Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Isosorbide Dinitrate”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,351 records · Page 75Linked to original sources
PubMed1989

Nitrate tolerance in angina pectoris.

Tolerance to the hemodynamic and antianginal effects of the organic nitrates develops rapidly during therapy. This has been documented with a variety of nitrate preparations and with different routes of administration. Dosing strategies designed to provide therapeutic plasma nitrate concentrations throughout the 24 hours of the day are regularly associated with the development of tolerance. Recent information indicates that dosing schedules providing a nitrate-free period will permit continued efficacy of the organic nitrates without tolerance development. This can be accomplished in several ways. With oral preparations of isosorbide dinitrate, medication can be given 3 times daily, omitting the evening dose. Buccal nitroglycerin is usually given 3 times daily after meals, and this has been shown not to be associated with tolerance. Likewise, preliminary studies suggest that removal of the nitroglycerin patches for a period of several hours each day will prevent the development of tolerance. Much needs to be learned about the nitrate-free period. With oral isosorbide dinitrate, it appears that 12 hours is required, but this could be substantially less with nitroglycerin preparations. It is also possible that several short periods with low nitrate levels each day would suffice. Thus, simply increasing the interval between dosing of oral preparations may provide an adequate, low, nitrate-free period.

Angina Pectoris↗
PubMed1996

Rationale and design of the third vasodilator-heart failure trial (V-HeFT III): felodipine as adjunctive therapy to enalapril and loop diuretics with or without digoxin in chronic congestive heart failure. V-HeFT III investigators.

Therapy with angiotensin-converting enzyme inhibitors and nonselective vasodilators (hydralazine and isosorbide dinitrate) has become accepted treatment in patients with symptomatic, chronic congestive heart failure (CHF), and has been demonstrated in large clinical trials to ameliorate symptoms, improve exercise performance, and reduce cardiac mortality. Nevertheless, the management of patients with CHF remains a therapeutic challenge. The second Vasodilator-Heart Failure Trial (V-HeFT II) showed that the average 2-year mortality with enalapril (18%) was significantly lower than that with hydralazine-isosorbide dinitrate (25%) but, somewhat surprisingly, the nonspecific vasodilators produced significantly more improvement in exercise performance and left ventricular function. Such data suggest that improvement in symptoms, hemodynamics, and survival may not be afforded by the use of a single class of vasodilator therapy, but might be optimized by the combined use of different agents. This report describes the rationale and design of V-HeFT III, a multicenter, prospective, randomized, double-blind, placebo-controlled trial comparing the effects of chronic oral extended-release felodipine (felodipine ER) 2.5 to 5 mg twice daily, when added to a stable regimen of enalapril and loop diuretics, with or without digoxin, on exercise performance, morbidity, and mortality in patients with New York Heart Association functional class II to III CHF followed for a minimum of 12 weeks. Felodipine is a second-generation dihydropyridine calcium antagonist with a high degree of vascular selectivity which, in the doses used in this study, exerts its systemic arterial effect by decreasing peripheral vascular resistance without producing negative inotropic effects. The results of V-HeFT III may shed important light on the role of additive vasodilator therapy in the management of patients with CHF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Noninvasive techniques in clinical pharmacology. Time intervals in assessment of vasodilators in coronary artery disease.

We enrolled 15 male volunteers with angiographic evidence of coronary artery disease (CAD) to investigate the effects of sublingual administration, on different days, at random, of placebo and three drugs with different action such as isosorbide dinitrate, nifedipine and molsidomine. We recorded simultaneously electrocardiogram, phonocardiogram and carotid pulse at paper speed of 100 mm/s; blood pressure was measured by auscultatory method. We calculated the systolic time intervals (STI) being noninvasive indices of left ventricular function and the ratio of diastolic time to heart rate (%D), well related to coronary blood flow in patients with severe obstructive lesions. Placebo decreased heart rate (HR) without effects on STI or %D. Isosorbide dinitrate induced a prolonged pre-ejection period (PEP) (by decreasing preload), tachycardia and a significantly decreased %D, suggesting a fall in coronary blood flow time. Nifedipine decreased diastolic blood pressure and values of PEP (by decreasing afterload) without effects on %D. Finally, molsidomine prolonged PEP (by decreasing preload) without reflex induced tachycardia and changes of %D. In conclusion, mechanocardiography can be useful in noninvasive assessment of vasodilators in CAD patients.

