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Biomedical subjects

J F Keaney

Publications and source records attributed to J F Keaney.

At least 73 records · Page 4Linked to original sources
PubMed1996

Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease.

BACKGROUND: In the setting of atherosclerosis, endothelial vasomotor function is abnormal. Increased oxidative stress has been implicated as one potential mechanism for this observation. We therefore hypothesized that an antioxidant, ascorbic acid, would improve endothelium-dependent arterial dilation in patients with coronary artery disease. METHODS AND RESULTS: Brachial artery endothelium-dependent dilation in response to hyperemia was assessed by high-resolution vascular ultrasound before and 2 hours after oral administration of either 2 g ascorbic acid or placebo in a total of 46 patients with documented coronary artery disease. Plasma ascorbic acid concentration increased 2.5-fold 2 hours after treatment (46+/-8 to 114+/-11 micromol/L, P=.001). In the prospectively defined group of patients with an abnormal baseline response (<5% dilation), ascorbic acid produced marked improvement in dilation (2.0+/-0.6% to 9.7+/-2.0%), whereas placebo had no effect (1.1+/-1.5% to 1.7+/-1.5%, P=.003 for ascorbic acid versus placebo). Ascorbic acid had no effect on hyperemic flow or arterial dilation to sublingual nitroglycerin. CONCLUSIONS: Ascorbic acid reverses endothelial vasomotor dysfunction in the brachial circulation of patients with coronary artery disease. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in patients with atherosclerosis and that endothelial dysfunction may respond to antioxidant therapy.

Adult↗
PubMed1996

The lack of effect of beta-carotene on restenosis in cholesterol-fed rabbits.

The success of percutaneous transluminal coronary angioplasty is limited by restenosis in 30-50% of cases. Cellular production of reactive oxygen species at the site of injury has been implicated as a contributing factor in the process of restenosis. beta-Carotene is a lipid-soluble antioxidant whose effects on this process have not been previously investigated. We attempted to elucidate whether beta-carotene treatment was capable of reducing restenosis. Femoral artery stenoses were produced by nitrogen-desiccation in rabbits fed a high-cholesterol diet. The animals were randomized to receive either a parenteral bolus of beta-carotene immediately prior to angioplasty, followed by 5 days of subcutaneous treatment (Acute Treatment); 5 days of subcutaneous pretreatment with beta-carotene followed by a parenteral bolus immediately prior to angioplasty and then another 5 days of subcutaneous treatment (Pretreatment); or vehicle only (Control). Angiography was performed immediately before and after angioplasty, and 28 days after angioplasty. The animals were then sacrificed, and the femoral arteries were harvested for histopathology. By quantitative angiography, the late loss of luminal diameter between angioplasty and final angiography was not significantly different between the acute treatment group, the pretreatment group and the control group. By histopathology, the area of intimal hyperplasia and the percent cross-sectional area stenosis were also not significantly different. The late loss in luminal diameter after angioplasty correlated significantly with the acute gain in luminal diameter produced by angioplasty. The amount of intimal hyperplasia correlated significantly with the arterial injury score assessed by histopathology. In summary, in this animal model of restenosis, parenteral beta-carotene failed to significantly reduce the amount of either intimal hyperplasia or late loss in luminal diameter after angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1996

Vasodilatory properties of recombinant maxadilan.

Maxadilan is a peptide from the salivary gland of the sand fly Lutzomyia longipalpis, a vector for leishmaniasis. Cutaneous injection of femtomolar quantities of maxadilan produces long-lasting erythema, making it the most potent vasodilator known. Isolated rabbit thoracic and abdominal aorta, carotid artery, and iliac artery demonstrated dose-dependent arterial relaxation in response to maxadilan with a mean effective concentration (EC50) of 2.7 +/- 1.5, 2.1 +/- 0.5, 2.6 +/- 0.4, and 1.9 +/- 0.5 nM, respectively. Maxadilan proved to be at least sevenfold more potent than nitroglycerin in each arterial bed (EC50 = 25 +/- 12, 32 +/- 9, 37 +/- 10, and 22 +/- 13 nM, respectively; P < 0.05 for each vs. maxadilan). Arterial relaxation to maxadilan was independent of endothelium and was equipotent in the thoracic and abdominal aorta, carotid artery, and iliac artery. Arterial relaxation to maxadilan was not inhibited by K(+)-channel antagonists, methylene blue, quinacrine, or ouabain. Maxadilan-mediated arterial relaxation was found to be adenosine 3',5'-cyclic monophosphate (cAMP) dependent, as it was potentiated by the phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine and theophylline, and it was inhibited by the protein kinase A inhibitor H-89. Consistent with this observation, incubation of thoracic aorta with maxadilan (0.1 microM) produced a time-dependent increase in arterial cAMP content coincident with arterial relaxation. Using rabbit aortic smooth muscle cells, we also observed a time-dependent reduction in intracellular calcium in response to maxadilan. Thus these data indicate that maxadilan, a peptide from the sand fly salivary gland, is a potent vasodilator that reduces intracellular calcium through a cAMP-dependent mechanism.

