ucn-1028-c and icatibant

In the collecting duct (CD), the interactions of renin angiotensin system (RAS) and kallikrein-kinin system (KKS) modulate Na

Topics: Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Cell Line; Isoquinolines; Kidney Cortex; Mice; Naphthalenes; NG-Nitroarginine Methyl Ester; Nitric Oxide; Protein Kinase C; Protein Kinase Inhibitors; Receptor, Bradykinin B2; Renin; Sulfonamides

We examined the involvement of the oxidative stress in high glucose-induced suppression of human aortic endothelial cell proliferation. Chronic glucose treatment for 72 h concentration-dependently (5.6-22.2 mol/l) inhibited human coronary endothelial cell proliferation. Temocaprilat, an angiotensin-converting enzyme inhibitor, at 10 nmol/l to 1 micromol/l inhibited high glucose (22.2 mmol/l)-mediated suppression of human aortic endothelial cell proliferation. Temocaprilat at 1 micromol/l inhibited high glucose-induced membrane-bound protein kinase C activity in human aortic endothelial cells. The protein kinase C inhibitors calphostin C 100 nmol/l or chelerythrine 1 micromol/l inhibited high glucose-mediated suppression of human aortic endothelial cell proliferation. Chronic high glucose treatment for 72 h increased intracellular oxidative stress, directly measured by flow cytometry using carboxydichlorofluorescein diacetate bis-acetoxymethyl ester, and this increase was significantly suppressed by temocaprilat 10 nmol/l to 1 micromol/l. Bradykinin B2 receptor antagonist icatibant 100 nmol/l significantly reduced the action of temocaprilat; whereas bradykinin B1 receptor antagonist des-Arg9-Leu8-bradykinin 100 nmol/l had no effect. These findings suggest that high glucose inhibits human aortic endothelial cell proliferation and that the angiotensin-converting enzyme inhibitor temocaprilat inhibits high glucose-mediated suppression of human aortic endothelial cell proliferation, possibly through suppression of protein kinase C, bradykinin B2 receptors and oxidative stress.

Topics: Alkaloids; Angiotensin-Converting Enzyme Inhibitors; Aorta; Benzophenanthridines; Bradykinin; Bradykinin B2 Receptor Antagonists; Cell Division; Cell Membrane; Cells, Cultured; Coronary Vessels; Dose-Response Relationship, Drug; Endothelial Cells; Glucose; Humans; Naphthalenes; Oxidative Stress; Phenanthridines; Protein Kinase C; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Thiazepines; Time Factors

Bronchial vascular remodeling is an important feature of the pathology of chronic asthma, but the responsible mechanisms and main sources of angiogenic factors are unclear. Here we report that human airway smooth muscle cells express vascular endothelial growth factor (VEGF)121, 165, 189, 206 splice variants and secrete VEGF protein constitutively. VEGF protein secretion was increased by the proinflammatory asthma mediator bradykinin through post-transcriptional mechanisms. Bradykinin-induced VEGF secretion was dependent on the B2 bradykinin receptor, activation of protein kinase C, and generation of endogenous prostanoids. This is the first report that bradykinin can increase VEGF secretion in any biological system and the first to show that airway smooth muscle cells produce VEGF. Our results suggest a novel role for human airway smooth muscle in contributing to bronchial mucosal angiogenesis in chronic asthma by secretion of VEGF and suggest a wider role for mesenchymal cell products in mediating angiogenesis in inflammatory and allergic diseases.

