Effect of inhaled nitroglycerine and sodium nitroprusside aerosol on hemodynamics and oxygenation in dogs with pulmonary hypertension

Purpose To test the hypothesis that inhalation of aerosol of glyceryl trinitrate or sodium nitroprusside might produce selective pulmonary vasodilation, causing an improvement of oxygenation with minimal systemic hypotension as inhaled nitric oxide gas, we investigated the effect of inhaled nitroglycerine and sodium nitroprusside aerosol on hemodynamics and oxygenation in dogs with pulmonary hypertension. Methods Pulmonary hypertension was induced by a continuous infusion of 1.0 to 4.0μg·kg⁻¹·min⁻¹ U-46619 in anesthetized and mechanically ventilated dogs. Aerosol preparations consisted of normal saline, 250, 500, 1000, and 2000 ppm solutions of either glyceryl trinitrate or sodium nitroprusside were administered sequentially via the breathing circuit. Results Inhaled nitroglycerine and sodium nitroprusside aerosol caused neither selective pulmonary vasodilation nor improved oxygenation in this pulmonary hypertension model, unlike inhaled nitric oxide gas. Conclusion These findings suggest that inhaled nitroglycerine and sodium nitroprusside aerosol is not effective in improving hemodynamic derangement or oxygenation in pulmonary hypertension. However, the effect of the substances in higher dose ranges remains to be defined. This study was supported in part by a grant from the University of Tsukuba Project Research     

Tolerance to glyceryl trinitrate in isolated human internal mammary arteries.

The purpose of this study was to examine the vascular reactivity of segments of internal mammary artery removed from patients undergoing coronary artery bypass operations. Responses to relaxant and contractile agents were compared in arteries removed from patients who had or had not been treated with glyceryl trinitrate after admission to the hospital until operation. Segments of mammary artery were removed from 13 patients who underwent coronary artery bypass grafting. Endothelium-containing rings of artery, 3 to 5 mm long, were suspended in physiologic saline solution in 20 ml organ baths. Responses to the endothelium-dependent relaxant acetylcholine and the endothelium-independent relaxants glyceryl trinitrate and sodium nitroprusside were compared. In addition, contractile responses to phenylephrine and 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F2 alpha (U46619) were examined. Glyceryl trinitrate-induced relaxation was significantly impaired in mammary artery segments from patients treated with that nitrate before operation; the responses to acetylcholine and sodium nitroprusside were not affected. Previous treatment with glyceryl trinitrate also reduced the contractile responses to both phenylephrine and U46619. These studies indicate that treatment of patients with glyceryl trinitrate before operation induces significant tolerance to this agent in the mammary artery; however, there was no evidence of cross tolerance to sodium nitroprusside or the endothelium-dependent vasodilator acetylcholine. Glyceryl trinitrate may therefore not always be effective in dilating mammary artery grafts and sodium nitroprusside may be a more effective dilator of the internal mammary artery in patients who have been treated with glyceryl trinitrate before operation.     

Sympatho-adrenergic reactions during drug-induced hypotension. A comparative study on probands

