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Potential roles of plasminogen activator system in coronary vascular remodeling induced by long-term nitric oxide synthase inhibition.
Kaikita K, Schoenhard JA, Painter CA, Ripley RT, Brown NJ, Fogo AB, Vaughan DE
(2002) J Mol Cell Cardiol 34: 617-27
MeSH Terms: Animals, Body Weight, Coronary Disease, Coronary Vessels, Enzyme Inhibitors, Fibrosis, Hemodynamics, Hypertension, Mice, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase, Plasminogen Activators, Reverse Transcriptase Polymerase Chain Reaction, Transforming Growth Factor beta
Show Abstract · Added December 10, 2013
Recent studies have indicated that a number of factors contribute to the pathophysiology in response to nitric oxide synthase (NOS) inhibition. We previously demonstrated that plasminogen activator inhibitor-1 deficient (PAI-1-/-) mice are protected against hypertension and perivascular fibrosis induced by relatively short-term NOS inhibition. In this study, we compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis induced by long-term treatment with N(omega)-nitro- L -arginine methyl ester (L -NAME) in wild type (WT), PAI-1(-/-) and tissue-type plasminogen activator deficient (t-PA-/-) mice. After initiating L -NAME, systolic blood pressure increased in all groups at 2 weeks. Over a 16 week study period, systolic blood pressure increased to 143+/-3 mmHg (mean+/-SEM) in WT animals, 139+/-2 in t-PA-/- mice vs 129+/-2 in PAI-1-/- mice (P < 0.01). Coronary perivascular fibrosis increased in L -NAME-treated WT and t-PA(-/-) mice compared to each control group (P<0.01 in WT, P<0.05 in t-PA-/-), while PAI-1-/- mice were protected against fibrosis induced by L -NAME. t-PA deficiency did not accentuate the vascular pathology or the changes in blood pressure. In situ zymography demonstrated augmented gelatinolytic activity in PAI-1-/- mice at baseline, suggesting that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Plasma TGF-beta1 levels increased in L -NAME-treated WT and PAI-1-/- mice (P < 0.01), but not in L -NAME-treated t-PA-/- mice. These findings support the hypothesis that the plasminogen activator system protects against the structural vascular changes induced by long-term NOS inhibition. While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension.
Copyright 2002 Elsevier Science Ltd. All rights reserved.
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15 MeSH Terms
Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition.
Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE
(2001) Circulation 104: 839-44
MeSH Terms: Animals, Blood Pressure, Body Weight, Collagen, Coronary Vessels, Enzyme Inhibitors, Fibrosis, Hemodynamics, Hypertension, Hypertrophy, Left Ventricular, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase, Plasminogen Activator Inhibitor 1, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Time
Show Abstract · Added December 10, 2013
BACKGROUND - Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by N(omega)-nitro-L-arginine methyl ester (L-NAME).
METHODS AND RESULTS - We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1-deficient (PAI-1(-/-)) and wild-type (WT) male mice (N=6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141+/-3 mm Hg in WT animals versus 112+/-4 mm Hg in PAI-1(-/-) mice (P<0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME-treated WT mice (P<0.01 versus PAI-1(-/-) mice). Cardiac type I collagen mRNA expression was greater in control (P<0.01) and L-NAME-treated PAI-1(-/-) (P<0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation.
CONCLUSIONS - These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.
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20 MeSH Terms
Insulin and heregulin-beta1 upregulate guanylyl cyclase C expression in rat hepatocytes: reversal by phosphodiesterase-3 inhibition.
Scheving LA, Russell WE
(2001) Cell Signal 13: 665-72
MeSH Terms: 3',5'-Cyclic-AMP Phosphodiesterases, Animals, Cells, Cultured, Cyclic AMP, Cyclic Nucleotide Phosphodiesterases, Type 3, Dexamethasone, Drug Antagonism, Drug Synergism, Enzyme Inhibitors, Glucagon, Guanylate Cyclase, Hepatocytes, Insulin, Male, NG-Nitroarginine Methyl Ester, Neuregulin-1, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Phosphatidylinositol 3-Kinases, Rats, Rats, Sprague-Dawley, Receptors, Enterotoxin, Receptors, Guanylate Cyclase-Coupled, Receptors, Peptide, Up-Regulation
Show Abstract · Added December 10, 2013
Guanylyl cyclase C (GC-C) is the receptor for the hormones guanylin and uroguanylin. Although primarily expressed in the rat intestine, GC-C is also expressed in the liver during neonatal or regenerative growth or during the acute phase response. Little is known about the hepatic regulation of GC-C expression. The influence of various hepatic growth or acute phase regulators on GC-C expression was evaluated by immunoblot analysis of protein from primary rat hepatocytes grown in a serum-free medium. Insulin and heregulin-beta1 strongly stimulated GC-C expression by 24 h of cell culture. Several different hormones and agents suppressed this action, including transforming growth factor beta (TGF-beta), as well as inhibitors of phosphatidylinositol 3-kinase (PI-3-kinase) and phosphodiesterase 3 (PDE-3, an insulin- and PI-3-kinase-dependent enzyme). The compartmental downregulation of cAMP levels by PDE-3 may be a critical step in the hormonal action that culminates in GC-C synthesis.
