Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels.
Glutathione S-transferases and the cytochrome P450 system have been proposed for the vascular biotransformation systems in the metabolic activation of organic nitrates. The present study was designed to elucidate the role of human cytochrome P450 isoforms on nitric oxide formation from organic nitrates using lymphoblast microsomes transfected with human CYP isoforms cDNA. CYP3A4-transfected microsomes had the most effective potential of nitric oxide formation from isosorbide dinitrate. Anti-CYP3A2 antibody (which cross-reacts with CYP3A4) or ketoconazole (an inhibitor of the CYP3A superfamily) inhibited nitric oxide formation from isosorbide dinitrate in rat heart microsomes. Immunohistochemistry of human heart also showed intense bindings of CYP3A4 antibody in the endothelium of the endocardium and coronary vessels. These results suggest that the CYP3A4-NADPH-cytochrome P450 reductase system specifically participates in nitric oxide formation from isosorbide dinitrate. (+info)
Effect of isosorbide mononitrate on the human optic nerve and choroidal circulations.
AIMS: To assess the effects of the nitric oxide donor 5-isosorbide mononitrate (ISMO) on blood flow in the optic nerve head (ON flow) and choroid (Ch flow). METHODS: Laser Doppler flowmetry was used to measure ON flow and Ch flow in 12 normal subjects by aiming the laser beam at the fovea and at the temporal rim, respectively. In a double masked, randomised, crossover design, each subject received orally on separate days either 20 mg of 5-isosorbide mononitrate (ISMO) or placebo. Ch flow and ON flow were determined monocularly at baseline and 1 hour after dosing. In the last six subjects, additional measurements were obtained at 3 hours. Mean arterial blood pressure (BPm), heart rate, and intraocular pressure (IOP) were monitored, and ocular perfusion pressure (PP) was estimated. RESULTS: No significant changes in ON flow, PP, IOP, or BPm were observed following placebo. Following ISMO, ON flow increased from baseline by 19.8% (SEM 9.3%) at 1 hour (paired t test, p = 0.058) and by 33.1% (7.5%) at 3 hours (p = 0.007). Compared with the changes following placebo, statistically significant increases in ON flow were observed both at 1 (p = 0.050) and 3 hours (p = 0.041) after ISMO treatment. Compared with placebo, PP decreased significantly 1 hour after ISMO dosing (p = 0.039), mainly as a function of reduced BPm. A significant inverse correlation (R = -0.618; p = 0.032) was observed between the percentage changes in PP and ON flow 1 hour following ISMO administration, but not after placebo. No significant change in foveal Ch flow was documented. CONCLUSIONS: These results suggest that, in normal subjects, ISMO increases significantly ON flow but not Ch flow. The inverse correlation observed between PP and ON flow suggests that the same mechanism(s) responsible for systemic vasodilatation and blood pressure decrease may also cause the ON flow increase. (+info)
Matrix metalloproteinases-2 and -9 and their inhibitors are produced by the human uterine cervix but their secretion is not regulated by nitric oxide donors.
We have investigated the presence of matrix metalloproteinases (MMP)-2 and -9 and their tissue inhibitors (TIMP) in the human uterine cervix. We postulate that during the process of cervical ripening, there is an increase in the activity of MMP in order to facilitate cervical connective tissue change. We have previously demonstrated that nitric oxide (NO) donors induce cervical ripening in vivo. A secondary hypothesis is that NO donors regulate MMP activity within the human uterine cervix. Cervical tissue biopsies were obtained from both pregnant and non-pregnant subjects. Cervical fibroblasts were cultured from the non-pregnant tissue. MMP-2 was present in conditioned media from pregnant and non-pregnant cervical explants and non-pregnant cervical fibroblasts. MMP-9 secretion was only detected in explants from non-pregnant women. TIMP-1, -2 and -4 were released by all cervical explants and fibroblast preparations. Pregnant women, in the first trimester, were treated with an NO donor (isosorbide mononitrate) in vivo. Cervical explants and fibroblasts from non-pregnant women were treated with the NO donor spermine nonoate in vitro. Treatment with an NO donor either in vivo or in vitro had no effect on the secretion of the MMP or TIMP studied. Further studies evaluating the mechanisms involved in cervical ripening are required. (+info)
Adaptive mechanisms of arterial and venous coronary bypass grafts to an increase in flow demand.