This study was undertaken to compare the influence of different regimens for induced hypotension down to Power a limit of 80 mmHg (systolic) on sympatho-adrenergic responses in 10 volunteers. Volunteers were investigated in five batteries of tests using glyceryl trinitrate (10 micrograms/kg BW/min), sodium nitroprusside (10 micrograms/kg BW/min maximal dosage), nifedipine (0.35 micrograms/kg BW/min) and urapidil (bolus injections of 25, 25 and 50 mg, followed by an infusion of 180 ml/h) and placebo. Catecholamines in plasma were detected by HPLC/ECD within a period of 1 h of hypotension and 1 h of recovery at 11 measuring points. Using sodium nitroprusside and glyceryl trinitrate, a significant hypotension was achieved. Urapidil was less potent. No hypotension was observed during or after treatment with nifedipine. Heart rate increased during treatment with sodium nitroprusside and glyceryl trinitrate. Sodium nitroprusside, glyceryl trinitrate and urapidil caused significant rises in noradrenaline levels. With nifedipine, noradrenaline increased within the normal range. Adrenaline left the normal range only during urapidil treatment. MAP, HR, and levels of noradrenaline and adrenaline returned to the initial values 5 min after discontinuation of the sodium nitroprusside infusion. After treatment with glyceryl trinitrate and urapidil, MAP was still low even 60 min after discontinuation of treatment. Urapidil caused marked increases in noradrenaline and adrenaline, which persisted even into the recovery phase. With regard to clinical management and sympatho-adrenergic responses, sodium nitroprusside is the most useful of these compounds for the reduction of hypotension. Having similar potency and active metabolites, glyceryl trinitrate has a longer duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Automatic control of arterial pressure after cardiac surgery Evaluation of a microcomputer-based control system using glyceryl trinitrate and sodium nitroprusside

Arterial hypertension after cardiac surgery is common and is associated with increased morbidity. Glyceryl trinitrate may be a more suitable agent for control of hypertension than sodium nitroprusside. We have developed a closed-loop system for the Atari 1040ST microcomputer to control arterial pressure by the simultaneous infusion of two vasodilators under computer control. Use of this system with glyceryl trinitrate and sodium nitroprusside in 24 patients who required vasodilators after cardiopulmonary bypass, revealed that hypertension was controlled by glyceryl trinitrate alone in 14 of the patients and 10 required supplementary sodium nitroprusside. The results suggest that glyceryl trinitrate is a suitable agent for control of hypertension after cardiac surgery in the majority of patients. They also show that a sizeable minority required additional sodium nitroprusside, and that an automated 'dual pump' system is a satisfactory method of administering two vasodilators in this way.     

Sequestration of glyceryl trinitrate (nitroglycerin) by cardiopulmonary bypass oxygenators

The effectiveness of glyceryl trinitrate (nitroglycerin) in controlling myocardial ischemia and blood pressure during coronary artery bypass graft surgery is frequently lost during surgery, possibly as a result of drug sequestration by the cardiopulmonary bypass circuit. The objective of this study was to utilize a gas-liquid chromatographic assay to determine the extent of removal of glyceryl trinitrate from the priming fluid by the bubble and membrane oxygenators. The apparatus was maintained at either 25 or 37 degrees C, the two extreme temperatures experienced by the patient during bypass surgery. At apparent steady state, the circulating glyceryl trinitrate concentration was decreased by 20.6%, 46.6%, and 67.3% with the Maxima membrane oxygenator, Cobe membrane oxygenator, and Bentley bubble oxygenator, respectively. The three-layer defoaming filters that are used in the Bentley bubble oxygenator were studied by immersing each of the three filters in fluid containing 60 nM glyceryl trinitrate and monitoring the drug concentration in Plasmalyte. The filters sequestered approximately 90% of the glyceryl trinitrate from the bathing solution of which 31% was recovered with a single methanol wash of the polyurethane filter. These data demonstrate that the different oxygenators used in the cardiopulmonary bypass circuit remove glyceryl trinitrate to varying degrees from the circulating fluid.     

Dialysis improves endothelial function in humans.