Blood Pressure↗
PubMed1994

Inhibition of nitrovasodilators by pyocyanin and methylene blue is dissociated from nitric oxide formation.

The phenazine pigment pyocyanin (Pyo), like methylene blue (MB), inhibits vascular relaxation induced by organic nitrates. These nitrovasodilators are pro-drugs that have in common the ability to generate nitric oxide (NO). In this study, we characterized responses of rabbit isolated aortic ring to 3-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside, glyceryl trinitrate (GTN), and isosorbide dinitrate in the presence and absence of 10 microM Pyo. We also examined the effect of Pyo (1 and 10 microM) and MB (1 and 10 microM) on vasorelaxation induced by authentic NO, and finally we tested the effects of Pyo and MB on the tissue-independent formation of NO from SIN-1, SNAP, and sodium nitroprusside, using the chemiluminescence--headspace gas method. Pyo (10 microM) surmountably inhibited aortic responses to GTN, isosorbide dinitrate, SIN-1, and SNAP with a characteristic rightward shift of the dose-response curve; the apparent EC50 of these drugs for relaxation of phenylephrine-contracted aorta was increased 18-, 4-, 13-, and 15-fold, respectively. Pyo (1 and 10 microM) and MB (10 microM) inhibited NO-induced vasorelaxation at the EC50 of NO by 35, 72, and 56%. In contrast, Pyo did not inhibit sodium nitroprusside induced vasodilation. For a 10-min incubation, 10 microM Pyro or MB increased NO production from SNAP 1.8- and 2.9-fold, respectively, and increased NO production from SIN-1 by 3.8- and 7.1-fold, respectively. Neither Pyo nor MB enhanced NO formation from sodium nitroprusside. These data indicate that Pyo and MB inhibit nitrovasodilator-induced relaxation of aortic ring by interfering with the action of NO, subsequent to its formation.

Animals↗
PubMed1991

Haemodynamic monitoring. Problems, pitfalls and practical solutions.

The synthesis of adenosine triphosphate (ATP) depends on the coordinated interaction of oxygen delivery and glucose breakdown in the Krebs cycle. Cellular oxygen depots are non-existent, therefore the peripheral cells are totally dependent on the circulation for sufficient oxygen delivery. Shock is the clinical manifestation of cellular oxygen craving. The commonly measured variables--blood pressure, heart rate, urinary output, cardiac output and systemic vascular resistance--are not sensitive or accurate enough to warn of impending death in acutely ill patients nor are they appropriate for monitoring therapy. Calculated oxygen transport and oxygen consumption parameters provide the best available measures of functional adequacy of both circulation and metabolism. In order to optimise oxygen delivery (DO2), 4 interacting factors must be taken into account: cardiac output, blood haemoglobin content, haemoglobin oxygen saturation and avidity of oxygen binding to haemoglobin. For viscosity reasons, the optimal haemoglobin concentration is in the vicinity of 90 to 100 g/L, but for optimising the oxygen transport 100 to 115 g/L or a haematocrit of 30 to 35% seems better. The p50 (the pO2 at which haemoglobin is 50% saturated) describes the oxygen-haemoglobin dissociation curve; normally its value is +/- 27 mm Hg. It can be influenced by attaining normal body temperature, pH, pCO2 and serum phosphorous levels. In order to obtain an arterial blood saturation (SaO2) of more than 90% with acceptable haemodynamics, the ventilation mode and inspired oxygen fraction (FiO2) must be adapted; care must be taken not to stress the labile circulation with haemodynamic compromising ventilation techniques [e.g. high positive end expiratory pressure (PEEP) levels, inverse-ratio ventilation, etc.]. The factor most amenable to manipulation is the cardiac output, with its 4 determinants--preload, afterload, contractility and heart rate. In daily clinical practice, heart rate should be between 80 and 120 beats/min; small variations are acceptable. Important deviations must be treated by chemically [isoprenaline (isoproterenol)] or electrically (pacing techniques) accelerating the heart, or with the different antiarrhythmic drugs. A wide variety of agents is available to decrease the preload: diuretics [especially furosemide (frusemide)], venodilators like nitroglycerin (glyceryl trinitrate), isosorbide dinitrate (sorbide nitrate) and sodium nitroprusside, ACE inhibitors, phlebotomy, and haemofiltration techniques (peritoneal or haemodialysis, continuous arteriovenous haemofiltration). To increase the preload, volume loading using a rigid protocol ('rule of 7 and 3'), preferably with colloids, or vasopressor agents [norepinephrine (noradrenaline), epinephrine (adrenaline), dopamine] are useful. Arterial vasopressors are needed to improve perfusion pressure of 'critical' (coronary and cerebral) arteries. Afterload can be decreased by arterial vasodilators. Predominantly arterial dilators are hydralazine and clonidine, while sodium nitroprusside, nitroglycerin and isosorbide dinitrate have combined arterial and venous dilating actions.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Glucose↗
PubMed1993

