ABSTRACT
To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Arterial Occlusive Diseases/etiology , Imidazoles/pharmacology , Imidazolidines , Nitric Oxide/physiology , Animals , Arterial Occlusive Diseases/immunology , Arterial Occlusive Diseases/pathology , Bradykinin Receptor Antagonists , Cell Division , Chemokine CCL2/genetics , Chemokine CCL2/immunology , Chemokine CCL2/metabolism , Constriction , Enzyme Inhibitors/pharmacology , Immunohistochemistry , Inflammation/etiology , Inflammation/immunology , Male , Mice , Mice, Knockout , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Receptor, Angiotensin, Type 1 , Receptor, Bradykinin B2 , Receptors, Angiotensin/genetics , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: In vitro studies suggest that angiotensin II type 1 and type 2 (AT1 and AT2) receptors exert opposite effects in terms of vasoconstriction, natriuresis, and cell growth, but the role of these receptors in cardiovascular remodeling in vivo is still an enigma. In this study, we tested the hypothesis that AT2 exerts an antiproliferative effect by inducing apoptosis, thereby antagonizing AT1a in vascular remodeling. METHODS AND RESULTS: Vascular injury was induced by polyethylene cuff placement around the left femoral artery of AT1a-null (AT1aKO), AT2-null (AT2KO), and wild-type mice. Neointimal formation as well as DNA synthesis in vascular smooth muscle cells (VSMC) after vascular injury was exaggerated in AT2KO mice, but they were both suppressed in AT1aKO mice compared with those in wild-type mice. In contrast, the number of apoptotic cells in the injured artery in VSMC was significantly increased in AT1aKO mice but decreased in AT2KO mice. Reverse transcriptase-polymerase chain reaction analysis revealed that the expression of bax mRNA was attenuated in AT2KO mice. On the other hand, the expression of bcl-2 and bcl-x(L) mRNA was enhanced in AT2KO mice but attenuated in AT1aKO mice. Immunohistochemical staining with antibody to the bcl-2 protein family supported these results. CONCLUSIONS: Our results suggest that AT2 exerts antiproliferative effects and proapoptotic changes in VSMC by counteracting AT1a in the process of neointimal formation after vascular injury.
Subject(s)
Angiotensin II/metabolism , Apoptosis/physiology , Arteriosclerosis/metabolism , Receptors, Angiotensin/metabolism , Tunica Intima/metabolism , Animals , Arteriosclerosis/pathology , Cell Count , Cell Division , Constriction, Pathologic , DNA/biosynthesis , Femoral Artery/injuries , Femoral Artery/metabolism , Femoral Artery/pathology , Immunohistochemistry , In Situ Nick-End Labeling , Male , Mice , Mice, Knockout , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-bcl-2/genetics , RNA, Messenger/biosynthesis , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , Receptors, Angiotensin/deficiency , Receptors, Angiotensin/genetics , Tunica Intima/pathology , Vascular Patency , bcl-2-Associated X Protein , bcl-X ProteinABSTRACT
The purpose of this study was to determine whether or not salivary gland dysfunction occurs within the first three months after brachytherapy in patients with head and neck carcinoma. Of the 20 patients with head and neck squamous cell carcinoma included in this study, 11 were treated with brachytherapy and the remaining 9 patients received external irradiation. All the patients underwent a salivary gland scintigraphy before and after radiotherapy. The scintigraphic parameters of each major salivary gland were then compared before and after the radiotherapy. In the brachytherapy group, none of the scintigraphic functional parameters showed a significant change before and after the radiotherapy. In contrast, all of the parameters with the exception of the uptake ratio (UR) of the submandibular glands significantly decreased after external irradiation. This observation was to be expected owing to the different irradiation doses administered by the two techniques. The scintigraphic technique used to evaluate salivary gland function should be used in future intensity-modulated radiation therapy salivary-gland-sparing studies in order to evaluate both the acute and chronic effects of irradiation in head and neck cancer patients.
ABSTRACT
The purpose of this study was to determine whether or not salivary gland dysfunction occurs within the first three months after brachytherapy in patients with head and neck carcinoma. Of the 20 patients with head and neck squamous cell carcinoma included in this study, 11 were treated with brachytherapy and the remaining 9 patients received external irradiation. All the patients underwent a salivary gland scintigraphy before and after radiotherapy. The scintigraphic parameters of each major salivary gland were then compared before and after the radiotherapy. In the brachytherapy group, none of the scintigraphic functional parameters showed a significant change before and after the radiotherapy. In contrast, all of the parameters with the exception of the uptake ratio (UR) of the submandibular glands significantly decreased after external irradiation. This observation was to be expected owing to the different irradiation doses administered by the two techniques. The scintigraphic technique used to evaluate salivary gland function should be used in future intensity-modulated radiation therapy salivary-gland-sparing studies in order to evaluate both the acute and chronic effects of irradiation in head and neck cancer patients.