BACKGROUND: Circulating inhibitors of endothelial function have been implicated in the pathogenesis of vascular disease in chronic renal failure. The aim of this study was to determine if lowering the plasma concentration of these and other dialysable toxins improves endothelial function. To do this we compared the acute effects on endothelial function of single episodes of haemodialysis with automated peritoneal dialysis. We hypothesized that endothelial function would improve after dialysis, with a greater effect seen after haemodialysis due to more substantial clearance of endothelial toxins per-treatment. METHODS: Subjects with end-stage renal failure undergoing haemodialysis (n=16) or automated peritoneal dialysis (n=14) were investigated. Endothelial function was determined using vascular ultrasound to measure flow-mediated dilatation of the brachial artery and was compared with the dilatation caused by sublingual glyceryl trinitrate. Endothelial function was assessed before and after a single dialysis treatment. Plasma concentrations of the inhibitors of endothelial function, asymmetric dimethyl-l-arginine and homocysteine were measured. Flow-mediated dilatation was expressed as percentage change from basal diameter and analysed using Student's t test. RESULTS: The plasma concentration of circulating inhibitors of endothelial function was reduced after haemodialysis but not peritoneal dialysis. Haemodialysis increased flow-mediated dilatation from 4.0+/-1.0% to 5.8+/-1.2% (P<0.002). These changes persisted for 5 h but returned to baseline by 24 h. Automated peritoneal dialysis had no acute effect on flow-mediated dilatation (5.9+/-1.1% vs 5.4+/-0.8% after, P>0.5). There were no effects of either dialysis modality on dilatation to glyceryl trinitrate. CONCLUSIONS: Short-term reduction of circulating inhibitors of endothelial function by haemodialysis is associated with increased flow-mediated dilatation. These data suggest that dialysable endothelial toxins have deleterious effects on endothelial function that are rapidly reversible.     

In vitro suppression of drug-induced methaemoglobin formation by Intralipid(®) in whole human blood: observations relevant to the 'lipid sink theory'

To provide further evidence for the lipid sink theory, we have developed an in vitro model to assess the effect of Intralipid^® 20% on methaemoglobin formation by drugs of varying lipid solubility. Progressively increasing Intralipid concentrations from 4 to 24 mg.ml^?1 suppressed methaemoglobin formation by the lipid soluble drug glyceryl trinitrate in a dose‐dependent manner (p < 0.001). Both dose and timing of administration of Intralipid to blood previously incubated with glyceryl trinitrate for 10 and 40 min resulted in significant suppression of methaemoglobin formation (p < 0.0001 and p < 0.05, respectively). Mathematical modelling demonstrated that the entire process of methaemoglobin formation by glyceryl trinitrate was slowed down in the presence of Intralipid. Intralipid did not significantly suppress methaemoglobin formation induced by 2‐amino‐5‐hydroxytoluene (partially lipid soluble) or sodium nitrite (lipid insoluble; both p > 0.5). This work may assist determination of the suitability of drugs taken in overdose for which Intralipid might be deployed.     

Three-year followup study of topical glyceryl trinitrate treatment of chronic noninsertional Achilles tendinopathy

BACKGROUND: Topical glyceryl trinitrate treatment has demonstrated short-term efficacy in chronic noninsertional Achilles tendinopathy. No long-term followup is reported. We aimed to assess if the demonstrated efficacy of this treatment persisted 3 years after discontinuation of therapy. METHODS: A follow-up study of 52 patients (68 tendons) treated with 6 months of glyceryl trinitrate therapy or placebo was performed 3 years after cessation of therapy. Assessment included pain scores, return to previous activity, the Victorian Institute of Sport Achilles tendon scale (VISA-A), asymptomatic patient outcomes, clinical assessment of tendon tenderness, and functional hop test. RESULTS: Patients treated with topical glyceryl trinitrate had significantly less Achilles tendon tenderness (p = 0.03), and improved VISA-A scores (p = 0.04) than those in the placebo group; 88% (28 of 32 tendons) of patients were completely asymptomatic at 3 years (VISA-A score of 100) compared to 67% (24 of 36 tendons) of patients treated with rehabilitation alone (p = 0.03 with Chi square analysis). Other outcome measures showed nonsignificant trends towards improvement in the glyceryl trinitrate group (pain scores p = 0.07, functional hop test p = 0.07, and return to sport p = 0.16). The mean estimated effect size for all outcome measures was 0.21. CONCLUSIONS: Topical glyceryl trinitrate treatment has demonstrated efficacy in treating chronic noninsertional Achilles tendinopathy, and the treatment benefits continue at 3 years. Significant differences in asymptomatic patient outcomes for the glyceryl trinitrate group continue at 3 years, and this is confirmed by the effect size estimate. This suggests that the mechanism of action of topical glyceryl trinitrate on chronic tendinopathies is more than an analgesic effect.     