Preliminary evidence for the mechanism underlying the development of tolerance to prazosin in congestive heart failure: the alpha-agonistic properties of dobutamine unmasked by prazosin treatment.

The hemodynamic effects of acute and chronic treatment with different vasodilators were assessed in patients with chronic heart failure of New York Heart Association (NYHA) class III-IV. Each of 24 patients was randomly allocated; 6 to each of four groups: isosorbide dinitrate, dihydralazine, captopril, or prazosin. In addition, we evaluated the hemodynamic response to dobutamine by using increasing infusion rates of 2.5, 5.0, and 10.0 micrograms/kg/min at the start and end of a 3-month period of chronic therapy with either vasodilator. Dobutamine caused a dose-dependent increase in cardiac index and a decrease in mean pulmonary artery pressure (PAP) at the start of the vasodilatory treatment and maintained the effects during a 3-month period of chronic treatment with either isosorbide dinitrate, dihydralazine, or captopril. After 3-month therapy with 6 mg/day prazosin, however, mean PAP was increased above pretreatment value and dobutamine caused a further increase in PAP, thus reversing the initial effects. The dobutamine-induced increase in cardiac index remained virtually unchanged. We conclude that the reversal of the effects on PAP after chronic treatment with prazosin may be, at least in part, due to upregulation of alpha 1-adrenoceptors. This appears to be unmasked by the alpha 1-adrenoceptor agonist of the (-)-enantiomer of the racemic mixture of (+/-)-dobutamine.

Adrenergic alpha-Agonists↗
PubMed1991

Inappropriate constriction of small coronary vessels as a possible cause of a positive exercise test early after successful coronary angioplasty.

BACKGROUND: The mechanism responsible for exercise-induced myocardial ischemia early after successful coronary angioplasty (PTCA) is poorly understood. METHODS AND RESULTS: Twelve patients who underwent one-vessel PTCA were studied. Exercise testing was performed before and on day 7 after PTCA, which was repeated after 10 mg sublingual isosorbide dinitrate if the test was positive. Quantitative coronary arteriography was also performed on day 8 after PTCA in the basal state, after intracoronary infusion of 0.9% saline, 1, 5, 10, and 20 micrograms ergonovine, and after 300 micrograms nitroglycerin. All patients had a positive exercise test before PTCA but on day 7, six patients had a positive exercise test (group 1) and six patients (group 2) had a negative exercise test. In group 1, all positive exercise tests on day 7 became negative when repeated after isosorbide dinitrate. Intracoronary ergonovine was associated with a dose-dependent constriction of the PTCA segment, a segment distal to it, and a control segment, with no significant difference in the magnitude of the response between the two groups; maximum constriction for group 1 was 19 +/- 3%, 23 +/- 2%, and 16 +/- 3% (p less than 0.001 versus basal), and in group 2 was 20 +/- 4%, 18 +/- 4%, and 9 +/- 2% (p less than 0.01 versus basal). No angina, ischemic ST segment changes, occlusive, or subocclusive spasm occurred in any patient of either group. CONCLUSIONS: We could find no evidence that exercise-induced myocardial ischemia early after PTCA is related to the presence of fixed angiographic restenosis or to dynamic constriction of any epicardial coronary segment. Therefore, inappropriate small coronary vessel constriction responsive to nitrates should be considered as a possible alternative explanation.

Adult↗
PubMedDate not supplied

Influences of cardiovascular drugs on leukotriene D4 action.