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25 MeSH Terms
Long-term measurement of arterial blood pressure in conscious mice.
Mattson DL
(1998) Am J Physiol 274: R564-70
MeSH Terms: Animals, Arginine, Arteries, Blood Pressure, Blood Pressure Determination, Blood Specimen Collection, Catheters, Indwelling, Drinking, Enzyme Inhibitors, Heart Rate, Infusions, Intravenous, Mice, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase
Show Abstract · Added September 9, 2013
This study describes a technique for the direct daily measurement of arterial blood pressure, sampling of arterial blood, and continuous intravenous infusion in free-moving, conscious, Swiss-Webster mice. Catheters were chronically implanted in the femoral artery and vein, tunneled subcutaneously, exteriorized at the back of the neck in a lightweight tethering spring, and attached to a swivel device at the top of the cage. Time-control experiments (n = 8) demonstrated stable values of mean arterial pressure (MAP, 116 +/- 1 mmHg) and heart rate (HR, 627 +/- 21 beats/min) for up to 35 days after catheter implantation. It was further observed that restraining mice (n = 7) increased MAP by 10 +/- 3 mmHg and HR by 78 +/- 8 beats/min from the values observed under free-moving conditions. To demonstrate the chronic use of the venous catheter, intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME, 8.6 mg.kg-1.day-1, n = 6) for 5 days significantly increased MAP from 117 +/- 4 to 131 +/- 4 mmHg without altering HR. In a final group of mice (n = 5), oral L-arginine (2% in drinking water) increased plasma arginine concentration from 90 +/- 7 to 131 +/- 17 microM and prevented L-NAME hypertension. These experiments illustrate the feasibility of long-term intravenous infusion, direct arterial blood pressure measurements, and arterial blood sampling in conscious mice.
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14 MeSH Terms
Release of multiple endothelium-derived relaxing factors from porcine coronary arteries.
Myers PR, Guerra R, Harrison DG
(1992) J Cardiovasc Pharmacol 20: 392-400
MeSH Terms: Adenosine Diphosphate, Animals, Arginine, Bradykinin, Calcimycin, Coronary Vessels, In Vitro Techniques, Muscle Relaxation, Muscle, Smooth, Vascular, NG-Nitroarginine Methyl Ester, Nitric Oxide, Oxidation-Reduction, Swine
Show Abstract · Added December 10, 2013
Using a chemiluminescence method in the present study, we measured nitric oxide and one-electron oxidation products of nitric oxide (NOX) released from porcine coronary artery segments in response to bradykinin, ADP, and the calcium ionophore A23187. Total NOX was compared with the bioactivity of endothelium-derived relaxing factors (EDRF) by a biodetector ring preparation before and after inhibition of L-arginine-dependent nitric oxide synthesis and in the presence of indomethacin. Under basal conditions, arterial segments released NOX and relaxed biodetector rings. Bradykinin, ADP, and A23187 elicited vasorelaxation greater than that observed basally; A23187, but not bradykinin or ADP, caused additional release of NOX greater than that measured basally. Hemoglobin completely reversed vasorelaxation elicited by all three agonists. We compared the amount of nitric oxide released under basal conditions and after stimulation with bradykinin, ADP, and A23187 with the amount of authentic nitric oxide necessary to elicit a bioequivalent response. Authentic nitric oxide did not account for the observed bioactivity as compared with the amount of nitric oxide actually measured in arterial segment effluent. To investigate whether a second non-nitric oxide-containing compound was responsible for the increased bioactivity and the discrepancy between the bioactivity and quantity of nitric oxide measured, we exposed arterial segments to omega-nitro-L-arginine methyl ester to inhibit L-arginine-dependent synthesis of nitroso compounds. The drug completely abolished the nitric oxide signal derived from both basally released and A23187-stimulated relaxing factor and completely reversed vasorelaxation. In contrast, omega-nitro-L-arginine methyl ester only partially reversed bradykinin-stimulated vasorelaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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13 MeSH Terms