Efficacy of topical use of 0.2% glyceryl trinitrate in reducing post-haemorrhoidectomy pain and improving wound healing

The aim of the study was to evaluate whether topical application of 0.2% glyceryl trinitrate ointment could reduce post-haemorrhoidectomy healing time and pain both at rest and during defecation. Thirty patients with grade III and IV haemorrhoids were included in the study and divided into two groups. All patients underwent Milligan-Morgan haemorrhoidectomy, and anorectal manometry was performed before surgery and after 5 and 30 days. In one group a placebo ointment was applied to the perianal wounds, while in the other group a 0.2% glyceryl trinitrate ointment was used. Maximum resting pressure was reduced in the glyceryl trinitrate group and increased in the placebo group after 5 days. Postoperative pain both at rest and during defecation, and the time to healing and return to normal activity were significantly reduced in the glyceryl trinitrate group, whilst analgesic consumption was similar. An elevated incidence of headache was observed In the glyceryl trinitrate group. Topical application of glyceryl trinitrate was effective in reducing postoperative pain and healing time, but the substantial incidence of side effects may limit its extensive use.     

Local application of EMLA and glyceryl trinitrate ointment before venepuncture

One hundred unpremedicated fit day surgery patients aged between 27 and 68 years were allocated randomly into one of four groups and EMLA, glyceryl trinitrate, EMLA and glyceryl trinitrate or a placebo ointment was applied to the dorsum of a hand. The pain and ease of venepuncture were determined at induction of anaesthesia 60 minutes later. Pain scores were also reassessed 1-2 hours after operation. Lower pain scores and easier venepuncture occurred when EMLA and glyceryl trinitrate ointment was applied to the dorsum of the hand.     

Enhanced Preservation of Pig Cardiac Allografts by Combining Erythropoietin With Glyceryl Trinitrate and Zoniporide

Erythropoietin has a tissue‐protective effect independent of its erythropoietic effect that may be enhanced by combining it with the nitric oxide donor glyceryl trinitrate (GTN) and the sodium–hydrogen exchange inhibitor zoniporide in rat hearts stored with an extracellular‐based preservation solution (EBPS). We thus sought to test this combination of agents in a porcine model of orthotopic heart transplantation incorporating donor brain death and total ischaemic time of approximately 260 min. Pig hearts were stored in one of four storage solutions: unmodified EBPS (CON), EBPS supplemented with GTN and zoniporide (GZ), EBPS supplemented with erythropoietin and zoniporide (EZ), or EBPS supplemented with all three agents (EGZ). A total of 4/5 EGZ hearts were successfully weaned from cardiopulmonary bypass compared with only 2/5 GZ hearts, 0/5 CON hearts and 0/5 EG hearts (p = 0.017). Following weaning from bypass EGZ hearts demonstrated superior contractility and haemodynamics than GZ hearts. All weaned hearts displayed impaired diastolic function. Release of troponin I from EGZ hearts was lower than all other groups. In conclusion, supplementation of EBPS with erythropoietin, glyceryl trinitrate and zoniporide provided superior donor heart preservation than all other strategies tested.     

Effect of glyceryl trinitrate and ice on dilation of hand veins

Application of glyceryl trinitrate to a finger produced significant dilation of superficial hand veins. Gently rubbing ice over these veins for one minute slightly reduced this dilation, whereas rubbing ice over veins without glyceryl trinitrate caused significant venoconstriction. These results indicate that application of glyceryl trinitrate followed by local cooling may provide a simple and painless means of assisting venepuncture.     