In anesthetized dogs, the effects of intracoronary leukotriene D4 (LTD4) (0.5 micrograms/kg) were studied on hemodynamics, the electrocardiogram (ECG) (lead II), flow in the left circumflex (LCX) coronary artery, and resistance in the absence or presence of intravenously administered cardiovascular drugs: nifedipine (10 micrograms/kg), nitroglycerin (5 micrograms/kg/min), isosorbide dinitrate (100 micrograms/kg), molsidomine (500 micrograms/kg), propranolol (500 micrograms/kg), and phentolamine (250 micrograms/kg). LTD4 increased left ventricular end-diastolic pressure (LVEDP) by 126% (p less than 0.01), the S-T segments of the ECG from 0.3 to 2.4 mV (p less than 0.001), and coronary resistance from 3.5 to 35.7 mm Hg X min X ml-1 (p less than 0.001). LCX blood flow fell from 33.8 to 3 ml/min (p less than 0.001), and LV dP/dtmax decreased by 51% (p less than 0.05). Nitroglycerin and isosorbide dinitrate were ineffective on cardiovascular LTD4 actions. Nifedipine and molsidomine inhibited the coronary flow reduction with LVEDP and S-T segment elevation by the LTD4 vasoconstriction. Negative inotropic LTD4 effects were counteracted by molsidomine. Phentolamine augmented the degree and duration of coronary constriction after LTD4. Propranolol weakened the coronary and circulatory eicosanoid actions. Indomethacin (5 mg/kg, i.v.) neither abolished the LTD4-caused hemodynamic and electrocardiographic consequences, nor attenuated beneficial nifedipine or molsidomine antagonism. Thus, it can be considered that nifedipine may inhibit the Ca2+ influx required for the effects of exogenously administered LTD4. LTD4 apparently does not act over cardiac alpha- or beta-receptor activation. Molsidomine effects on cardiohemodynamics with platelet and coronary vascular eicosanoid actions may protect the heart against LTD4 induced derangement.

Animals↗
PubMed1981

Acute and long-term effects of vasodilator therapy on resting and exercise hemodynamics and exercise tolerance.

The acute hemodynamic response to vasodilators in patients with chronic heart failure has been well characterized, but less is known about the long-term hemodynamic effects of vasodilator therapy. We measured hemodynamic variables at rest and during upright exercise in 11 patients during the initiation of therapy with oral hydralazine and sublingual isosorbide dinitrate and, in eight of these, after 3 months of continuous treatment. Marked initial increases in resting cardiac output and stroke volume and reductions in wedge pressure were sustained during chronic therapy. Similarly, the early improvement in exercise hemodynamic measurements persisted in most subjects. Exercise tolerance, quantified as the maximum duration of treadmill exercise, increased modestly (7.7 +/- 2.6 to 8.9 +/- 3.3 minutes, 0.05 less than p less than 0.10) after several days on vasodilators and further (10.2 +/- 3.7 minutes, p less than 0.01) during long-term treatment. The acute hemodynamic effects of vasodilator therapy at rest or during exercise did not correlate well with the changes in exercise tolerance. Our findings suggest that the combination of hydralazine and isosorbide dinitrate improves cardiac performance at rest and during exercise in patients with chronic heart failure and that this improvement persists during chronic therapy. In most patients, this hemodynamic improvement is accompanied by greater exercise tolerance.

Acute Disease↗
PubMed2004

Improvement of endothelium-dependent coronary vasodilation after a single LDL apheresis in patients with hypercholesterolemia.

The purpose of this study was to determine whether a single LDL apheresis would improve impaired endothelium-dependent dilation of the coronary artery in patients with hypercholesterolemia. Hypercholesterolemia is associated with impaired endothelial function, and human studies using cholesterol-lowering drugs indicate that endothelial function in the coronary arteries improves with reduction of serum LDL cholesterol over 6 to 12 months. The internal diameter of the left coronary artery and the coronary blood flow were measured by intracoronary Doppler-wire measurement and quantitative angiography before and immediately after a single LDL apheresis in a population of 15 patients with familial hypercholesterolemia. Endothelium-dependent vasodilation was assessed by intracoronary infusion of acetylcholine (1, 10, and 50 microg/min), and endothelium-independent vasodilation was assessed by intracoronary bolus infusion of isosorbide dinitrate (2.5 mg) or papaverine (10 mg). A single 3-hour LDL apheresis reduced serum LDL cholesterol by an average of 86.6 +/- 1.7%. After the LDL apheresis, the changes in the coronary artery diameter and coronary blood flow in response to an infusion of 50 microg/min of acetylcholine increased significantly compared to the pre-apheresis values (from -19.7 +/- 4.8 to -2.9 +/- 3.0% [P < 0.01] and from 80.7 +/- 27.6 to 155.3 +/- 23.5% [P < 0.01], respectively). The LDL apheresis did not significantly change the response of either parameter to infusion with isosorbide dinitrate or papaverine. The endothelial function of the epicardial coronary artery and the coronary microvasculature improved in hypercholesterolemic patients after only a single LDL apheresis, a procedure that markedly reduces the serum level of LDL cholesterol.