OBJECTIVE: To compare the mechanisms by which arterial and venous grafts increase their flow during pacing induced tachycardia, early and later after coronary bypass surgery. DESIGN: 43 grafts (13 epigastric artery, 15 mammary artery, 15 saphenous vein) evaluated early (9 (3) days (mean (SD)) after bypass surgery were compared with 41 other grafts (15 epigastric, 11 mammary, 15 saphenous vein) evaluated later after surgery (mean 23 months, range 6 to 168 months) by quantitative angiography and intravascular Doppler velocity analysis during atrial pacing. Controls were 17 normal coronary arteries. RESULTS: Baseline graft flow tended to be lower later after surgery than early (41 (16) v 45 (21) ml/min, NS). Blood flow increased during pacing by 30 (16)% early after surgery, less than later after surgery (+46 (18)%, p < 0.001) and less than in normal coronary arteries (+54 (27)%, p < 0.001 v early grafts; NS v late grafts). There was no difference between venous and arterial grafts. No significant vasodilatation was observed during pacing early after surgery in arterial and venous grafts. Later after surgery, significant vasodilatation was observed only in arterial grafts (mammary and epigastric grafts), from 2.41 (0.37) to 2.53 (0. 41) mm (+5.1% v basal, p < 0.001). Early after surgery and in venous grafts later after surgery, the increase in flow was entirely due to an increase in velocity. In later arterial grafts, the relative contribution of the increase in velocity to the increase in flow during pacing was lower in arterial grafts (70 (22)%) than in venous grafts (102 (11)%, p < 0.001) and similar to normal coronary arteries (68 (28)%). CONCLUSIONS: Early and later after surgery, arterial grafts and venous grafts both increase their flow similarly during pacing. Early arterial grafts and venous grafts increase their flow only through an increase in velocity. Later after surgery, arterial grafts act as more physiological conduits and increase their flow in the same way as normal coronary arteries, through an increase in velocity and calibre mediated by the endothelium. (+info)
Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide.
BACKGROUND: Several nonpharmacological interventions, including exercise, are recommended in primary prevention of hypertension and other cardiovascular diseases in which the pathogenetic role of endothelial dysfunction has been suggested. We studied the effects of long-term aerobic exercise on endothelial function in patients with essential hypertension. METHODS AND RESULTS: The forearm blood flow was measured by strain-gauge plethysmography. The responses of forearm vasculature to acetylcholine were smaller in the hypertensive patients than in the normotensive subjects. There was no significant difference in forearm vascular responses to isosorbide dinitrate in the normotensive and hypertensive subjects. We evaluated the effects of physical exercise for 12 weeks on forearm hemodynamics in untreated patients with mild essential hypertension who were divided randomly into an exercise group (n=10) and a control group (n=7). After 12 weeks, the forearm blood flow response to acetylcholine increased significantly, from 25.8+/-9.8 to 32.3+/-11.2 mL. min(-1). 100 mL tissue(-1) (P<0.05), in the exercise group but not in the control group. The increase in the forearm blood flow after isosorbide dinitrate was similar before and after 12 weeks of follow-up in both groups. The infusion of N(G)-monomethyl-L-arginine abolished the exercise-induced enhancement of forearm vasorelaxation evoked by acetylcholine in the exercising group. In normotensive subjects also, long-term aerobic exercise augmented acetylcholine-stimulated nitric oxide release. CONCLUSIONS: These findings suggest that long-term physical exercise improves endothelium-dependent vasorelaxation through an increase in the release of nitric oxide in normotensive as well as hypertensive subjects. (+info)
Nitric oxide donors stimulate prostaglandin F(2alpha) and inhibit thromboxane B(2) production in the human cervix during the first trimester of pregnancy.
