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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↗
PubMed2005

Composition analysis of two batches of polysorbate 60 using MS and NMR techniques.

Batch variation in Tween 60 has shown to influence the rheological properties of semisolid emulsions. MS (LC-MS, GC-MS, MS(n)) and NMR ((13)C, (1)H, (1)H COSY and HMBC) techniques were used to analyze and compare the composition of two batches of Tween 60 with particular emphasis on the number of POE groups and their distribution within the molecule. Acid and saponification values were also determined. The batches contained different proportions of components (sorbitan polyethoxylates, sorbitan monoester-diester-polyethoxylates and isosorbide monoester-diester-polyethoxylates). The number of POE groups were averaged over the four sites in sorbitan and the two sites in isosorbide molecules. The batches differed from each other in terms of (i) the POE sorbitan stearate/POE sorbitan palmitate ratios (batch 1, 3:2 and batch 2, 4:5), (ii) the ratio of sorbitans to isosorbides (batch 1, 2:3; batch 2, 7:13); and (iii) the acid values (batch 1, 3.1; batch 2, 0). It is concluded that liquid chromatography combined with electrospray mass spectrometry and ion trap separation is a useful tool for establishing the compositional profile of different batches of Tweens. (1)H NMR could provide a simple and rapid pharmacopoeial test for the ratio of sorbitan to isosorbide in Tweens.

Chromatography, High Pressure Liquid↗
PubMed2004

Cerebral cortical abnormalities seen in a non-human primate model of prenatal cocaine exposure are not related to vasoconstriction.

In our previous studies [J. Comp. Neurol. 435 (2001) 263] we demonstrated that rhesus monkeys born to mothers receiving cocaine orally during the period of pregnancy when neurons destined for the cerebral neocortex were generated displayed inappropriate positioning of neocortical neurons, loss of normal neocortical lamination, and reduction in neocortical volume, density and total number of neocortical neurons. In the present paper, we examined whether these cytoarchitectural abnormalities were related to the relatively high blood levels of the cocaine metabolite, benzoylecgonine, associated with oral cocaine administration. We also evaluated the role of vasoconstriction of the uteroumbilical and fetal brain vessels in the generation of these abnormalities. For these purposes, we compared cerebral neocortical cytoarchitecture in 2-month-old monkeys from five groups of mothers: (1). a drug-naïve group, (2). a cocaine-treated group, (3). a group treated with benzoylecgonine at doses producing higher blood levels of this metabolite and stronger vasoconstriction that those in the cocaine-treated group, (4). a group treated with cocaine plus the vasodilator, isosorbide dinitrate, which counteracted the vasoconstrictive actions of cocaine, and (5). a group exposed to isosorbide dinitrate alone. All treatments were carried out from the 45 th through 102 nd day of pregnancy. We found that the general appearance of the neocortex and the position and number of neocortical neurons in the offspring of benzoylecgonine- and isosorbide dinitrate-treated mothers were indistinguishable from those in the offspring of drug-naïve mothers. In contrast, significant alterations in these parameters (similar to those seen in our previous studies) were observed in the offspring of cocaine and cocaine + isosorbide dinitrate-treated mothers. These findings suggest that it is unlikely that either benzoylecgonine or vasoconstriction are responsible for the abnormalities seen in the neocortical cytoarchitecture in our non-human primate model of prenatal cocaine exposure.

Animals↗
PubMed2006

Aortic responsiveness to nitric oxide is affected by seasonal variation.

Cardiac attacks and sudden cardiac deaths are more common in cold seasons. Up to now the underlying pathophysiologic mechanism of the seasonal variation in cardiovascular accidents is scarcely known. There are many physiological mechanisms which exhibit seasonal variation (e.g. blood pressure). Nitric oxide (NO) is a potent vasodilator, and impaired responsiveness to its physiological effects has been reported in many pathological situations including cardiovascular accidents. The aim of the present study was to evaluate the role of NO-dependent mechanisms on seasonal variation in aortic relaxation in vitro in rats. Male Sprague-Dawley rats grown up in different seasons in natural light/dark situation were used in the study, while the temperature and humidity were kept constant throughout the study (22+/-1 degrees C). The in vitro aortic ring responsiveness to an NO donor was studied in different seasons. Intact and denuded rings were pre-contracted with phenylephrine and vaso-relaxatory response to sodium isosorbide dinitrate (10(-8) to 10(-4)M) was recorded in vitro. The vaso-relaxatory response to isosorbide dinitrate (10(-6)M) was higher in aortic rings obtained in summer compared with those in winter and fall. There was a significant difference in EC(50) of sodium isosorbide dinitrate-induced vaso-relaxation of rings obtained from rats which were grown up in summer and winter (EC(50): 2.23+/-0.069 versus 4.31+/-0.088, P<0.05). The maximum response (R(max)) to isosorbide dinitrate was, however, identical in rings obtained from these rats. In conclusion, the in vitro responsiveness of aorta to NO is affected by seasonal light/dark periods the rats are exposed. This might be one of the reasons why more sudden cardiac deaths occur also in humans during winter.