Animals↗
PubMed1996

Inhibition of nitric oxide synthase augments myocardial contractile responses to beta-adrenergic stimulation.

Recent in vitro evidence suggests a role for nitric oxide (NO) in the modulation of myocardial contractility. The specific role of NO in the control of cardiac function in vivo, however, remains unclear. We investigated the effect of NO synthase (NOS) inhibition on myocardial contractility in response to beta-adrenergic stimulation in autonomically blocked dogs. Intracoronary infusions of dobutamine (1-50 micrograms/min) and isoproterenol (0.1 and 0.5 microgram/min) were performed before and after the intracoronary administration of the specific NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Intracoronary dobutamine resulted in a dose-dependent increase in peak first derivative of pressure (dP/dtmax) to a maximum of 195 +/- 10% (P < 0.001). After inhibition of NOS with intracoronary L-NAME at rates of 0.1 and 1 mg/min, the response to dobutamine was significantly enhanced with dP/dtmax, increasing 276 +/- 17 and 317 +/- 26%, respectively (P < 0.001). Intracoronary isoproterenol resulted in a maximum increase in dP/dtmax of 116 +/- 15% (P < 0.001) that further increased to 154 +/- 17 and 157 +/- 18% after NOS inhibition with 0.1 and 1 mg/min L-NAME, respectively (both P < 0.002). L-NAME had no effect on baseline dP/dtmax but did produce a reduction in myocardial guanosine 3',5'-cyclic monophosphate content. These results suggest a role for NO in the control of myocardial contractility in response to beta-adrenergic stimulation in vivo.

Adrenergic beta-Agonists↗
PubMed1996

Animal studies on antioxidants.

The wealth of existing epidemiologic evidence suggests that antioxidant intake limits the clinical expression of coronary artery disease. Because the oxidative modification of low-density lipoprotein is an important event in atherogenesis, it has been attractive to speculate that antioxidants act by limiting low-density lipoprotein orientation and, as a consequence, atherosclerotic lesion development. Early studies on animals also suggested that a number of structurally distinct antioxidant compounds could limit the extent of lesion development in animal models of atherosclerosis. More recently, however, secure evidence linking the antioxidant protection of low-density lipoprotein with a reduction in atherosclerosis has been elusive. This discrepancy may be explained by emerging evidence demonstrating that antioxidants may prove beneficial through tissue-specific effects that are not strictly related to the antioxidant protection of low-density lipoprotein.

Animals↗
PubMed1995

Role of nitric oxide in parasympathetic modulation of beta-adrenergic myocardial contractility in normal dogs.

