In vivo human brachial artery elastic mechanics: effects of smooth muscle relaxation. (33/1442)

BACKGROUND: The effects of smooth muscle relaxation on arterial wall mechanics are controversial. We used a new, in vivo, noninvasive technique to measure brachial artery wall mechanics under baseline conditions and following smooth muscle relaxation with nitroglycerin (NTG). METHODS AND RESULTS: Eight healthy, normal subjects (6 male, 2 female; age 30+/-3.1 years) participated in the study. The nondominant brachial artery was imaged through a water-filled blood pressure cuff using an external ultrasound wall-tracking system at baseline and following 0.4 mg sublingual NTG. Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Brachial artery area, unstressed area, compliance, stress, strain, incremental elastic modulus (Einc), and pulse wave velocity (PWV) were measured over a TP range from 0 to 100 mm Hg. Baseline area versus TP curves generated 30 minutes apart were not significantly different. NTG significantly shifted area versus TP (P<0.0001) and compliance versus TP (P<0.001) curves upward, whereas the Einc versus TP (P<0.05) and PWV versus TP (P<0. 01) curves were shifted downward. NTG also significantly shifted stress versus strain (P<0.01) and Einc versus strain (P<0.01) curves to the right. CONCLUSIONS: We conclude that brachial artery elastic mechanics can be reproducibly measured over a wide range of TP and smooth muscle tone using a new noninvasive ultrasound technique. Smooth muscle relaxation with NTG increases isobaric compliance and decreases isobaric Einc and PWV in the human brachial artery.  (+info)

A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure. (34/1442)

BACKGROUND AND METHODS: Lateral internal sphincterotomy, the most common treatment for chronic anal fissure, may cause permanent injury to the anal sphincter, which can lead to fecal incontinence. We compared two nonsurgical treatments that avert the risk of fecal incontinence. We randomly assigned 50 adults with symptomatic chronic posterior anal fissures to receive treatment with either a total of 20 U of botulinum toxin injected into the internal anal sphincter on each side of the anterior midline or 0.2 percent nitroglycerin ointment applied twice daily for six weeks. RESULTS: After two months, the fissures were healed in 24 of the 25 patients (96 percent) in the botulinum-toxin group and in 15 of the 25 (60 percent) in the nitroglycerin group (P=0.005). No patient in either group had fecal incontinence. At some time during treatment, five patients in the nitroglycerin group had transient, moderate-to-severe headaches that were related to treatment. None of the patients in the botulinum-toxin group reported adverse effects. Ten patients who did not have a response to the assigned treatment - 1 in the botulinum-toxin group and 9 in the nitroglycerin group - crossed over to the other treatment; the fissures subsequently healed in all 10 patients. There were no relapses during an average of about 15 months of follow-up. CONCLUSIONS: Although treatment with either topical nitroglycerin or botulinum toxin is effective as an alternative to surgery for patients with chronic anal fissure, botulinum toxin is the more effective nonsurgical treatment.  (+info)

Nitrate resistance in platelets from patients with stable angina pectoris. (35/1442)

BACKGROUND: Hemodynamic resistance to nitrates has been previously documented in congestive heart failure. In patients with stable angina pectoris (SAP), we have observed a similar phenomenon: decreased platelet response to disaggregating effects of nitroglycerin (NTG) and sodium nitroprusside (SNP). METHODS AND RESULTS: In blood samples from normal subjects (n=32) and patients with SAP (n=56), we studied effects of NO donors (NTG and SNP) on ADP-induced platelet aggregation and on intraplatelet cGMP. NTG and SNP inhibited platelet aggregation in patients to lesser extents than in normal subjects (P<0.01). The cGMP-elevating efficacy of NTG and SNP was diminished in platelets from patients in comparison with those from normals (P<0.001). Inhibition of the anti-aggregatory effects of NTG and SNP by ODQ, a selective inhibitor of NO-stimulated guanylate cyclase, was significantly less pronounced in patients than in normal subjects. Content of O2- was higher in blood samples from patients than in those from normal subjects (P<0. 01). In blood samples from patients with SAP, but not in normal subjects, the O2- scavenger superoxide dismutase (combined with catalase) suppressed platelet aggregation (P<0.01) and increased the extent of anti-aggregatory effect of SNP (P<0.01). CONCLUSIONS: In patients with SAP, platelets are less responsive to the anti-aggregating and cGMP-stimulating effects of NO donors; this may reflect both reduction in guanylate cyclase sensitivity to NO and inactivation of the released NO by O2-. The implied impairment of anti-platelet efficacy of endogenous NO (in the form of EDRF) may contribute to platelet hyperaggregability associated with angina pectoris.  (+info)