Journal Article↗
PubMed1992

Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris.

Nicorandil belongs to the class of compounds known as potassium channel activators which are characterised by their arterial vasodilator properties. In addition, nicorandil has venodilating properties which are attributable to a nitrate group in its chemical structure. Therefore, by combining these two vasodilator mechanisms, nicorandil represents a novel type of compound for use in the treatment of angina pectoris. Furthermore, increasing experimental evidence suggests that potassium channel activation may also exert a direct cytoprotective effect by augmenting normal physiological processes which protect the heart against ischaemic events. Comparative studies of up to 3 months' duration suggest that nicorandil is equivalent in efficacy to isosorbide dinitrate, propranolol, atenolol, nifedipine or diltiazem in the treatment of stable angina. Preliminary evidence suggests that an improvement of anginal and ischaemic symptoms is maintained for up to 1 year. Whilst the efficacy of nicorandil in other types of angina has not been extensively studied, preliminary results indicate that intravenous nicorandil is as effective as isosorbide dinitrate in the treatment of unstable angina and is also effective in patients with variant angina. In addition, the limited data available indicate that nicorandil may be effective in patients with unstable and variant angina who are refractory to therapy with conventional antianginal agents, a potentially important area for further study. Headache, mostly of mild to moderate intensity was the most commonly reported adverse event, occurring in one-third of patients receiving the recommended therapeutic regimen of nicorandil 10 to 20mg twice daily. In comparative trials involving a total of 84 patients who received nicorandil, the incidence of headache was similar to that produced by isosorbide mononitrate and isosorbide dinitrate. Headache was most frequent on initiating therapy but declined with continued treatment. To date, approximately 5% of patients participating in European trials have withdrawn due to headache, although this rate may be reduced by using a lower starting dose of nicorandil (5 mg twice daily). In summary, clinical experience thus far indicates that nicorandil, with its novel combination of two distinct vasodilator mechanisms, offers an effective alternative to established vasodilator therapy with conventional nitrates and calcium antagonists in the long term treatment of stable angina pectoris. Further studies are warranted to establish whether the unique pharmacodynamic profile of nicorandil is advantageous for the treatment of other types of angina and/or the ischaemic myocardium.

Angina Pectoris↗
PubMed1991

Comparison of nicorandil-induced relaxation, elevations of cyclic guanosine monophosphate and stimulation of guanylate cyclase with organic nitrate esters.

Nicorandil increases cyclic 3'5'-guanosine monophosphate (cGMP) in vascular smooth muscle. However, high concentrations are required to activate guanylate cyclase (GC). We examined the relationship between activation of GC, increases in cGMP and relaxation in canine mesenteric artery and vein, renal and coronary artery and thoracic aorta. Nicorandil (10-100 microM) relaxed in each of the blood vessels. Relaxation was associated with elevations of cGMP but independent of release of endothelium-derived relaxing factor, and inhibited by methylene blue and hemoglobin. The organic nitrate esters nitroglycerin, pentaerythritol tetranitrate, isosorbide dinitrate, 2-isosorbide mononitrate, and 5-isosorbide mononitrate each behaved in a similar manner. In each blood vessel pentaerythritol tetranitrate was the most potent and 5-isosorbide mononitrate the least potent relaxant and stimulant of cGMP. Each of the organic nitrate esters (1 microM to 1 mM) except nicorandil stimulated soluble GC activity in the presence of 10 mM cysteine. Nicorandil (EC50 38 mM) increased GC activity. Moreover, nicorandil (0.1 microM to 30 microM) did not inhibit cGMP phosphodiesterase. The EC50 for vascular relaxation was directly correlated with the EC50 for elevation of cGMP for each of the agonists in each blood vessel type. The EC50 for activation of GC was directly related to the reciprocal of the rate constant for nitric oxide formation for each of the organic nitrate esters. However, a direct correlation existed between the EC50 for activation of GC and the EC50 for 1) elevation of cGMP and 2) relaxation, for each of the organic nitrate esters except nicorandil. Thus, the high concentrations of nicorandil required to activate GC cannot account for the low concentrations required to elevate cGMP or relax smooth muscle. We postulate that nicorandil may interact with a membrane receptor or release a second messenger, distinct from nitric oxide or endothelium-derived relaxing factor, which then activates GC. This may represent a physiologic mechanism for regulation of GC activity in smooth muscle.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1990

