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Endothelium-derived hyperpolarizing factor (EDHF) was envisaged as a chemical entity causing vasodilation by hyperpolarizing vascular smooth muscle (VSM) cells and distinct from nitric oxide (NO) ([aka endothelium-derived relaxing factor (EDRF)]) and prostacyclin. The search for an identity for EDHF unraveled the complexity of signaling within small arteries. Hyperpolarization originates within endothelial cells (ECs), spreading to the VSM by 2 branches, 1 chemical and 1 electrical, with the relative contribution varying with artery location, branch order, and prevailing profile of VSM activation. Chemical signals vary likewise and can involve potassium ion, lipid mediators, and hydrogen peroxide, whereas electrical signaling depends on physical contacts formed by homocellular and heterocellular (myoendothelial; MEJ) gap junctions, both able to conduct hyperpolarizing current. The discovery that chemical and electrical signals each arise within ECs resulted in an evolution of the single EDHF concept into the more inclusive, EDH signaling. Recognition of the importance of MEJs and particularly the fact they can support bidirectional signaling also informed the discovery that Ca2+ signals can pass from VSM to ECs during vasoconstriction. This signaling activates negative feedback mediated by NO and EDH forming a myoendothelial feedback circuit, which may also be responsible for basal or constitutive release of NO and EDH activity. The MEJs are housed in endothelial projections, and another spin-off from investigating EDH signaling was the discovery these fine structures contain clusters of signaling proteins to regulate both hyperpolarization and NO release. So, these tiny membrane bridges serve as a signaling superhighway or infobahn, which controls vasoreactivity by responding to signals flowing back and forth between the endothelium and VSM. By allowing bidirectional signaling, MEJs enable sinusoidal vasomotion, co-ordinated cycles of widespread vasoconstriction/vasodilation that optimize time-averaged blood flow. Cardiovascular disease disrupts EC signaling and as a result vasomotion changes to vasospasm.

Arterial wall viscosity (AWV) is a major cause of energy dissipation along the arterial tree. Its determinants remain controversial but an active endothelial regulation has been suggested. Our objective was to assess in humans the physiological role of endothelium-derived nitric oxide (NO), epoxyeicosatrienoic acids and the effect of modulating smooth muscle tone in the regulation of AWV. We simultaneously measured radial artery diameter, wall thickness, and arterial pressure in healthy volunteers during the local infusion of inhibitors of NO-synthase ( N G -monomethyl- l -arginine), epoxyeicosatrienoic acids synthesis by cytochrome P450 (fluconazole), the epoxyeicosatrienoic acids cellular targets calcium-activated potassium channels (tetraethylammonium), alone and in combination. AWV was estimated from the relative viscosity expressed as the ratio of the area of the hysteresis loop of the pressure–diameter relationship to the area under the loading phase. Arterial tone was assessed by measuring change in wall stiffness and midwall stress. N G -monomethyl- l -arginine paradoxically reduced relative viscosity (34.9±8.9%–28.9±8.6%). Conversely, relative viscosity was not modified by fluconazole (33.5±15.5%–32.0±13.6%) but increased by tetraethylammonium (31.7±6.6%–35.7±8.0%). This increase was more marked with N G -monomethyl- l -arginine+fluconazole (31.1±10.7%–43.3±13.2%) and N G -monomethyl- l -arginine+tetraethylammonium (29.5±2.3%–41.5±11.1%) compared with inhibitors alone. Sodium nitroprusside decreased AWV (35.4±2.9%–28.7±2.0%). These effects were associated with parallel change in tone but of different magnitude for similar variations in viscosity, suggesting tone-dependent and independent mechanisms. In conclusion, this is the first demonstration that the endothelial factors, NO and epoxyeicosatrienoic acids, regulate AWV in humans and support the role of arterial tone in this regulation. Clinical Trial Registration— URL: https://eudract.ema.europa.eu . Unique identifier: RCB2007-A001-10-53.

Ischemia-reperfusion injury forms the basis of tissue damage and cellular apoptosis in many pathologic and traumatic processes. The tissue damage follows a natural progression of cellular and metabolic events initiated by an ischemic episode. Ischemia causes intracellular/extracellular changes principally resulting in increased intracellular calcium, pH changes, and adenosine triphosphate depletion that end in cell death if the process is not interrupted. This interruption takes the form of reperfusion, characterized by a "flushing" of tissues with toxic metabolites, principally reactive oxygen species. The immediate effect is mitochondrial pore permeability, complement activation, cytochrome release, cytokine activation, inflammation, edema, neutrophil platelet adhesion, capillary plugging, and thrombosis. This sets the stage for the long recognized "no-reflow" phenomenon and progressive tissue death. Current recognition of cellular "cross-talk" and molecular events have introduced new logical strategies to sequentially combat the events occurring in relation to ischemia-reperfusion injury. These include mechanical preconditioning and pharmacological preconditioning and postconditioning strategies. It is likely that success in reversing or limiting tissue damage will be found in a sequential multitargeted approach using a combination of these strategies-clinical trials in this regard are sorely needed.