Glyceryl Trinitrate Ointment (0.25%) and Anal Cryothermal Dilators in the Treatment of Chronic Anal Fissures

Introduction  Chronic anal fissure is a common benign disorder; for this condition, lateral internal sphincterotomy is the “gold standard” of treatment. Alternative medical treatments have not proven to be as effective as left lateral internal sphincterotomy. Aim  This randomized trial was designed to compare the use of 0.25% glyceryl trinitrate ointment and anal cryothermal dilators with the use of 0.4% glyceryl trinitrate ointment alone in the treatment of chronic anal fissures. Methods  Between 1 June 2006 and 31 December 2007, 60 consecutive patients who were suffering from chronic anal fissures were randomized into two groups. The patients in group A (n = 30) were treated with 0.25% glyceryl trinitrate ointment and anal cryothermal dilators twice daily, and those in group B (n = 30) were treated with 0.4% glyceryl trinitrate ointment alone twice daily. The treatment was administered to the patients in each group for 6 weeks, and all patients were examined 7 weeks after the start of the trial. Results  Prior to treatment, the symptoms and the measurements of anal pressure were similar in both groups. At 7 weeks, the maximum resting pressure was significantly lower in group A (P < 0.05), in which 86.6% of the patients were asymptomatic in comparison with 73.3% of the patients in group B. After 1 year of follow-up, 25 patients (83.3%) in group A and 18 patients (60%) in group B presented no recurrence of symptoms (P < 0.05) Conclusions  Treatment of chronic anal fissures with 0.25% glyceryl trinitrate ointment and anal cryothermal dilators was more effective than the administration of 0.4% glyceryl trinitrate ointment alone.     

Overcoming perioperative spasm of the internal mammary artery: which is the best vasodilator?

After mobilization, vasospasm often reduces flow through the internal mammary artery. An established method of relaxing the artery and increasing flow is to wrap it in a papaverine-soaked swab. To our knowledge the ability of other topical vasodilators to overcome spasm of the internal mammary artery has not been studied clinically. In 50 patients in whom the left mammary artery was used for myocardial revascularization, we have investigated the effect of five agents on internal mammary artery free flow. The agents investigated were normal saline, papaverine, nifedipine, glyceryl trinitrate, and sodium nitroprusside. Under controlled hemodynamic conditions, free flow was measured before any pharmacologic intervention and a median of 18.5 minutes after the pedicle had been sprayed with one of the five agents. Normal saline produced a small increase in flow from a median of 23 ml/min (range 17 to 88) to 38 ml/min (20 to 84) (not significant), whereas a significant increase occurred with papaverine, from 25 (16 to 78) to 43 ml/min (34 to 112) (p less than 0.01). Nifedipine and glyceryl trinitrate raised free flow by almost threefold, from 23 (14 to 66) to 71 ml/min (45 to 118) and from 23 (14 to 58) to 62 ml/min (46 to 126), respectively (both p less than 0.001). Sodium nitroprusside, however, with an increase in flow from 26 (10 to 58) to 108 ml/min (46 to 196), 250% over control, proved to be more effective than nifedipine and glyceryl trinitrate (p less than 0.05). We therefore recommend the topical use of sodium nitroprusside to relieve perioperative spasm of the internal mammary artery.     

A randomised study comparing systemic transdermal treatment and local application of glyceryl trinitrate ointment in the management of chronic anal fissure.

OBJECTIVE: To compare a systemic transdermal therapeutic system with local application of glyceryl trinitrate ointment in the treatment of anal fissure. DESIGN: Prospective, multicentre, randomised trial. SETTING: Three teaching hospitals, Turkey. SUBJECTS: 89 outpatients with chronic anal fissure were randomly assigned to be treated with either transdermal (n = 52) or 0.2% glyceryl trinitrate ointment (n = 37). INTERVENTIONS: The patients were assessed at the sixth and the twelfth week after initial evaluation by physical examination, anoscopy, and anal manometry. MAIN OUTCOME MEASURES: Changes in the maximal anal resting pressure, healing rate. RESULTS: Anal fissure was completely healed in 38 (73%) and 24 (64%) of the patients after 6 weeks and 48 (81%) and 27 (79%) of the patients in transdermal group and ointment group, respectively. Maximal anal resting pressure was reduced by 24% and 21% in transdermal and ointment groups, respectively. CONCLUSION: Systemic transdermal application of glyceryl trinitrate gave a satisfactory healing rate, which was comparable to that of local application of ointment.     