Acetylcholine↗
PubMed1979

Blood levels after sublingual nitroglycerin.

Pharmacokinetic analysis of nitroglycerin (GTN) has been hampered by the lack of a sensitive and specific method for measuring GTN in blood. Therefore, we examined the appearance of GTN in blood after administering 0.6 mg sublingually in 10 studies of normal volunteers. We used a gas-liquid chromatographic method with electron-capture detection and isosorbide dinitrate as the internal standard. GTN appeared in blood at 0.5 minutes, reached a peak of 2.3 +/- 0.36 ng/ml at 2 minutes, fell to 50% of peak value at 7.5 minutes and was barely detectable at 20 minutes. These blood levels paralleled the changes in heart rate and systolic blood pressure. These data show rapid appearance and disappearance of GTN from blood after sublingual administration, a large volume of distribution, and a rapid rate of total body clearance that precludes the liver from being the sole elimination site. This method for analysis of GTN and isosorbide dinitrate should be helpful in defining the role of chronic nitrate therapy.

Adult↗
PubMed2000

Calf and forearm blood flow in hypercholesterolemic patients.

Patients with hypercholesterolemia without vascular disease have an impaired endothelium-dependent (nitric oxide-mediated) vasodilation in coronary and peripheral vascular beds. This study was designed to establish whether hypercholesterolemia (and its reduction) affects also the microcirculation vasomotion during postischemic hyperemia in both calf and forearm. Thirteen male patients, aged 36.2+/-8.5 years, mean +/-SD, with heterozygous familial hypercholesterolemia and 10 male control subjects, aged 32.2+/-3.6 years free from vascular lesions were studied. Plasma lipids, hematologic parameters, and limb vasoreactivity were evaluated while the patients were treated only with diet and during therapy with simvastatin. Calf and forearm blood flows were determined by venous occlusion strain gauge plethysmography at rest, during reactive hyperemia, and after sublingual isosorbide dinitrate administration. Calf resting flow rate of the hypercholesterolemic patients during and without treatment was similar to that of the controls. Calf resting vascular resistance was greater in the untreated hypercholesterolemic subjects than in the normal controls, but during treatment this difference was abolished. Peak flow during reactive hyperemia and flow debt repayment were lower in the untreated hypercholesterolemic subjects as compared to the controls, but they were normalized following hypocholesterolemic therapy. No differences were observed in forearm blood flow measurements between hypercholesterolemic subjects (without and during therapy) and control subjects. The blood flow and vascular resistance after isosorbide dinitrate were modified in a similar manner in the hypercholesterolemic (without and during therapy) and control subjects at both calf and forearm. Hypercholesterolemia does not affect vasodilation in the forearm as determined by postocclusive reactive hyperemia, while in the calf hypercholesterolemia is associated with higher resting vascular resistance, lower peak flow during reactive hyperemia, and lower flow debt repayment. These abnormalities are corrected by the hypocholesterolemic treatment.

Adult↗
PubMed2002

Nicorandil and leukocyte activation.

Nicorandil, a hybrid compound of an ATP-sensitive potassium (KATP ) channel opener and a nitric oxide donor, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. The aim of the current study was to test the hypothesis that nicorandil suppresses activation of polymorphonuclear leukocytes (PMNLs), resulting in reduction of PMNL migration into tissue upon ischemia/reperfusion. Nicorandil, along with the mitochondrial KATP channel opener diazoxide and the nitric oxide donors nitroglycerin and isosorbide dinitrate, suppressed pseudopod projection in human PMNLs treated with 10(-9)-formyl-methionyl-leucyl-phenylalanine (FMLP) and subjected to shear stress (5 dyn/cm(2)) with a cone-and-plate shear device. Suppression by nicorandil and diazoxide was reversed by KATP channel blockers, 5 hydroxydecanoate and glibenclamide. FMLP-induced increase of [Ca2+] in PMNLs was suppressed by nicorandil and diazoxide, and 5 hydroxy-decanoate and glibenclamide reversed this suppression. Results of reverse transcription polymerase chain reaction with rat PMNL mRNA indicated the presence of mRNAs of Kir6.2 and Kir6.1 but not mRNAs of sulfonylurea receptor 1 or 2. Isosorbide dinitrate, diazoxide, and nicorandil reduced leukocyte migration and microvascular obstruction in reperfused ischemic tissue of rat mesenteric microcirculation. In conclusion, nicorandil attenuates ischemia/reperfusion-induced PMNL activation via donation of nitric oxide and K channel-related cascade.