Evidence from our laboratory and others suggests a negative effect for cyclosporine A (CSA) on renovascular reactivity. This study investigated the role of peroxisome proliferator-activated receptor gamma (PPAR gamma)/nitric oxide synthase (NOS) signaling in the CSA-induced attenuation of endothelium-dependent vasodilations in phenylephrine-preconstricted perfused kidneys of rats. Bolus injection of carbachol (4 micromoL) reduced the renal perfusion pressure with a peak depressor effect observed at 2 minutes. CSA (5 microM) infusion significantly attenuated the vasodilatory action of carbachol. The specificity of this interaction was verified by the lack of effect of CSA on renal vasodilation caused by papaverine (50 nmol). The carbachol-induced renal vasodilations were also reduced after infusion of N-nitro-L-arginine methyl ester (L-NAME, NOS inhibitor, 100 microM) or 2-chloro-5-nitro-N-phenylbenzamide (GW9662, PPAR gamma antagonist, 1 microM). The attenuation of carbachol vasodilation by CSA was abolished in presence of L-arginine or L-NAME in contrast to no effect for GW9662. Pioglitazone (PPAR gamma agonist, 10 microM) abolished the CSA-induced attenuation of carbachol responses, an effect that was not manifest in presence of GW9662 or l-NAME. These findings suggest that PPAR gamma act tonically to facilitate renovascular dilatory response to endothelial muscarinic receptor activation. More importantly, NOS signaling downstream of PPAR gamma mediates, at least partly, the inhibitory effect of CSA on carbachol vasodilations.

Background— The aim of this study was to compare the impact of transradial catheterization with hydrophilic-coated catheter sheaths versus uncoated sheaths on NO-mediated endothelial-dependent and -independent vasodilator function. Methods and Results— Thirty-five subjects undergoing transradial catheterization were recruited and assessed before and the day after catheterization. A subgroup was also assessed 3 to 4 months after catheterization. Subjects received hydrophilic-coated sheaths (n=15) or uncoated sheaths (n=20). Radial artery flow-mediated dilatation and endothelium- and NO-dependent arterial dilatation were assessed within the region of sheath placement. Glyceryl trinitrate endothelium-independent NO-mediated function was also assessed. The noncatheterized arm provided an internal control. Flow-mediated dilatation in the catheterized arm decreased from 10.3�3.8% to 5.3�3.3% and 8.1�2.4% to 5.2�3.7% in the coated and uncoated groups, respectively ( P P P P P Conclusions— Placement of a catheter sheath inside the radial artery disrupts vasodilator function, which recovers after 3 months. No differences were evident between hydrophilic-coated and uncoated sheaths.

Pharmacologic strategies to reduce pulmonary vascular tone and to treat pulmonary hypertension originally aimed to enrich vascular smooth muscle cyclic adenosine monophosphate levels. Alternatively, increasing cyclic guanosine monophosphate (cGMP) also reduces pulmonary vascular tone. Inhaled nitric oxide is extremely efficacious in increasing cGMP and selectively reducing mean pulmonary arterial pressure in pediatric cardiac patients. It is considered standard treatment in most centers. However, not all patients respond to inhaled nitric oxide and withdrawal is sometimes problematic. This has prompted investigation of alternative methods to increase intracellular vascular smooth muscle cGMP. Phosphodiesterase type 5 is particularly abundant in the lung vasculature of patients with severe pulmonary hypertension. Its inhibition with the sildenafil class of drugs is now commonplace. Drugs that affect cGMP metabolism in children with acute pulmonary hypertension are the subject of this review and consensus statement. Oral sildenafil is recommended in postoperative pulmonary hypertension after failed withdrawal of inhaled NO (class I, level of evidence B). The effectiveness of prolonged treatment with sildenafil in documented postoperative pulmonary hypertension is not well established (class IIb, level of evidence C). Sildenafil is indicated in idiopathic pulmonary hypertension, although data have been extrapolated mainly from adult trial (class I, level of evidence A, extrapolated). Recently, completed pediatric trials have seemed to support this recommendation. Longer-acting and intravenous forms of phosphodiesterase type 5 inhibitors, brain natriuretic peptides, and direct soluble guanylate cyclise activators all have appeal, but there is insufficient experience in children with acute pulmonary hypertensive disorders for recommendations on treatment.