Nitrate therapy in patients with coronary artery disease--preparations and doses with and without development of tolerance.

Rapid tolerance development with respect to hemodynamic, anti-anginal and anti-ischemic effects is a relevant clinical problem associated with any longterm treatment with nitroglycerin, isosorbide dinitrate or isosorbide 5-mononitrate. Tolerance occurs with any dosing regimen that results in nitrate accumulation in the plasma or nearly-constant plasma concentrations, as is the case with multiple daily doses of oral nitrates or continuous application of transdermal patch systems. Nitrate tolerance can be prevented by the interval treatment. This encompasses incorporation of an application-free interval which prevents meaningful nitrate accumulation such that, from a low baseline level, renewed drug administration leads to an increase in the nitrate plasma concentration greater than 2.5-fold. From controlled studies, dosing regimens for interval treatment proven to be effective have been designated for isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin patch systems. The early attenuation of nitroglycerin, seen within the first 12 h of its use, according to the results of a recently completed study, can be counteracted through continuously increasing plasma concentrations during this period. Interval treatment does not enable 24-h therapeutic protection. Studies with ST-Holter monitoring, however, have shown that adequate coverage can be provided for the period during which the vast majority of ischemic episodes occur. Clinically-relevant rebound phenomena do not occur during interval treatment. Pharmacological approaches to prevent nitrate tolerance, on the basis of the limited and, in part, conflicting data available, do not provide an alternative to interval treatment.

Administration, Cutaneous↗
PubMed1990

Sorption of various drugs in polyvinyl chloride, glass, and polyethylene-lined infusion containers.

The sorption of chloroquine sulfate, diazepam, isosorbide dinitrate, lorazepam, midazolam, nitroglycerin, promethazine hydrochloride, thiopental sodium, and warfarin sodium to three types of containers was studied. Appropriate amounts of the drugs were added to 500 mL of 0.9% sodium chloride injection in polyvinyl chloride (PVC) bags, glass bottles, and Clear-Flex bags composed of a laminate of polyethylene, nylon, and polypropylene. The containers were stored in the dark at room temperature for 24 hours. Samples were taken at various intervals and assayed for drug concentration by high-performance liquid chromatography. There were no appreciable changes in pH after 24 hours, and all the admixtures remained clear and colorless. The potency of chloroquine sulfate, lorazepam, midazolam, promethazine hydrochloride, and thiopental sodium remained unchanged in glass, PVC, and Clear-Flex containers. Diazepam, isosorbide dinitrate, nitroglycerin, and warfarin sodium did not show any sorption to glass bottles and Clear-Flex bags. In PVC bags, however, up to 55% of diazepam, 23% of isosorbide dinitrate, 51% of nitroglycerin, and 24% of warfarin sodium was lost during the 24-hour study period. Diazepam, isosorbide dinitrate, nitroglycerin, and warfarin sodium in 0.9% sodium chloride injection showed a loss of potency when stored in PVC containers for 24 hours at room temperature, but none of the drugs studied lost potency when stored in glass bottles and Clear-Flex bags.

Adsorption↗
PubMed1989

Inhibition of platelet activating factor-induced platelet aggregation by molsidomine, SIN-1, and nitrates in vitro and ex vivo.

