General Pharmacology-the Vascular System最新文献

Bisphosphonates are used for the treatment of bone resorption, hypercalcemia, osteoporosis and Paget's disease. Etidronate, pamidronate and clodronate also inhibit the development of experimental atherosclerosis without altering serum lipid profile. Bisphosphonates inhibit the arterial calcification, lipid accumulation and fibrosis. They accumulate extensively in arterial walls and suppress macrophages in atheromatous lesions. In macrophage cultures, bisphosphonates inhibit the cellular accumulation and degradation of atherogenic LDL-cholesterol and foam cell formation. Further, they inhibit various enzymes involved in cell signal transduction and cholesterol biosynthesis. Recently, etidronate has been shown to inhibit the thickening of carotid arterial wall even in man.

The mechanism of hypocapnic constriction of the cerebral vasculature under conditions of altered acid–base balance has not been investigated. As K_ATP channels and NO have been implicated in hypocapnic constriction, this study investigated their roles in the constriction due to lowered pCO₂ in hypercapnic rabbits with acute metabolic alkalosis. Metabolic alkalosis was induced acutely following ketamine/xylazine injection. Lowering blood pCO₂ from initial baseline hypercapnic levels to near normocapnic and hypocapnic levels constricted basilar artery by 10.2±0.8% (4) and 16.2±0.6% (44), respectively (means±S.E., n), as determined in an in situ cranial window preparation. The constrictions were maintained for 4–5 h and return of pCO₂ to hypercapnic levels relaxed the constriction. Changing the suffusate pH to either the pH of the cerebral spinal fluid observed during initial baseline hypercapnia or following lowered pCO₂ did not alter the magnitude of constriction due to lowered pCO₂. Neither 0.3 mM N^G-monomethyl-l-arginine monoacetate, an NO synthase inhibitor, nor 10 μM glibenclamide, a K_ATP channel blocker, altered the magnitude of hypocapnic constriction. These results demonstrated that under conditions of acute metabolic alkalosis and accompanying compensatory hypercapnia, subsequent pCO₂ reduction induces prolonged constriction of the basilar artery that is independent of (1) cerebral spinal fluid pH over a physiologic range, and (2) NO and K_ATP channels.

This study investigated the influence of superoxide anion on the norepinephrine (NE)-induced contractile response in spontaneously diabetic mice. In aortic rings with intact endothelium, NE elicited only a slight increase in tension in nondiabetic mice (db/+M), but a much greater dose-dependent contraction in spontaneously diabetic mice (db/db mice). The NE-induced contractile response was significantly reduced by pretreatment with SOD (180 U/ml) in diabetic mice, but not in control mice. The NE-induced contraction was significantly enhanced by pretreatment with diethyldithiocarbamic acid (DETCA, 10⁻³ M), a Cu/Zn SOD inhibitor, in control mice, but not in diabetic mice. The dose–response curve for the acetylcholine-induced relaxation was slightly, but significantly attenuated in diabetic mice. When aortic rings from control mice were incubated with a mixture of hypoxanthine (10⁻⁵ M), xanthine oxidase (0.1 U/ml) and catalase (1000 U/ml) in control mice, they gradually contracted. This contraction was abolished by pretreatment with SOD (180 U/ml) or indomethacin (10⁻⁵ M) or by removal of the endothelium. The enhanced NE-induced dose-dependent contraction seen in diabetic mice was markedly attenuated by indomethacin. These results suggest that in db/db diabetic mice, superoxide anion, perhaps via vasoconstrictor prostanoids, may enhance the contraction induced by NE.

This study was designed to determine whether the relaxant effect of apigenin was endothelium dependent and to examine the possible antiproliferative effect of apigenin. Apigenin relaxed the phenylephrine-precontracted endothelium-intact aortic rings with IC₅₀ value of 3.7±0.5 μM and removal of a functional endothelium significantly attenuated this relaxation (IC₅₀=8.2±0.9 μM). However, apigenin did not affect the 0.1 μM phorbol 12,13-dibutyrate-induced contraction (IC₅₀=34.6±1.2 μM) within the concentration range that relaxed the phenylephrine-contracted arteries, suggesting that apigenin did not influence protein kinase C-mediated contractile mechanisms in rat aorta. Pretreatment of apigenin significantly potentiated the relaxant effect of acetylcholine on phenylephrine-induced contraction. Pretreatment with N^G-nitro-l-arginine methyl ester (l-NAME) or methylene blue reduced the relaxant effect of apigenin. Apigenin (10 μM) increased the guanosine 3′,5′-cyclic monophosphate (cGMP) content of endothelium-intact tissues. Pretreatment with l-NAME (100 μM) or removal of endothelium significantly suppressed the effect of apigenin on cGMP production. In addition, apigenin significantly inhibited [³H]thymidine incorporation into DNA of primary cultured rat aortic smooth muscle cell in a dose-dependent manner. These findings suggest that besides influx and release of Ca²⁺, nitric oxide (NO) and cGMP may account for the apigenin-induced endothelium-dependent relaxation and hypotensive activity. Both vasorelaxant and antiproliferative activities may contribute to a benefit of apigenin in the vascular system.

The plasmin-mediated lysis of fibrin present in a wound, or in chronic inflammatory disease, results in the release of fibrin degradation products. One of the two major products is fibrin fragment E, which has been shown to stimulate cell proliferation in many cell types including endothelium, fibroblasts, and smooth muscle cells, and to be angiogenic in the chick chorioallantoic membrane (CAM) system. The activity of fibrin fragment E is dependent on N-terminus thrombin action. Antibodies against fibrin E, which block the cell proliferative activity, were used to locate the active site. Phage epitope display libraries were used to identify the sequence of a peptide, which resembles a region of the N terminus structure. The equivalent synthetic peptide (WTM110) has optimal stimulatory properties at equimolar concentrations to the parent molecule. Such peptide information has therapeutic potential for both stimulating and suppressing angiogenesis and cell proliferation.