Background— Arterial hypertension is one of the major diseases in industrial countries and a major cause of mortality. One of the main vascular factors responsible for the relaxation of blood vessels and regulation of blood pressure is nitric oxide (NO). NO acts predominantly via NO-sensitive guanylyl cyclase (NO-GC), which is made up of 2 different subunits (α and β). Deletion of the β 1 subunit leads to a global NO-GC knockout, and these mice are hypertensive. However, global deletion of NO-GC in mice does not allow identification of the cell/tissue type responsible for the elevated blood pressure. Methods and Results— To determine the relative contribution of smooth muscle cells to the hypertension seen in NO-GC knockout mice, we generated smooth muscle–specific knockout mice for the β 1 subunit of NO-GC using a tamoxifen-inducible system. Male mice were investigated because the Cre transgene used is located on the Y chromosome. Tamoxifen injection led to a rapid reduction of NO-GC expression in smooth muscle but did not affect that in other tissues. Parallel to a reduction in NO-induced cGMP accumulation, NO-induced relaxation of aortic smooth muscle was gradually lost after induction by tamoxifen. Concomitantly, these animals developed hypertension within 3 to 4 weeks. Conclusions— We generated a model in which the development of hypertension can be visualized over time by deletion of a single gene in smooth muscle cells. In sum, our data provide evidence that deletion of NO-GC solely in smooth muscle is sufficient to cause hypertension.

Rationale: The cardiac inwardly rectifying K + current ( I K1 ) plays a critical role in modulating excitability by setting the resting membrane potential and shaping phase 3 of the cardiac action potential. Objective: This study aims to analyze the effects of nitric oxide (NO) on human atrial I K1 and on Kir2.1 channels, the major isoform of inwardly rectifying channels present in the human heart. Methods and Results: Currents were recorded in enzymatically isolated myocytes and in transiently transfected CHO cells, respectively. NO at myocardial physiological concentrations (25 to 500 nmol/L) increased inward and outward I K1 and I Kir2.1 . These effects were accompanied by hyperpolarization of the resting membrane potential and a shortening of the duration of phase 3 of the human atrial action potential. The I Kir2.1 increase was attributable to an increase in the open probability of the channel. Site-directed mutagenesis analysis demonstrated that NO effects were mediated by the selective S -nitrosylation of Kir2.1 Cys76 residue. Single ion monitoring experiments performed by liquid chromatography/tandem mass spectrometry suggested that the primary sequence that surrounds Cys76 determines its selective S -nitrosylation. Chronic atrial fibrillation, which produces a decrease in NO bioavailability, decreased the S -nitrosylation of Kir2.1 channels in human atrial samples as demonstrated by a biotin-switch assay, followed by Western blot. Conclusions: The results demonstrated that, under physiological conditions, NO regulates human cardiac I K1 through a redox-related process.

Female mice are protected from the cerebrovascular dysfunction induced by angiotensin II (Ang II), an effect attributed to estrogen. We examined whether such cerebrovascular protection from Ang II is related to the estrous cycle. Cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6 female mice equipped with a cranial window. The phase of the estrous cycle was determined by vaginal smear cytology and plasma estrogen measurement. Ang II (0.25 μg/kg per minute, IV, 30 to 45 minutes) elevated arterial pressure (15 to 20 mm Hg) equally across the estrous cycle. However, in proestrus and estrus, phases in which estrogen is relatively high, Ang II did not impair the increase in the cerebral blood flow induced by neural activity or by endothelium-dependent vasodilators ( P >0.05 from vehicle). In contrast, in diestrus (lower estrogen), Ang II induced a marked cerebrovascular dysfunction comparable to that of male mice. For example, the cerebral blood flow responses to whisker stimulation and to the endothelium-dependent vasodilator acetylcholine were attenuated by 41±12% and 49±12%, respectively ( P P P >0.05 from control). Topical treatment with ICI182,780 reestablished Ang II–induced oxidative stress in proestrus ( P >0.05 from diestrus). We conclude that the protection from the neurovascular dysfunction induced by acute administration of Ang II in females depends on the estrous cycle and may underlie the increased propensity to cerebrovascular damage associated with low estrogen states.