We compared in vitro the effects of molsidomine, its active metabolite SIN-1, sodium nitroprusside, and the organic nitrates nitroglycerin, isosorbide-5-mononitrate, and isosorbide-2,5-dinitrate on platelet aggregation induced by platelet activating factor and on the activity of soluble guanylate cyclase. In addition, the effects of molsidomine and of isosorbide-5-mononitrate on ex vivo platelet function were studied. In vitro, SIN-1 and sodium nitroprusside were about 100-fold more potent activators of platelet guanylate cyclase and inhibitors of platelet activating factor-induced aggregation than the other agents. In contrast, in ex vivo experiments, not only molsidomine but also isosorbide-5-mononitrate inhibited platelet activating factor-induced aggregation. These data indicate that molsidomine, SIN-1, and organic nitrates can in vivo, like endothelium-derived relaxing factor, inhibit platelet aggregation and exert antithrombotic properties, although nitrates apparently cannot be converted in platelets to active metabolites. Since the antiaggregatory properties are observed when platelet activating factor is used as an aggregant, and since platelet activating factor-induced aggregation is only weakly influenced by inhibitors of cyclo-oxygenase, this effect might be useful clinically.

Cyclic GMP↗
PubMed1981

[Ergometric study of a new vasodilator agent in angina: molsidomine. Value of combination with beta-blockaders].

Molsidomine, a new venous vasodilator, was studied in 40 cases of stable angina by ergometric stress testing. 1. In 10 patients, one hour after 2 mg molsidomine sublingually, the work inducing a 1 mm ST depression (WST 1) increased by 94% (p less than 0,05), the total work by 52% (p less than 0,005) and the maximum ST depression (ST max) fell by 45% (p less than 0,01). Resting heart rate was unchanged. There was a mild fall in systemic blood pressure. 2. Molsidomine had a significant synergic effect in 3 groups of 10 patients on betablocker therapy but with ischaemic changes on exercise: a) Molsidomine 1 mg sublingually increased WST 1 by 36% (p less than 0,05); at a 2 mg dosage, by 55% (p less than 0,001). ST max decreased from 2,4 +/- 0,4 mm to 1,3 +/- 0,3 (p less than 0,005) and 1,2 +/- 0,33 (p less than 0,001) respectively. The maximal effect was obtained with 1 mg in 5 out of 10 patients. b) One and three hours after 2 mg Molsidomine sublingually or orally: WST 1 increased from 97% to 110% (p less than 0,005): ST max decreased in similar proportions (p less than 0,005). c) 2 mg Molsidomine and 230 mg isosorbide dinitrate orally were compared after two hours: WST 1 increased by 130% after Molsidomine (p less than 0,005) and by 112% after isosorbide (p less than 0,005). ST max decreased in similar proportions (p less than 0,005). The blood pressure fell less with molsidomine. Molsidomine appeared to be better tolerated than isosorbide. (5 cases of mild headache in 40 patients compared to 4 cases out of 10 patients). The results of a preliminary clinical trial are reported. The association of molsidomine (2 mg per os three times daily) reduced the number of anginal attacks by over 50% in 16 out of 17 patients inadequately controlled by betablockade alone. 3 patients complained of headache at the onset of therapy. The efficacity was comparable and the tolerance better than in 28 patients with isosorbide dinitrate and betablockade, and in 10 patients with nifedipine and betablockade. In conclusion, molsidomine is a venous vasodilator with useful pharmacokinetic properties. It seems to be effective and well tolerated in the treatment of angina whether used alone or in association with betablockers.

Administration, Oral↗
PubMed1994

Costs and effectiveness of angiotensin converting enzyme inhibition in patients with congestive heart failure.

BACKGROUND: Chronic heart failure is associated with a poor prognosis and reduced survival rates. The addition of vasodilator drug therapy to conventional therapy for congestive heart failure has resulted in improved survival. METHODS: Adopting a societal viewpoint, we designed a decision analytic model to analyze the costs and effectiveness of three therapies available for the treatment of congestive heart failure: standard therapy (digoxin and diuretic therapy) plus (1) no vasodilator agents, (2) hydralazine hydrochloride-isosorbide dinitrate combination, and (3) enalapril. In addition, we performed sensitivity analyses to determine which model variables were influential in determining incremental cost-effectiveness ratios (cost of drug, cost of hospitalization, efficacy of agents, etc). We used data from three major randomized controlled trials to estimate treatment efficacy, mortality rates, and hospitalization rates. RESULTS: An additional year of life gained by a patient receiving hydralazine-isosorbide combination therapy compared with standard therapy required an additional expense (incremental cost-effectiveness ratio) of $5600. Compared with the hydralazine-isosorbide combination therapy, the incremental cost-effectiveness ratio for enalapril therapy was $9700 per year of life saved. These results were insensitive to wide variations in our baseline assumptions. CONCLUSIONS: The cost per year of life saved by vasodilator therapy is much lower than that of other accepted medical therapies. Although the cost per year of life saved for hydralazine-isosorbide combination therapy is lower than that for enalapril therapy, enalapril therapy saves more lives, and the incremental cost of enalapril therapy is justified by the added benefits.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

[Principles and rules of the use of nitrates].