Animals↗
PubMed1988

Direct comparison of the effects of nitroprusside, SIN 1, and various nitrates on platelet aggregation and soluble guanylate cyclase activity.

We have directly compared the effects of the nitrates isosorbide-5-mononitrate, nitroglycerin and isosorbide dinitrate and of the nitric oxide-containing sodium nitroprusside and 3-morpholino-sydnonimine (SIN 1) as well as of the bioinactive precursor of SIN 1, molsidomine, on platelet activating factor-induced platelet aggregation and activation of soluble guanylate cyclase. The effects of these agents on the aggregation and on soluble guanylate cyclase activity of human platelets were closely correlated. Whereas nitroprusside and SIN 1 were very potent inhibitors of aggregation and activators of soluble guanylate cyclase in micromolar concentrations, the other drugs were effective only at millimolar concentrations. Preincubation of platelets with cysteine did not or only slightly increase the ability of isosorbide-5'-mononitrate and isosorbide dinitrate to inhibit aggregation, but a clear increase was observed after preincubation with nitroglycerin. These data support the concept that cyclic GMP is the mediator of nitric oxide-induced inhibition of platelet aggregation and indicate that nitrates cannot directly inhibit aggregation or be converted to nitric oxide-containing agents by a specific mechanism in platelets. The data also suggest that SIN 1 and nitroprusside, but not or only to a certain degree the nitrates, can be considered as exogenous endothelium-derived relaxing factors.

Adult↗
PubMed1983

[Evaluation of a new percutaneous nitroglycerin preparation in effort angina].

In 10 subjects with constant threshold effort angina ascertained by two bicycle exercise tests, the efficacy of a new transdermal preparation of nitroglycerin (104 mg) applied once daily was evaluated and compared to that of oral long-acting isosorbide dinitrate (20 mg every 8 hours). The two drugs were administered according to a complete crossover plan. The effectiveness of each drug was evaluated by testing the patients before treatment, on the third and on the twenty-first hour of treatment. In each case the exercise was continued until electrocardiographic signs of ischemia appeared. The total work during treatment with transdermal nitroglycerin was significantly higher (average increase greater than 44%) than without the drug (1311 +/- 545 Kgm before treatment, 2145 +/- 968 Kgm at the third hour, 1899 +/- 657 Kgm at the twenty-first hour of treatment). Similar results were obtained during treatment with isosorbide dinitrate (1332 +/- 581 Kgm before treatment, 1837 +/- 526 at the third hour, 1869 +/- 570 at the twenty-first hour of treatment; average work increase greater than 37%). In conclusion, with this new transdermal preparation of nitroglycerin an increased work-load can be achieved before ischemia appears. Its beneficial action remains constant for 21 hours.

Adult↗
PubMed2003

S-nitrosothiol detection in isolated perfused rat heart.

Nitrogen monoxide (NO) has important cardiovascular actions, and it has been suggested that they may be partly mediated by the reaction with protein sulfhydryl groups to produce S-nitrosothiols. In this work we describe and test a method that allows S-nitrosothiol detection in crude membrane preparations obtained from isolated perfused rat hearts. Isolated rat hearts were perfused under control conditions or in the presence of the NO donors SIN-1 and isosorbide dinitrate. Additional hearts were subjected to 10-20 min of ischemia followed or not by 10-20 min of reperfusion. At the end of perfusion a crude membrane fraction was prepared, and S-nitrosothiol concentration was assayed fluorometrically, on the basis of 2,3-naphthotriazole production from 2,3-diaminonaphthylene. The sensitivity of the method, as evaluated using S-nitrosoalbumin, was on the order of 1-2 pmol/mg of protein. S-nitrosothiols were undetectable under control conditions, as well as after ischemia or ischemia-reperfusion. On the other hand, significant S-nitrosothiol formation was observed after infusion of SIN-1 or isosorbide dinitrate (26.4 +/- 7.4 and 19.9 +/- 5.6 pmol per mg of protein, respectively). In conclusion, S-nitrosothiol production was observed in rat heart membranes after exposure to NO donors, while S-nitrosothiol concentration was below the sensitivity limits of the assay either under baseline conditions or after acute ischemia and reperfusion.