Cardiovascular events are accelerated in chronic kidney disease (CKD). Although deranged nitric oxide (NO) pathways and asymmetric dimethylarginine (ADMA) cause endothelial dysfunction, no direct evidence for coronary artery endothelial dysfunction in CKD has been documented. CKD was induced in male dogs by heminephrectomy (1/2Nx) or five-sixths nephrectomy (5/6Nx). After 4 wk, renal ablation reduced GFR (control 76 [54 to 85]; 1/2Nx 38 [29 to 47]; 5/6Nx 15 [12 to 46] ml/min) and elevated plasma ADMA (control 1.88 [1.68 to 2.54]; 1/2Nx 2.51 [2.11 to 3.55]; 5/6Nx 3.84 [2.16 to 3.95] micromol/L). Coronary circulatory responses to acetylcholine revealed marked increases in coronary blood flow in control group (83 +/- 17% increment) but blunted responses in 1/2Nx (34 +/- 8% increment) and 5/6Nx (20 +/- 4% increment). The acetylcholine-induced changes in epicardial arteriolar diameter, using needle-lens probe charge-coupled device videomicroscopy, showed similar results. The responsiveness to sodium nitroprusside did not differ among three groups. Plasma nitrite/nitrate levels decreased in 1/2Nx and 5/6Nx, and the mRNA expressions of dimethylarginine dimethylaminohydrolase-II (DDAH-II), ADMA-degrading enzyme, and endothelial NO synthase (eNOS) in coronary arteries were downregulated in 1/2Nx and 5/6Nx. Finally, 4-wk treatment with all-trans retinoic acid restored the impaired endothelium-dependent vasodilation and reversed the expression of eNOS but not DDAH-II. Coronary endothelial function is impaired in the early stage of CKD. The dysfunction is attributed to the downregulation of eNOS and/or DDAH-II in coronary arteries. Furthermore, the manipulation of NO pathways may constitute a therapeutic strategy for the prevention of coronary dysfunction in CKD.

Pulmonary arterial hypertension (PAH) is a rare and debilitating disease characterized by abnormal proliferation and contraction of pulmonary vascular smooth muscle cells. The resulting increase in pressure and pulmonary vascular resistance results in progressive right heart failure, low cardiac output, and ultimately death if left untreated. PAH is defined by a persistent elevation in pulmonary artery pressure with normal left-sided pressures, differentiating it from left-sided heart disease. Symptoms progress from shortness of breath and decreasing exercise tolerance to right heart failure, with peripheral edema and marked functional limitation. Exercise-induced syncope, worsening symptoms at rest, and intractable right heart failure indicate critical disease. PAH may be idiopathic with no identifiable cause or associated with collagen vascular diseases, drugs, HIV, liver disease, and/or congenital heart disease. Familial or genetically mediated PAH accounts for a small percentage of cases. Advances in the understanding of pathobiological pathways that contribute to vascular proliferation and remodeling have resulted in new therapies that improve quality of life and survival. Emerging therapies focus on the nitric oxide, prostacyclin, and endothelin pathways. Nursing interventions are critical to ensure patients' success with these expensive and complex treatments and their optimal adjustment to living with PAH.

The ability of oxyhemoglobin to inhibit nitric oxide (NO)-dependent activation of soluble guanylate cyclase and vasodilation provided some of the earliest experimental evidence that NO was the endothelium-derived relaxing factor (EDRF). The chemical behavior of this dioxygenation reaction, producing nearly diffusion limited and irreversible NO scavenging, presents a major paradox in vascular biology: The proximity of large amounts of oxyhemoglobin (10 mmol/L) to the endothelium should severely limit paracrine NO diffusion from endothelium to smooth muscle. However, several physical factors are now known to mitigate NO scavenging by red blood cell encapsulated hemoglobin. These include diffusional boundaries around the erythrocyte and a red blood cell free zone along the endothelium in laminar flowing blood, which reduce reaction rates between NO and red cell hemoglobin by 100- to 600-fold. Beyond these mechanisms that reduce NO scavenging by hemoglobin within the red cell, 2 additional mechanisms have been proposed suggesting that NO can be stored in the red blood cell either as nitrite or as an S-nitrosothiol (S-nitroso-hemoglobin). The latter controversial hypothesis contends that NO is stabilized, transported, and delivered by intra-molecular NO group transfers between the heme iron and β-93 cysteine to form S-nitroso-hemoglobin (SNO-Hb), followed by hypoxia-dependent delivery of the S-nitrosothiol in a process that links regional oxygen deficits with S-nitrosothiol–mediated vasodilation. Although this model has generated a field of research examining the potential endocrine properties of intravascular NO molecules, including S-nitrosothiols, nitrite, and nitrated lipids, a number of mechanistic elements of the theory have been challenged. Recent data from several groups suggest that the nitrite anion (NO 2 − ) may represent the major intravascular NO storage molecule whose transduction to NO is made possible through an allosterically controlled nitrite reductase reaction with the heme moiety of hemoglobin. As subsequently understood, the hypoxic generation of NO from nitrite is likely to prove important in many aspects of physiology, pathophysiology, and therapeutics.