Nitrates, which have been used for more than a century, are the second oldest drug (after digitalis alkaloids) in the cardiological pharmacological arsenal. However, several facets of their mode of use still remain controversial. Their vasodilator and arteriolodilator action (especially in coronary vessels) and their platelet aggregation inhibitory effect make them useful drugs, particularly in all clinical forms of ischaemic heart disease (unstable or stable angina and acute myocardial infarction), for the prevention or treatment of ischaemic episodes (silent or not) and also in heart failure where nitrates are useful not only as symptomatic treatment (alone or associated with diuretics), but also in view of their positive effect on survival (associated with hydralazine: V-Heft I trial). At the present time, nitrates can be administered via the sublingual, oral, intravenous of transdermal routes in the form of nitroglycerin and isosorbide dinitrate or mononitrate (short-acting and sustained-effect forms). Their rare contraindications concern patients suffering from severe hypotension (< 70 mmHg), severe anaemia, glaucoma or intracranial hypertension. The most serious adverse effects are pulsatile headache (which usually disappear after several days), postural hypotension (possibly causing fainting), facial erythema, vertigo, palpitations or nausea and vomiting. Most of these adverse effects can be controlled by dosage adaptation and it is rarely necessary to stop treatment. However, the major problem raised by the use of nitrates concerns the development of a tolerance. The pathophysiology of this multifactorial phenomenon is still unclear. The protagonist role played by loss of SH groups or activation of humoral feedback mechanisms, with an increase of circulating catecholamine levels, activation of the R-A-A system and increased plasma volume, has been postulated. This complication can be avoided by prescribing intermittent treatment, with a drug-free interval of 10-12 hours per day. A single dose of a sustained-release preparation (60 mg of isosorbide dinitrate or 40 to 60 mg of isosorbide mononitrate), or 2 or 3 doses of a short-acting preparation (20-40 mg of isosorbide mononitrate) can be prescribed via the oral route. When the transdermal route is used, the patch should be left in place for 12 hours. Treatment should be started at low doses, which are then gradually increased. The free period is usually at night, which can be covered, when necessary, by other antiischaemic drugs (for example, beta-blockers and/or calcium channel blockers), already usually used in combination with nitrates. This interruption is not accompanied by a rebound phenomenon. It must be remembered that nitrates potentiate the action of other vasodilators and calcium channel blockers and that, in some patients, intravenous nitroglycerin reduces the anticoagulant effect of heparin, while indomethacin can inhibit their vasodilator effect. Nitrates are therefore in very good health despite their advanced age and, when used correctly, they continue to be very useful in the pharmacological treatment of cardiovascular diseases.

Drug Resistance↗
PubMed1998

Acute changes of left atrial distensibility in congestive heart failure.

BACKGROUND: Investigations of the left atrial (LA) distensibility have revealed that it plays a major role in atrial function; however, LA distensibility has not as yet been studied in congestive heart failure (CHF). HYPOTHESIS: The study was undertaken to determine the effects of acute administration of esmolol, isosorbide dinitrate, dobutamine, and normal saline infusion on LA dimension, pressure, and distensibility. METHODS: The study included 23 patients with CHF (18 with ischemic heart disease and 5 with idiopathic dilated cardiomyopathy). Left atrial diameters (D) and pressures (P) were recorded at rest and thereafter during acute tests. P and D data during the ascending limb of the V loop were fitted to the exponential function P = b.ead, where a is the passive elastic chamber stiffness constant and b is the elastic constant. The instantaneous diastolic LA distensibility (IDLAD) was calculated as 1/(dP/dD) = 1/a.P. RESULTS: The constant, a, increased significantly after normal saline and esmolol infusion (p < 0.001), while it significantly decreased after isosorbide dinitrate (p < 0.001) and dobutamine administration (p < 0.05) compared with baseline. Instantaneous diastolic LA distensibility (in mm/Hg) was 0.16 at baseline; it significantly increased after isosorbide dinitrate (0.32) and dobutamine (0.24) administration, while it significantly decreased after normal saline (0.11) and esmolol (0.12) infusion (p < 0.001 for all). CONCLUSION: In CHF, LA distensibility may acutely increase with vasodilators or inotropics or may decrease with beta blockade or volume loading.