Topical glyceryl trinitrate treatment of chronic noninsertional achilles tendinopathy. A randomized, double-blind, placebo-controlled trial

BACKGROUND: Noninsertional Achilles tendinopathy is a degenerative overuse disorder. No method has been universally successful in treating this condition. Topically applied nitric oxide has been shown, in animal models, to be effective for the treatment of fractures and cutaneous wounds through mechanisms that may include stimulation of collagen synthesis in fibroblasts. The goal of the present study was to determine if topical glyceryl trinitrate improves clinical outcome measures in patients with Achilles tendinopathy. METHODS: A prospective, randomized, double-blind, placebo-controlled trial involving a total of sixty-five patients (eighty-four Achilles tendons) was performed to compare continuous application of topical glyceryl trinitrate (at a dosage of 1.25 mg per twenty-four hours) with rehabilitation alone for the treatment of noninsertional Achilles tendinopathy. RESULTS: Compared with the control group, the glyceryl trinitrate group showed reduced pain with activity at twelve weeks (p = 0.02) and twenty-four weeks (p = 0.03), reduced night pain at twelve weeks (p = 0.04), reduced tenderness at twelve weeks (p = 0.02), decreased pain scores after the hop test at twenty-four weeks (p = 0.005), and increased ankle plantar flexor mean total work compared with the baseline level at twenty-four weeks (p = 0.04). Twenty-eight (78%) of thirty-six tendons in the glyceryl trinitrate group were asymptomatic with activities of daily living at six months, compared with twenty (49%) of forty-one tendons in the placebo group (p = 0.001, chi-square analysis). The mean effect size for all outcome measures was 0.14. CONCLUSIONS: Topical glyceryl trinitrate significantly reduced pain with activity and at night, improved functional measures, and improved outcomes in patients with Achilles tendinopathy.     

Use of sublingual glyceryl trinitrate as a supplement to volatile inhalational anaesthesia in a case of uterine inversion

We present a case of uterine inversion in which glyceryl trinitrate was used via the sublingual route, as opposed to the intravenous route, in association with volatile inhalational anaesthesia in order to achieve relaxation of the uterus. A transient, but significant, hypotensive response occurred, which was easily corrected with a colloid infusion and vasopressors. Sublingual glyceryl trinitrate is easily administered, has a fast onset of action and may have a role in situations where rapid relaxation of the uterus is required.     

Effect of topical vasodilators on gastroepiploic artery graft.