Topics: Adult; Arachidonic Acid; Bradykinin; Bradykinin Receptor Antagonists; Cell Survival; Cells, Cultured; Cyclic AMP; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Female; Gene Expression; Humans; Indomethacin; Lymphokines; Male; Middle Aged; Muscle, Smooth, Vascular; Naphthalenes; Nitrobenzenes; Prostaglandins; Protein Isoforms; Protein Kinase C; Receptor, Bradykinin B2; Receptors, Bradykinin; Reverse Transcriptase Polymerase Chain Reaction; RNA; Sulfonamides; Time Factors; Trachea; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To investigate the role of protein kinase C in the attenuation of bradykinin-induced thermal hyperalgesia in diabetic mice, we examined the effects of a protein kinase C activator or inhibitor on the i.t. bradykinin-induced hyperalgesia in diabetic and non-diabetic mice. Intrathecal injection of bradykinin caused a transient antinociceptive effect, which diminished within 30 min, and then produced a thermal hyperalgesia, which lasted about 120 min, in non-diabetic mice. Although the duration of the antinociceptive phase was longer in diabetic mice than in non-diabetic mice, the hyperalgesic response was not observed in diabetic mice. The bradykinin-induced hyperalgesia was dose-dependently and significantly enhanced by pretreatment with calphostin C (0.3 to 3 pmol, i.t.), a specific protein kinase C inhibitor, in diabetic mice. However, calphostin C (3 pmol, i.t.) had no significant effect on bradykinin-induced hyperalgesia in non-diabetic mice. On the other hand, pretreatment with phorbol-12, 13-dibutyrate (12.5 to 50 pmol, i.t.), a protein kinase C activator, significantly and dose-dependently reduced bradykinin-induced hyperalgesia in non-diabetic mice. However, phorbol-12, 13-dibutyrate (50 pmol, i.t. ) had no significant effect on bradykinin-induced hyperalgesia in diabetic mice. These results suggest that the change in bradykinin-induced thermal hyperalgesia in diabetic mice may be due, at least in part, to the modification of nociceptive transmission in the spinal cord by the activation of protein kinase C.

Topics: Animals; Bradykinin; Diabetes Mellitus, Experimental; Enzyme Activators; Enzyme Inhibitors; Hot Temperature; Hyperalgesia; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Naphthalenes; Phorbol 12,13-Dibutyrate; Protein Kinase C; Reaction Time

1. Pretreatment with ramiprilat, an angiotensin-converting enzyme (ACE) inhibitor, induced cardioprotection and its possible mechanism of action was investigated in guinea-pig Langendorff perfused heart. 2. Superoxide anion (*O2-), produced by hypoxanthine and xanthine oxidase, and the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical were used for triggering free radical injury in cardiac tissue. 3. 1,1-Diphenyl-2-picryl-hydrazyl and *O2- significantly reduced left ventricular developed pressure (LVDP), +/-dP/dt(max), heart rate and coronary flow. Left ventricular end-diastolic pressure (LVEDP) was elevated and lactate dehydrogenase (LDH) leakage and the formation of thiobarbituric acid-reactive substances (TBARS) formation were significantly increased. 4. Pretreatment with ramiprilat induced cardioprotection against DPPH and *O2- free radical injury. Cardiac functions (LVDP, LVEDP and +/-dP/dt(max)) were significantly improved. Both LDH and TBARS were reduced. 5. HOE 140 (a selective bradykinin B2 receptor antagonist), calphostin C (a protein kinase C (PKC) inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) all abolished the cardiac protective effect of ramiprilat. However, N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, had no effect. 6. In conclusion, ramiprilat pretreatment induces cardioprotection against either DPPH or *O2- free radical injury. The protective effect depends on activation of B2 receptors and PKC. Prostaglandin synthesis is also involved.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bepridil; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Cardiovascular Agents; Cyclooxygenase Inhibitors; Diastole; Free Radicals; Guinea Pigs; Heart; Heart Rate; In Vitro Techniques; Indomethacin; L-Lactate Dehydrogenase; Male; Myocardium; Naphthalenes; NG-Nitroarginine Methyl Ester; Picrates; Prostaglandins; Protein Kinase C; Ramipril; Receptors, Bradykinin; Thiobarbituric Acid Reactive Substances; Ventricular Function, Left