products, Advanced; Imidazoles; Myocytes, Smooth Muscle; NADPH Oxidases; Rabbits; Renin-Angiotensin System; Signal Transduction; Tetrazoles; Thiazepines

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) have potent antioxidant effects in addition to antihypertensive effects.. We investigated the ability of ACEIs and ARBs to enhance the superoxide scavenging ability of polymorphonuclear leukocytes (PMNLs) from type 2 diabetic patients (n = 32) and healthy subjects (n = 32). The scavenging ability (U/10(3) cells) of superoxide was measured by electron spin resonance. We used ascorbic acid as a positive control antioxidant and tested captopril, temocapril (an inactive form of ACEI), and temocaprilate (an active form of ACEI) as ACEIs, as well as RNH-6270 as an ARB.. Captopril, temocaprilate, and RNH-6270 showed dose-dependent enhancement in scavenging ability. The scavenging ability with captopril and temocaprilate was greater than with RNH-6270. The changes in scavenging ability induced by all of the drugs in diabetic patients were similar to the changes in healthy subjects. A high-glucose medium (400-800 mg/dL) greatly attenuated the drug-induced enhancement of scavenging ability.. We demonstrated that both ACEIs and ARBs enhance superoxide scavenging by PMNLs from type 2 diabetic patients and that a high-glucose environment markedly attenuates the ability of these drugs to augment superoxide scavenging.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Ascorbic Acid; Blood Glucose; Captopril; Diabetes Mellitus, Type 2; Female; Free Radical Scavengers; Humans; Imidazoles; In Vitro Techniques; Male; Middle Aged; Neutrophils; Superoxide Dismutase; Superoxides; Tetrazoles; Thiazepines

We examined whether the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) synergistically mediates coronary vasodilation and improves myocardial metabolic and contractile dysfunction in ischemic hearts.. Either an ACE inhibitor or ARB mediates coronary vasodilation in ischemic hearts.. In dogs with myocardial ischemia, we infused an ACE inhibitor (temocaprilat, 10 microg/kg/min) or ARB (RNH-6270, 10 microg/kg/min) into the coronary artery.. Perfusion pressure of the left anterior descending coronary artery was reduced from 104 +/- 8 to 42 +/- 2 mm Hg, so that coronary blood flow (CBF) decreased to one-third of the baseline value. Ten minutes after starting the infusion of temocaprilat, the cardiac bradykinin level increased (from 32 +/- 6 to 98 +/- 5 pg/ml). Coronary blood flow (29 +/- 2 to 44 +/- 3 ml/100 g/min) and the cardiac level of nitric oxide (NO) (7.8 +/- 1.9 to 17.5 +/- 3.2 microm) also increased, with these changes being attenuated by either N(omega)-nitro-L-arginine methyl ester or HOE140. RNH-6270 alone caused a modest increase in CBF (34 +/- 3 ml/100 g/min), with no increase in the cardiac NO or bradykinin levels. Both temocaprilat and RNH-6270 caused a further increase in both CBF (51 +/- 4 ml/100 g/min) and cardiac NO levels, without increasing the bradykinin level, and these changes were inhibited by HOE140. In the nonischemic heart, RNH-6270 augmented bradykinin-induced increases in CBF.. The combination of an ACE inhibitor and ARB mediates greater increases in CBF and more potent cardioprotective effects through bradykinin-dependent mechanisms than either drug alone.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin Receptor Antagonists; Coronary Circulation; Coronary Vessels; Dogs; Drug Synergism; Imidazoles; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide; Receptors, Angiotensin; Tetrazoles; Thiazepines; Vasodilation