Plasma alpha-tocopherol and coronary endothelium-dependent vasodilator function. (36/1442)

BACKGROUND: In the presence of atherosclerosis, the coronary endothelial vasomotor response to acetylcholine is frequently abnormal but is variable between patients. We tested the hypothesis that the plasma concentration of alpha-tocopherol is associated with the preservation of nitric oxide-mediated endothelium-dependent vasomotion. METHODS AND RESULTS: We studied 15 men and 6 women (mean age 61+/-10 years) at coronary angiography who were not taking vitamin supplements. Coronary endothelium-dependent and -independent vasomotion was assessed by intracoronary infusions of acetylcholine and nitroglycerin. The vasomotor responses were compared with the plasma concentration of alpha-tocopherol and the plasma alpha-tocopherol concentration relative to total lipid (total cholesterol plus triglycerides). The mean plasma alpha-tocopherol was 25.6+/-6.1 micromol/L, total cholesterol 193+/-27 mg/dL, triglycerides 115+/-66 mg/dL, and alpha-tocopherol to total lipid 4. 2+/-0.9 micromol. L(-1). (mmol/L)(-1). The mean vasomotor response to acetylcholine was -1% (range -33% to 28%) and to nitroglycerin 22% (range 0% to 54%). Plasma alpha-tocopherol was significantly correlated with the acetylcholine response (r=0.49, P<0.05) but not the nitroglycerin response (r=0.13, P>0.05). The acetylcholine response remained significant after adjustment for other potential sources of oxidant stress (total cholesterol, diabetes mellitus, smoking, angina class) (P<0.01). The relative concentration of alpha-tocopherol to total lipid was not related to endothelial function (r=0.24, P=0.3, n=20). CONCLUSIONS: alpha-Tocopherol may preserve endothelial vasomotor function in patients with coronary atherosclerosis. This effect may be related primarily to the action of alpha-tocopherol in the vascular wall. Further studies that assess the impact of alpha-tocopherol supplementation as therapy of endothelial dysfunction are justified.  (+info)

Spinal antinociceptive effect of epidural nonsteroidal antiinflammatory drugs on nitric oxide-induced hyperalgesia in rats. (37/1442)

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) suppress various hyperalgesia perhaps via inhibition of cyclooxygenase activity at the spinal cord. The present study aimed to examine whether epidural application of NSAIDs affects hyperalgesia induced by nitric oxide. METHODS: The authors studied the antinociceptive effects of epidurally administered NSAIDs in rats with a chronically in-dwelling epidural catheter by three hyperalgesic models, including nitric oxide-induced hyperalgesia by nitroglycerin (10 microg) or l-arginine (100 microg), and the biphasic response in the formalin test. RESULTS: Epidural, but not systemic, nitroglycerin induced hyperalgesia that was completely blocked by methylene blue but not by N(omega)-nitro-L-arginine methyl ester (L-NAME). Epidural l-arginine, but not d-arginine, also induced hyperalgesia that was completely blocked by L-NAME. Epidural S(+)ibuprofen (100-1,000 microg) suppressed the nitroglycerin- and l-arginine-induced thermal hyperalgesia and also the second phase response in the formalin test. Neither systemic S(+)ibuprofen nor epidural R(-)ibuprofen suppressed the hyperalgesia Epidural indomethacin (10-100 microg) or diclofenac (10-1,000 microg) dose-dependently suppressed nitroglycerin-induced thermal hyperalgesia The order of potency for this suppression (ID50 in microg) was indomethacin = didofenac > S(+)ibuprofen >> R(-)ibuprofen. CONCLUSIONS: The antinociceptive action of epidurally administered NSAIDs could be the result of suppression of spinal sensitization, perhaps induced with nitric oxide in the spinal cord. The ID50 values for epidural indomethacin, diclofenac, and S(+)ibuprofen were about 10 times higher than those reported in other studies for intrathecal NSAIDs in hyperalgesia models. (Key words: Cyclooxygenase inhibitors; NO donor; NO precursor; optical isomers; neuroplasticity.)  (+info)

Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability. (38/1442)

OBJECTIVES: We investigated whether glutathione (GSH), a reduced thiol that modulates redox state and forms adducts of nitric oxide (NO), improves endothelium-dependent vasomotion and NO activity in atherosclerosis. BACKGROUND: Endothelial dysfunction and reduced NO activity are associated with atherosclerosis and its clinical manifestations such as unstable angina. METHODS: In the femoral circulation of 17 patients with atherosclerosis or its risk factors, endothelium-dependent vasodilation with acetylcholine (ACH), and endothelium-independent vasodilation with nitroglycerin and sodium nitroprusside were studied before and after GSH. In 10 patients, femoral vein plasma cyclic guanylate monophosphate (cGMP) levels were measured during an infusion of ACH before and after GSH. Femoral artery flow velocity was measured using a Doppler flow wire and the resistance index (FVRI) calculated as mean arterial pressure divided by flow velocity. RESULTS: Glutathione strongly potentiated ACH-mediated vasodilation; at the two doses, FVRI decreased by 47% and 56% before, and by 61% and 67% after GSH (p = 0.003). Glutathione also elevated cGMP levels in the femoral vein during ACH infusion from 17.6 +/- 3 to 23.3 +/- 3 pmol/ml (p = 0.006). Augmentation of ACH responses was only observed in patients with depressed endothelial function. Glutathione did not influence endothelium-independent vasodilation with either NO donor. CONCLUSIONS: Thiol supplementation with GSH selectively improves human endothelial dysfunction by enhancing NO activity.  (+info)

Effect of K+ channel openers, KRN2391 and Ki1769, and nitroglycerin on the urinary tract of rats in vivo. (39/1442)

The effects of KRN2391 (N-cyano-N'-(nitroxyethyl)-3-pyridine carboximidamide methane-sulfonate), which possesses ATP-sensitive potassium (K+) channel opening (KCO) activity and nitrate activity; Ki1769 (N-cyano-N'-(phenylethyl)-3-pyridinecarboximidamide methanesulfonate), which possesses only KCO activity; and nitroglycerin (NG) were determined on the motility of the ureter, urinary bladder and urethra of rats. Bladder contraction was induced by infusion of fluid into the bladder of conscious rats and recorded on a cystometrogram. KRN2391 and Ki1769 (both 0.3 mg/kg, i.v.) prolonged the micturition interval immediately after the injection, but NG (5 mg/kg, i.v.) did not. Peristaltic movement of the ureter, recorded in anesthetized rats, was inhibited by i.v. injection of KRN2391 and Ki1769 (both 0.03 mg/kg). However, when NG, NaNO2, N-nitro L-arginine methylester and methylene blue were applied directly to the ureter, no change in movement of the ureter was detected. KRN2391 (0.03 mg/kg, i.v.) and Ki1769 (0.3 mg/kg, i.v.) reduced the resistance to fluid infusion through the urethral lumen in anesthetized rats, whereas NG (0.5 mg/kg, i.v.) only reduced this resistance transiently. These results indicate that KCO activity had an inhibitory effect on the motility of the ureter, bladder and urethra. On the other hand, nitrate activity had an inhibitory effect on urethral tonus, corresponding to that induced by KCO activity.  (+info)

Lateral internal sphincterotomy is not redundant in the era of glyceryl trinitrate therapy for chronic anal fissure. (40/1442)

Lateral internal sphincterotomy has been the standard treatment for chronic anal fissure, but fissure healing rates of up to 80% with topical glyceryl trinitrate (GTN) treatment have suggested that this operation may become redundant. We evaluated the results of topical treatment of chronic anal fissures with 0.2% GTN for 6 weeks in the outpatient clinical setting, outside the confines of a randomized clinical trial. The role of lateral internal sphincterotomy in the GTN era was also assessed. GTN induced fissure healing in 21 of 49 consecutive patients. Fissures healed spontaneously in 2 patients who discontinued GTN because of headache. Lateral internal sphincterotomy was performed in 26 patients who had persistent symptoms after 6 weeks of GTN therapy. At the 6-week post-sphincterotomy review, all fissures had healed and there were no complications. In this study topical GTN for treatment of chronic anal fissure in the outpatient setting was not as effective as demonstrated in controlled clinical trials. Lateral internal sphincterotomy is still a good therapeutic option, especially in patients not responding to GTN.  (+info)