In vitro studies indicate that muscarinic cholinergic inhibition of beta-adrenergic cardiac responses may be modulated in part by nitric oxide (NO). To evaluate the role of NO in parasympathetic inhibition of the beta-adrenergic contractile response in vivo, we assessed the inotropic response to dobutamine before and during bilateral vagus nerve stimulation in closed-chest dogs. Dobutamine administration and vagal stimulation were repeated during intracoronary infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 10 mumol/min) and again following infusion of L-arginine (100 mg/kg). In eight dogs, intracoronary dobutamine infusion at rates of 25 and 50 micrograms/min increased peak +dP/dt by 131 +/- 24 and 168 +/- 22%, respectively (P < 0.0001). Vagal stimulation (2.5 Hz) attenuated the responses to dobutamine (25 and 50 micrograms/min) by 23 +/- 4 and 21 +/- 4%, respectively (P < 0.001). L-NMMA reduced (by 44-62%; P < 0.001) and L-arginine restored vagal inhibition of the dobutamine-stimulated inotropic response. In a second group of nine dogs, dobutamine was administered systemically to assure a constant concentration in the coronary circulation. Vagal stimulation (2.5 Hz) attenuated the dobutamine-stimulated inotropic response (2.5 and 5.0 micrograms/kg per min) by 40 +/- 12% and 57 +/- 8%, respectively (P < 0.004). As with intracoronary dobutamine, L-NMMA diminished and L-arginine restored vagal inhibition of the inotropic response to dobutamine. Intracoronary infusion of atropine (12 micrograms/min) abolished the vagal inhibitory effect, and intracoronary infusion of 8-bromo-cyclic GMP (1 and 10 mM) caused a dose-dependent attenuation of the dobutamine-stimulated increase in +dP/dt. These data suggest that NO mediates, at least in part, vagal inhibition of the inotropic response to beta-adrenergic stimulation by dobutamine, and thus may play a role in normal physiologic regulation of myocardial autonomic responses.

Amino Acid Oxidoreductases↗
PubMed1995

Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation.

Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.

Animals↗
PubMed1995

Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide.

Endothelium-derived relaxing factor is important for vascular homeostasis and possesses qualities that may modulate vascular injury, including vasodilation, platelet inhibition, and inhibition of smooth muscle proliferation. S-nitrososerum albumin is a naturally occurring adduct of nitric oxide (NO) with a prolonged biologic half-life and is a potent vasodilator and platelet inhibitor. Given the avidity of serum albumin for subendothelial matrix and the antiproliferative effects of NO, we investigated the effects of locally delivered S-nitroso-bovine serum albumin (S-NO-BSA) and a polythiolated form of bovine serum albumin (pS-BSA) modified to carry several S-nitrosothiol groups (pS-NO-BSA) on neointimal responses in an animal model of vascular injury. Locally delivered S-NO-BSA bound preferentially to denuded rabbit femoral vessels producing a 26-fold increase in local concentration compared with uninjured vessels (P = 0.029). pS-NO-BSA significantly reduced the intimal/medial ratio (P = 0.038) and did so in conjunction with elevations in platelet (P < 0.001) and vascular cGMP content (P < or = 0.001). pS-NO-BSA treatment also inhibited platelet deposition (P = 0.031) after denuding injury. Comparison of BSA, S-NO-BSA, pS-NO-BSA, and control revealed a dose-response relationship between the amount of displaceable NO delivered and the extent of inhibition of neointimal proliferation at 2 wk (P < or = 0.001). Local administration of a stable protein S-nitrosothiol inhibits intimal proliferation and platelet deposition after vascular arterial balloon injury. This strategy for the local delivery of a long-lived NO adduct has potential for preventing restenosis after angioplasty.

1-Methyl-3-isobutylxanthine↗
PubMed1994

17 beta-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine.

BACKGROUND: Cardiovascular events are less prevalent in premenopausal women and women receiving estrogen replacement than in postmenopausal women or men. Endothelium-derived relaxing factor (EDRF) is an important local modulator of vascular tone, and abnormal endothelial function is related, in part, to the oxidative modification of low-density lipoprotein (LDL). Estrogens possess substantial antioxidant activity and inhibit LDL modification in vitro. METHODS AND RESULTS: We investigated the effects of 17 beta-estradiol (E2) on endothelial vasomotor function in cholesterol-fed miniature swine. Animals underwent ovariectomy or a sham procedure and received E2 or placebo via implant yielding three groups: sham, ovariectomy (E2 placebo), and implant (E2 implant). After 16 weeks, coronary arteries were harvested and endothelial function was examined in vitro. Vessels from the sham and implant groups demonstrated preserved endothelium-dependent relaxation to bradykinin, substance P, and A23187. Vessels from the ovariectomy group exhibited impaired relaxation to bradykinin and substance P (P < .05 versus sham and implant groups) but not to A23187. Plasma E2 levels were strongly correlated with the response to bradykinin (R = .82, P < .001), substance P (R = .64, P < .01), and A23187 (R = .65, P < .01). Compared with the ovariectomy group, LDL derived from the sham and implant groups was markedly resistant to ex vivo oxidation (P < .05), and this effect correlated with preserved endothelium-dependent relaxation to bradykinin (R = .62, P < .03) and substance P (R = .61, P < .03). CONCLUSIONS: Thus, E2 preserves endothelial function in cholesterol-fed swine in association with protection of LDL against oxidative modification. These data suggest that E2 may, in part, favorably affect vascular function and coronary artery disease by virtue of its antioxidant properties.