BACKGROUND: Mobilization of the gastroepiploic artery (GEA) often results in a vasospasm with reduction of early graft flow. In order to prevent or suppress this highly reactive artery's spasm, we have compared the effect of 4 vasodilators, used in external application to prepare the GEA graft, prior to myocardial revascularization. METHODS: WE performed a double-blind clinical study to compare the effects of external application of vasodilators on gastroepiploic artery grafts. Fifty patients, whose gastroepiploic artery was used for coronary artery bypass grafting, were randomized into 5 groups of 10 patients. Gastroepiploic artery free flow and hemodynamic measurements were evaluated immediately after harvesting, before any pharmacological manipulation, and 10 minutes after the topical application of vasodilators, respectively: papaverine, linsidomine, nicardipine, glyceryl trinitrate, and normal saline solution. RESULTS: A significant increase in free flow occurred in all groups except for the normal saline solution group with measurements from 26.1+/-3.6 mL/min to 26.4+/-6.5 mL/min; p = 0.9. The most important increase in flow before and after local application occurred with glyceryl trinitrate and papaverine: from 25.5+/-2 mL/min to 50+/-6.1 mL/min (p < or = 0.01) and from 36.8+/-3.2 mL/min to 62+/-7.8 mL/min (p < 0.01) respectively. Nicardipine and linsidomine produced a less significant increase in flow: from 33.1+/-3.6 mL/min to 47.7+/-8.9 mL/min (p < 0.05) and from 28+/-3.8 mL/min to 39.8+/-7.5 mL/min (p < 0.05) respectively. When comparing percentage of flow increase, glyceryl trinitrate appeared to be significantly more efficient than nicardipine and linsidomine (p < 0.01 versus both groups). Although papaverine was more efficient than nicardipine and linsidomine, it did not reach statistical significance. CONCLUSIONS: During intraoperative preparation of the GEA graft, glyceryl trinitrate and papaverine to a lesser extent, used as topical vasodilators, appear to be more efficient in external application to increase the free flow of the GEA.     

Topical glyceryl trinitrate and eutectic mixture of local anaesthetics in children A randomised controlled trial on choice of site and ease of venous cannulation

One hundred and four children aged between 1 and 11 years were studied in a double-blind randomised controlled trial of glyceryl trinitrate ointment versus placebo, when used in addition to standard eutectic mixture of local anaesthetics cream. Each child received glyceryl trinitrate ointment on one hand and placebo on the other, and thus acted as his/her own control. A group of 30 children who received only the eutectic mixture on both hands (60 measurements) was also studied. The choice of site and ease of cannulation was scored. Skin colour and venous dilatation under the eutectic mixture were scored on a visual analogue scale. The addition of topical glyceryl trinitrate ointment to the standard eutectic mixture positively affected venous dilatation (p less than 0.01), choice of cannulation site (p less than 0.001), and ease of cannulation (p less than 0.001) of topical anaesthetic-treated skin.     

Skin Blood Flow and Plasma Catecholamines during Removal of Pheochromocytoma

Background: Endothelium-derived hyperpolarizing factor is thought to be a cytochrome P450-derived arachidonic acid metabolite that hyperpolarizes vascular smooth muscle cells by opening Calcium2+ -activated Potassium sup + channels (K sup +Ca channels). In the rabbit carotid artery both volatile and intravenous anesthetics inhibit the acetylcholine-stimulated release of endothelium-derived hyperpolarizing factor. Because the release of this factor may help to maintain vascular tone in humans under conditions of a failing nitric oxide synthesis, e.g., in atherosclerosis, the effects of two intravenous anesthetics, thiopental and etomidate, on the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine were investigated in human isolated renal artery segments.

Methods: The segments were suspended in Krebs-Henseleit solution (37 degrees C) containing the cyclooxygenase inhibitor diclofenac (1 micro Meter) and preconstricted with norepinephrine (6 micro Meter). Relaxations caused by acetylcholine (1 micro Meter) were compared in the presence and absence of the nitric oxide synthase inhibitor NG -nitro-L-arginine (0.1 mM) in control segments and in segments exposed to etomidate or thiopental (0.03-0.3 mM). In addition, the effects of the two anesthetics on the relaxant response to the nitric oxide donors glyceryl trinitrate (3 micro Meter) and sodium nitroprusside (0.1 micro Meter) were examined.

Results: The relaxant response to acetylcholine, which was resistant to both nitric oxide synthase and cyclooxygenase blockade, was markedly reduced by the K sup +Ca channel antagonist tetrabutyl ammonium (3 mM) and the cytochrome P450 inhibitor clotrimazole (30 micro Meter). Both etomidate and thiopental, at a concentration of 0.3 mM, selectively attenuated the relaxant response to acetylcholine in NG -nitro-L-arginine-treated segments, but did not affect relaxations elicited by glyceryl trinitrate or sodium nitroprusside.