Bradykinin causes arterial relaxation and hyperpolarization, which is mediated by a transferable endothelium-derived hyperpolarizing factor (EDHF). In coronary arteries, epoxyeicosatrienoic acids (EETs) are involved in the EDHF response. However, the role of EETs as transferable mediators of EDHF-dependent relaxation remains poorly defined. Two small bovine coronary arteries were cannulated and perfused in tandem in the presence of the nitric oxide synthase inhibitor, nitro- l -arginine (30 μmol/L), and the cyclooxygenase inhibitor, indomethacin (10 μmol/L). Luminal perfusate from donor arteries with intact endothelium perfused endothelium-denuded detector arteries. Detector arteries were constricted with U46619 and diameters were monitored. Bradykinin (10 nmol/L) added to detector arteries did not induce dilation (5±2%), whereas bradykinin addition to donor arteries dilated detector arteries by 26.5±7% ( P

Background— Endothelium-dependent dilatation is mediated by 3 principal vasodilators: nitric oxide (NO), prostacyclin (PGI 2 ), and endothelium-derived hyperpolarizing factor (EDHF). To determine the relative contribution of these factors in endothelium-dependent relaxation, we have generated mice in which the enzymes required for endothelial NO and PGI 2 production, endothelial NO synthase (eNOS) and cyclooxygenase-1 (COX-1), respectively, have been disrupted (eNOS −/− and COX-1 −/− mice). Methods and Results— In female mice, the absence of eNOS and COX-1 had no effect on mean arterial blood pressure (BP), whereas BP was significantly elevated in eNOS −/− /COX-1 −/− males compared with wild-type controls. Additionally, endothelium-dependent relaxation remained intact in the resistance vessels of female mice and was associated with vascular smooth muscle hyperpolarization; however, these responses were profoundly suppressed in arteries of male eNOS −/− /COX-1 −/− animals. Similarly, the endothelium-dependent vasodilator bradykinin produced dose-dependent hypotension in female eNOS −/− /COX-1 −/− animals in vivo but had no effect on BP in male mice. Conclusions— These studies indicate that EDHF is the predominant endothelium-derived relaxing factor in female mice, whereas NO and PGI 2 are the predominant mediators in male mice. Moreover, the gender-specific prevalence of EDHF appears to underlie the protection of female eNOS −/− /COX-1 −/− mice against hypertension.

Endothelial dysfunction occurs early in atherosclerosis in response to cardiovascular risk factors. The occurrence of endothelial dysfunction is primarily the result of reduced nitric oxide (NO) bioavailabilty. It represents an independent predictor of cardiovascular events and predicts the prognosis of the patient. Therefore, endothelial function has been identified as a target for therapeutic intervention. Regular exercise training is a nonpharmacological option to improve endothelial dysfunction in patients with cardiovascular disease by increasing NO bioavailability.

OBJECTIVES: To determine the effects of inhaled nitric oxide on endogenous cyclic adenosine monophosphate in the intact lamb, and to determine the potential role of cyclic adenosine monophosphate in the rebound pulmonary hypertension associated with nitric oxide withdrawal. DESIGN: Prospective, placebo-controlled experimental study. SETTING: University-based basic science research laboratory. SUBJECTS: One-month-old lambs. INTERVENTIONS: Six 1-month-old control lambs, and 6 milrinone- (phosphodiesterase-3 inhibitor) treated lambs, were mechanically ventilated. Inhaled nitric oxide (40 ppm) was administered for 24 hrs and then acutely withdrawn. Sequential peripheral lung biopsies were obtained before, during, and 2 hrs after withdrawing inhaled nitric oxide therapy. MEASUREMENTS AND MAIN RESULTS: In control lambs, initiation of nitric oxide decreased left pulmonary vascular resistance by 29.6%, and withdrawal rapidly increased pulmonary vascular resistance by 77.1% (p