Animals↗
PubMed1994

Methylene blue reverses endotoxin-induced hypotension.

Hypotension in septic shock is a reflection of unregulated nitric oxide (NO) production and vascular smooth muscle guanylyl cyclase activation. We examined the effect of methylene blue on lipopolysaccharide (LPS)-induced shock in anesthetized rabbits. Shock was induced with 150 micrograms/kg LPS after measurement of mean arterial pressure, platelet cGMP, and total plasma NO (nitrogen monoxide+S-nitrosothiol) content. Measurements were repeated before and after the intravenous administration of 1, 5, and 10 mg/kg methylene blue in response to a 55% reduction in mean arterial pressure. At baseline, mean +/- SEM arterial pressure was 88 +/- 3 mm Hg, which fell to 51 +/- 3 mm Hg after LPS (P < .05). Methylene blue at doses of 1, 5, and 10 mg/kg produced a prompt dose-dependent increase in mean arterial pressure to 69 +/- 2, 77 +/- 3, and 81 +/- 2 mm Hg, respectively (P < .05 versus mean arterial pressure after LPS) in association with normalization of plasma total NO content (P < .05); however, methylene blue did not significantly affect intraplatelet cGMP levels. Thus, methylene blue restores normal arterial pressure in rabbits with septic shock. This effect is associated with persistent elevation of intraplatelet cGMP levels and normalization of total plasma NO content. These data are consistent with methylene blue-mediated inhibition of NO synthase and/or degradation of NO in this model and suggest a novel therapeutic approach to the treatment of septic shock.

Animals↗
PubMed1994

Low-dose alpha-tocopherol improves and high-dose alpha-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits.

Abnormalities in endothelium-dependent arterial relaxation develop early in atherosclerosis and may, in part, result from the effects of modified low-density lipoprotein (LDL) on agonist-mediated endothelium-derived relaxing factor (EDRF) release and EDRF degradation. alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in human plasma and lipoproteins, therefore, we investigated the effects of AT on endothelium-dependent arterial relaxation in male New Zealand White rabbits fed diets containing (a) no additive (controls), (b) 1% cholesterol (cholesterol group), or 1% cholesterol with either (c) 1,000 IU/kg chow AT (low-dose AT group) or (d) 10,000 IU/kg chow AT (high-dose AT group). After 28 d, we assayed endothelial function and LDL susceptibility to ex vivo copper-mediated oxidation. Acetylcholine-and A23187-mediated endothelium-dependent relaxations were significantly impaired in the cholesterol group (P < 0.001 vs. control), but preserved in the low-dose AT group (P = NS vs. control). Compared to the control and cholesterol groups, vessels from the high-dose AT group demonstrated profound impairment of arterial relaxation (P < 0.05) and significantly more intimal proliferation than other groups (P < 0.05). In normal vessels, alpha-tocopherol had no effect on endothelial function. LDL derived from both the high- and low-dose AT groups was more resistant to oxidation than LDL from control animals (P < 0.05). These data indicate that modest dietary treatment with AT preserves endothelial vasodilator function in cholesterol-fed rabbits while a higher dose of AT is associated with endothelial dysfunction and enhanced intimal proliferation despite continued LDL resistance to ex vivo copper-mediated oxidation.

Acetylcholine↗
PubMed1994

In vivo transfer of nitric oxide between a plasma protein-bound reservoir and low molecular weight thiols.