Nitric oxide (NO) donors are capable of ripening the human cervix during pregnancy. The purpose of this study was to examine how NO donors may be involved in this process. Cervical biopsies were obtained from pregnant women randomized to receive isosorbide mononitrate (n = 10) or no treatment (n = 10) prior to suction termination. Enzyme-linked immunosorbent assays (ELISA) were performed on culture supernatant for interleukin (IL)-1, IL-6, IL-8, IL-10, IL-15, tumour necrosis factor-alpha, monocyte chemoattractant protein-1 and prostaglandin metabolites. Immunohistochemistry was performed to localize these cytokines, cyclooxygenase (COX)-1, COX-2 and prostaglandin dehydrogenase in cervical tissue and reverse transcription-polymerase chain reaction (RT-PCR) to identify COX-1 and COX-2 expression. Biopsies treated with the NO donor isosorbide mononitrate (IMN) produced significantly greater amounts of prostaglandin F(2alpha) in culture and lower amounts of thromboxane B(2) than controls (572.8 versus 34.9 pg/ml, P < 0.05; 53.3 pg/ml versus 530.9 pg/ml, P < 0.01 respectively). The release of other prostaglandins and of cytokines was not affected by treatment with NO. Inflammatory mediators were localized to cervical tissue and COX-1 and COX-2 expression was confirmed by RT-PCR. In conclusion, the mechanism of NO donor-induced cervical ripening during pregnancy may be mediated in part via increased prostaglandin F(2alpha) synthesis. (+info)
Dissociation of vascular tolerance and plasma norepinephrine adjustment during long-term nitrate therapy in human coronary arteries.
OBJECTIVE: We examined whether changes in plasma norepinephrine (NE) concentration contribute to the development of nitrate tolerance in human coronary arteries. METHODS: Patients with stable angina were randomized to receiving nitrate (isosorbide dinitrate: ISDN or nitroglycerin: TNG) infusion for 30 minutes (group A), 48 hours (group B), or 78 hours (group C). Coronary diameters were measured angiographically at baseline (CT), during maximum dilation by ISDN (N1), at the end of nitrate infusion (N2) and after additional ISDN (1 mg) injection (N3). RESULTS: In groups A and B, N1, N2, and N3 were greater than CT, and there was no significant difference between N1, N2, and N3 for each group. In group C, N1 and N3 were greater than CT, but there was no difference between CT and N2, in the development of nitrate tolerance. In group A, NE increased significantly during nitrate infusion (304+/-163 vs. 418+/-273 pg/ml). NE did not change in groups B and C. CONCLUSION: The change in NE concentration is not a primary contribution to the development of nitrate tolerance. (+info)
Somatostatin plus isosorbide 5-mononitrate versus somatostatin in the control of acute gastro-oesophageal variceal bleeding: a double blind, randomised, placebo controlled clinical trial.
BACKGROUND: Variceal bleeding is a severe complication of portal hypertension. Somatostatin reduces portal pressure by decreasing splanchnic blood flow, and nitrates by diminishing intrahepatic resistance. Experimental studies have shown that the combination of somatostatin and nitrates has an additive effect in decreasing portal pressure. AIM: To compare the therapeutic efficacy of either intravenous infusion of somatostatin plus oral isosorbide 5-mononitrate or somatostatin alone in gastro-oesophageal variceal bleeding associated with liver cirrhosis. METHODS: A unicentre, double blind, placebo controlled, clinical trial was conducted. Sixty patients bleeding from oesophageal or gastric varices were randomised to receive intravenous infusion of somatostatin (250 microg/hour) plus oral isosorbide 5-mononitrate (40 mg/12 hours) (group I) or somatostatin infusion plus placebo (group II) for 72 hours. RESULTS: The two groups of patients had similar clinical, endoscopic, and haematological characteristics. Control of bleeding was achieved in 18 out of 30 patients (60%) in group I and 26 out of 30 patients (87%) in group II (p<0.05). There was no significant difference in mean transfusion requirements between the two groups: 2.6 (2.2) v 1.8 (1.6) respectively; means (SD). Mortality and side effects were similar in the two groups, but development of ascites was higher in group I (30%) than in group II (7%) (p<0.05). CONCLUSION: In cirrhotic patients with acute gastro-oesophageal variceal bleeding, addition of isosorbide 5-mononitrate to somatostatin does not improve therapeutic efficacy, induces more adverse effects, and should not be used. (+info)