Aim: The diagnosis and treatment of Hirschsprung disease are well standardized. Symptoms of obstruction after surgery for Hirschsprung disease may result from residual spasticity of the internal anal sphincter. Nitric oxide (NO) is the chemical messenger mediating relaxation of the internal anal sphincter and its exogenous application results in a relaxation response in smooth muscle. The purpose of this study was to investigate topical NO application for obstructive symptoms after surgery for Hirschsprung disease and to correlate the symptoms with manometric findings with a view to directing further management. Materials and Methods: The authors reviewed application of topical NO on six symptomatic children who were operated for Hirschsprung disease. Eighteen patients older than 3 years of age were evaluated for anorectal manometric, functional and clinical outcome. The symptoms included enterocolitis in three patients and constipation in three patients. NO ointment was applied twice daily for 6 weeks in symptomatic patients and manometry was repeated. Results: Anorectal manometric evaluation of six patients showed high internal anal sphincter tone without reflex relaxation on applying distending pressure to the rectum. Marked improvement of symptoms was noted after 6-week application of topical NO and maximal internal anal resting pressure decreased significantly (35% reduction). After ceasing application of topical ointment, increased maximal anal resting pressure was seen again. Conclusion: Although anal sphincter hypertonicity is not thought to be the only cause of post-operative obstructive symptoms, relaxation of the internal anal sphincter may improve the symptoms. Topical NO can be used for treatment of obstructive symptoms in Hirschsprung disease. We managed our symptomatic patients successfully with local NO application with a reversible chemical sphincterotomy. NO could be used as a therapeutic modality.

Vasoactive factors produced and released by endothelium exert a powerful influence on vascular tone in the cerebral circulation. Endothelium-derived relaxing factor (EDRF), which has been identified as nitric oxide (NO) or an NO-containing compound, is produced under basal conditions in cerebral blood vessels. EDRF mediates endothelium-dependent relaxation in response to a number of stimuli in the cerebral circulation. The influence of NO on the cerebral circulation appears to be particularly important and complex because both neurons and glia, in addition to endothelium, produce NO in response to some stimuli. Neuronally derived NO may mediate local vasodilation in response to increased neuronal activity. In addition to EDRF, cerebral endothelium may produce other relaxing factors, including prostacyclin, endothelium-derived hyperpolarizing factor, and oxygen-derived free radicals. Several pathophysiological conditions are associated with impaired endothelium-dependent responses that may involve the decreased production of EDRF and release of endothelium-derived contracting factors, such as the cyclooxygenase products of arachidonic acid and endothelin. The release of endothelin, an extremely potent and long-lasting vasoconstrictor peptide, may contribute to vasospasm after subarachnoid hemorrhage.

EDRF (endothelium-derived relaxing factor) is a cellular and intercellular messenger that activates soluble guanylate cyclase. In blood vessels it is released from the endothelium and causes relaxation of vascular smooth muscle. Halothane previously has been shown to attenuate EDRF-induced vasodilation elicited by the receptor-mediated vasodilators acetylcholine and bradykinin and to alter muscarinic receptor activity. We examined and compared the effects of the inhaled anesthetics halothane, enflurane, and isoflurane on endothelium-dependent vasodilation and tested the hypothesis that these agents inhibit EDRF-mediated vasodilation solely through inhibition of endothelial cell receptor-mediated EDRF release. Isolated rat thoracic aortic rings were mounted for isometric tension recording and preconstricted with phenylephrine. Cumulative dose-response curves were obtained to methacholine, a receptor-mediated endothelium-dependent dilator; to A23187, a nonreceptor-mediated endothelium-dependent dilator; and to sodium nitroprusside, a direct-acting endothelium-independent dilator before, during, and after inhalational anesthetic exposure. Both receptor-mediated and non-receptor-mediated endothelium-dependent relaxation by methacholine and A23187, respectively, were significantly (P less than 0.01 to P less than 0.05) and reversibly attenuated by halothane, enflurane, and isoflurane at 2 MAC and by isoflurane at 1 MAC. Endothelium-independent relaxation by sodium nitroprusside, an agent that acts directly on the vascular smooth muscle cell to activate guanylate cyclase, was unaffected by any of the anesthetics at any concentration tested. Indomethacin had no significant effect on the inhibition of endothelium-dependent vasodilation by these inhalational anesthetics. We conclude that halothane, enflurane, and isoflurane inhibit endothelium-dependent vasodilation; that isoflurane is more potent than halothane and enflurane in this regard.(ABSTRACT TRUNCATED AT 250 WORDS)