Plasma albumin reacts with nitric oxide (NO) to form the bioactive adduct, S-nitroso-albumin (S-NO-albumin). The limited intracellular access of S-NO-albumin suggests the need for a vascular transfer mechanism of NO from a large plasma S-NO-albumin pool to effect biologic function. To study the role of low molecular weight (LMW) thiols in NO transfer in vivo, we administered intravenous S-NO-albumin (1-300 nmol/kg) to rabbits before and after an intravenous infusion of L-cysteine or N-acetyl-L-cysteine. S-NO-albumin produced dose-dependent hypotension that was significantly augmented by prior infusion of either LMW thiol. LMW thiol infusion significantly accelerated the rate of onset and reduced the duration of action of the hypotension induced by S-NO-albumin. The hemodynamic effects of S-NO-albumin after pretreatment with LMW thiols were mimicked by administration of the corresponding LMW S-nitrosothiol. The transfer of NO from albumin to L-cysteine was directly measured in rabbit plasma using a novel technique that couples high performance liquid chromatography to electrochemical detection. These data demonstrate that NO exchange between plasma protein thiol-bound NO and available LMW thiol pools (transnitrosation) occurs in vivo.

Acetylcysteine↗
PubMed1993

Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits.

Recent evidence suggests that dietary therapy with lipid-soluble antioxidants may be beneficial for patients with atherosclerotic vascular disease but the potential mechanism(s) for these observations remain obscure. Abnormalities in endothelium-dependent control of vascular tone develop early in the course of atherosclerosis and may result from oxidative modification of low density lipoproteins. We examined the role of dietary antioxidants in preserving normal endothelial cell vasodilator function in cholesterol-fed rabbits with particular attention to possible effects on serum lipoproteins, low density lipoprotein oxidation, and atherogenesis. Male New Zealand White rabbits were fed diets containing no additive (controls), 1% cholesterol (cholesterol group), or 1% cholesterol chow supplemented with either beta-carotene (0.6 g/kg of chow) or alpha-tocopherol (1000 international units/kg of chow) for a 28-day period. After dietary therapy, thoracic aortae were harvested for assay of vascular function and for pathologic examination and tissue antioxidant levels. Compared to controls, acetylcholine- and A23187-mediated endothelium-dependent relaxations were significantly impaired in vessels from the cholesterol group (P < 0.001), whereas vessels from animals treated with beta-carotene or alpha-tocopherol demonstrated normal endothelium-dependent arterial relaxation. Preservation of endothelial function was associated with vascular incorporation of alpha-tocopherol and beta-carotene but was unrelated to plasma lipoprotein levels, smooth muscle cell function, or the extent of atherosclerosis. Increased low density lipoprotein resistance to ex vivo copper-mediated oxidation was observed only in the alpha-tocopherol group. Our results suggest that dietary antioxidants may benefit patients with atherosclerosis by preserving endothelial vasodilator function through a mechanism related to vascular tissue antioxidant content and not reflected by assay of low density lipoprotein resistance to ex vivo oxidation.

Acetylcholine↗
PubMed1993

Coronary artery perforation during excimer laser coronary angioplasty. The percutaneous Excimer Laser Coronary Angioplasty Registry.

OBJECTIVES: The aim of this study was to analyze the risk of vessel perforation during excimer laser angioplasty. BACKGROUND: Vessel perforation is a serious complication of angioplasty. METHODS: A total of 764 patients had 858 stenoses treated with excimer laser angioplasty. Laser catheters had a diameter of 1.4, 1.7 or 2 mm. Laser energy was delivered in pulses of 135 ns, at a frequency of 25 s-1 and at a fluence of 30 to 60 mJ/mm2. Follow-up angiography was requested for all patients who did not require emergency bypass surgery. RESULTS: In the 764 consecutive patients treated with excimer laser coronary angioplasty, vessel perforation occurred in 23 patients (3%). Nine patients had a major complication resulting directly from vessel perforation (cardiac tamponade, myocardial infarction or need for bypass surgery) and 14 had no clinical complications after successful sealing of the puncture site. No patient with a perforation died. Multivariate analysis showed that bifurcation lesions (odds ratio [OR] = 3.5; p = 0.049), diabetes mellitus (OR = 3.15; p = 0.029) and female gender (OR = 2.86; p = 0.013) were associated with an increased risk of vessel perforation. Lesions > 10 mm in length (OR = 0.45; p = 0.206), calcified stenoses (OR = 0.26; p = 0.088) and saphenous vein graft lesions (OR = 0.50; p = 0.295) were not at increased risk. Vessel perforation was seen in 10 (8.3%) of 120 lesions in which the laser catheter was equivalent in diameter to the target vessel (< or = 0.5 mm smaller in size) but in only 8 (1.5%) of 525 lesions in which the laser catheter was > 1 mm smaller than the target vessel (p = 0.001). CONCLUSIONS: Most lesions thought to be suitable for excimer laser treatment are not at increased risk of perforation. The complication may be avoided by improved patient and laser catheter size selection.