Animals↗
PubMed1993

Hemoglobin inhibits endothelium-dependent relaxation to acetylcholine in human coronary arteries in vivo.

BACKGROUND: The endothelium can regulate vascular tone by releasing both endothelium-derived relaxing factor (EDRF or nitric oxide) and contracting factors. To date, there has only been circumstantial evidence to indicate EDRF activity in vivo in human coronary arteries. Using human hemoglobin as a specific inhibitor, the hypothesis that acetylcholine-induced coronary vasodilation is due to EDRF release was tested. METHODS AND RESULTS: We studied the response of normal coronary arteries to acetylcholine (an endothelium-dependent vasodilator) and isosorbide dinitrate (an endothelium-independent vasodilator) in seven patients. The specificity of any vasodilator response was assessed by the infusion of reduced free human hemoglobin. Hemoglobin 10(-5) M infusion alone had no effect on coronary artery diameter. Drugs were infused into the coronary artery, and the diameter changes were assessed by quantitative angiography. Acetylcholine 10(-7) M increased left anterior descending coronary artery diameter from control: 2.30 +/- 0.12 mm to 2.79 +/- 0.20 mm (mean +/- SEM, n = 7, p < 0.01). Hemoglobin both in a concentration of 10(-6) M and 10(-5) M reversed this vasodilator effect, causing constriction to 2.11 +/- 0.18 mm (p < 0.001 compared with acetylcholine 10(-7) M) and 2.29 +/- 0.14 mm (p < 0.05 compared with acetylcholine 10(-7) M). Isosorbide dinitrate in the presence of hemoglobin caused dilatation of the coronary artery in all cases to 3.04 +/- 0.24 mm (p < 0.001 compared with acetylcholine 10(-7) M and hemoglobin 10(-6) M). CONCLUSIONS: Using a specific inhibitor of nitric oxide, reduced free hemoglobin, we have demonstrated that basal EDRF release does not appear to play an important role in the maintenance of human epicardial coronary artery diameter in vivo but is responsible for the acetylcholine-induced dilatation.

Acetylcholine↗
PubMed1996

Variable coronary vasomotor responses to acetylcholine in patients with normal coronary arteriograms: evidence for localised endothelial dysfunction.

OBJECTIVE: The vasomotor responses of the epicardial coronary arteries to acetylcholine were examined in patients with normal coronary arteries and chest pain. DESIGN: Quantitative angiography was used to measure minimum lumen diameter of proximal and distal coronary artery segments at baseline, during intracoronary infusion of acetylcholine (10(-7) - 10(-3) mol/l), and following an intracoronary bolus (2 mg) of isosorbide dinitrate. PATIENTS: Coronary arteriograms were obtained in 15 patients (mean (SEM) age 48 (10) years) with normal coronary arteries and chest pain. MAIN RESULTS: In response to the low concentrations of acetylcholine (10(-7) - 10(-6) mol/1) 20 (61%) distal and 11 (41%) proximal segments showed dilatation (group 1), whereas 13 (39%) distal segments and 14 (52%) proximal segments showed constriction (group 2) (P < 0.05 v group 1). In group 1, the maximum dilatation induced by acetylcholine in the proximal and distal segments was 7.83 (1.19)% and 11.6 (2.2)% respectively. In group 2, the maximum constriction at higher concentration was 16.55 (3.3)% and 33.11 (11.63)% in the proximal and distal segments respectively. The two different patterns of the vasomotor response coexisted in eight (53%) of the 15 patients. Intracoronary isosorbide dinitrate caused a greater increase in the coronary luminal diameter of distal segments than in proximal segments in group 1 (25.63 (5.16)% v 12.43 (3.48)%, P < 0.01) but not in group 2 (12.65 (2.53)% v 10.82 (3.33)%. CONCLUSIONS: Constriction and dilatation may occur in proximal and distal coronary artery segments, suggesting local areas of endothelial dysfunction, in response to acetylcholine in patients with chest pain and angiographically normal coronary arteries.

Acetylcholine↗