Adult↗
PubMed1993

Antiplatelet properties of protein S-nitrosothiols derived from nitric oxide and endothelium-derived relaxing factor.

S-nitrosothiols may serve as carriers in the mechanism of action of endothelium-derived relaxing factor (EDRF) by stabilizing the labile nitric oxide (NO) radical from inactivation by reactive species in the physiological milieu and by delivering NO to the heme activator site of guanylyl cyclase. Low-molecular-weight thiols, such as cysteine and glutathione, form S-nitrosothiol adducts with vasodilatory and antiplatelet properties, and protein thiols can interact in the presence of NO and/or EDRF to form uniquely stable S-nitroso-proteins. We now show that the S-nitroso-proteins, S-nitroso-albumin, S-nitroso-tissue type plasminogen activator, and S-nitroso-cathepsin B, have potent antiplatelet effects with an IC50 of approximately 1.5 microM. In the dog, S-nitroso-albumin inhibits ex vivo platelet aggregation and significantly prolongs the template bleeding time from 2.15 +/- 0.13 (mean +/- SEM) to 9.70 +/- 1.24 minutes. The antiplatelet action of S-nitroso-proteins is associated with the stimulation of guanylyl cyclase and a significant decrease in fibrinogen binding to platelets. S-Nitroso-proteins undergo thiol-nitrosothiol exchange with low-molecular-weight thiols to form low-molecular-weight S-nitroso-thiols, and they also interact directly with the platelet surface, both of which processes facilitate generation of NO. These data suggest that S-nitroso-proteins are potent antiplatelet agents and may be intermediates in the antiplatelet mechanism of EDRF action.

Adenosine Diphosphate↗
PubMed1993

NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties.

Recent evidence suggests that sulfhydryl species can react with oxides of nitrogen under physiologic conditions and thereby stabilize endothelium-derived relaxing factor (EDRF) activity, but the presence of a specific in vivo thiol carrier for nitric oxide (NO) remains controversial. The single free sulfhydryl of serum albumin is the most abundant thiol species in plasma (approximately 0.5 mM) and is particularly reactive towards NO. To examine the potential role of serum albumin in endogenous nitric oxide metabolism, we synthesized S-nitroso-BSA (S-NO-BSA), a model S-nitroso-protein, and examined its effects on platelet function and coronary and systemic vascular tone in 16 mongrel dogs. Intravenous bolus S-NO-BSA markedly reduced mean arterial pressure in a dose-dependent manner and proved seven and a half-fold less potent than intravenous nitroglycerin and 10-fold less potent than intravenous S-nitroso-cysteine (half-maximal response of 75 nmol/kg compared to 10 and 7.5 nmol/kg, respectively; P < 0.05); when given by intravenous infusion (half-maximal response = 10 nmol/kg per min), however, S-NO-BSA and nitroglycerin were equipotent. Intravenous bolus S-NO-BSA had a greater duration of action than either nitroglycerin or S-nitroso-cysteine and produced marked prolongation of the template bleeding time associated with dose-dependent inhibition of ex vivo platelet aggregation (half-maximal response approximately 70 nmol/kg). Intracoronary S-NO-BSA increased coronary blood flow (mean +/- SEM) less effectively than nitroprusside, acetylcholine, or S-nitroso-cysteine (165% +/- 24% vs. 315% +/- 82%, 483% +/- 55%, or 475% +/- 66%, respectively; P < 0.05) although with much longer duration of action. On a molar basis, S-nitroso-cysteine proved more effective than S-nitroso-BSA, nitroprusside, or acetylcholine as an epicardial coronary vasodilator. Thus, serum albumin reacts with oxides of nitrogen to form a stable S-nitroso-thiol with properties reminiscent of authentic EDRF supporting the view that protein associated thiol may participate in the action and metabolism of EDRF.

Acetylcholine↗