Adrenergic beta-Agonists↗
PubMed1998

A comparative study of eccentric and concentric coronary stenosis vasomotion in patients with Prinzmental's variant angina and patients with stable angina pectoris.

BACKGROUND AND HYPOTHESIS: In patients with stable angina pectoris, eccentric stenoses have a greater potential for dynamic changes of caliber in response to vasoactive stimuli than concentric lesions. It is not known whether in patients with coronary artery spasm the degree of coronary vasoconstriction differs in eccentric versus concentric stenoses. Therefore, we examined the relationship between coronary stenosis morphology and the vasomotor response to vasoactive stimuli in patients with variant angina. METHODS: Computerized quantitative angiography was used to measure minimum luminal diameter of eccentric and concentric stenoses before and after the administration of ergonovine and isosorbide dinitrate in 22 patients with Prinzmetal's variant angina and in 20 patients with chronic stable angina. RESULTS: In patients with variant angina, mean stenosis diameter reduction with ergonovine was -0.85 +/- 0.38 and -1.12 +/- 0.69 mm in eccentric and concentric stenoses, respectively (p = NS). Isosorbide dinitrate promptly relieved spasm in all patients and increased the diameter of eccentric stenoses by 0.26 +/- 0.34 mm and that of concentric stenoses by 0.24 +/- 0.32 mm (p = NS). In patients with chronic stable angina, mean diameter reduction with ergonovine was -0.23 +/- 0.12 and -0.12 +/- 0.10 mm for eccentric and concentric stenoses, respectively (p < 0.05). Isosorbide dinitrate increased coronary diameter by 10% from baseline in 70% of eccentric and 38% of concentric stenoses (p < 0.01). CONCLUSION: In patients with variant angina pectoris, eccentric and concentric spastic stenoses react similarly in response to vasoactive stimuli. In patients with chronic stable angina, eccentric stenoses are more likely to show vasomotor responses than concentric stenoses.

Adult↗
PubMedDate not supplied

Bioavailability of organic nitrates: a comparison of methods for evaluating plethysmographic responses.

Erythrityl tetranitrate, a long-acting organic nitrate, was compared with isosorbide dinitrate in a double-blind, placebo-controlled complete crossover study in 15 healthy male volunteers. A digital plethysmogram and ear densitogram were used to assess the physiologic response to these two sublingual nitrates, with the intensity and duration of drug effect calculated by differences in diastolic amplitude intensity before and after drug administration. Both 5 mg sublingual erythrityl tetranitrate and 5 mg isosorbide dinitrate produced significant increases in diastolic amplitude intensity for up to 3 hours. The erythrityl tetranitrate peak effect was less than that of the isosorbide dinitrate, but the incidence of headaches was also less. The ear densitogram was found to be an effective means of assessing the diastolic amplitude intensity changes.

Adult↗
PubMed1998

Pentaerithrityl tetranitrate and its phase I metabolites are potent activators of cellular cyclic GMP accumulation.

Using pig kidney epithelial cells (LLC-PK1), the present study assesses the cyclic GMP stimulatory effect of pentaerithrityl tetranitrate and its metabolites in comparison to other therapeutically used nitric oxide donors. Pentaerithrityl tetranitrate was found to be the most potent activator of cyclic GMP synthesis compared to other clinically relevant organic nitrates (glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate). The phase I metabolite pentaerithrityl trinitrate was equipotent with its parent compound in stimulating cyclic GMP. The concentration-response curves of pentaerithrityl dinitrate and isosorbide dinitrate for cyclic GMP accumulation were virtually identical. In contrast, pentaerithrityl mononitrate and the phase II metabolite pentaerithrityl trinitrate glucuronide did not alter basal cyclic GMP levels. It is concluded that the long-term vasodilatory and antiischemic effects of pentaerithrityl tetranitrate are caused to a substantial extent by cyclic GMP-mediated actions of its pharmacologically active phase I metabolites.

Animals↗
PubMed1996

The effect of oxygen tension on responses evoked by methacholine and bronchodilators in bovine isolated bronchial rings.

This study examined the effect of acute changes in oxygen tension on responses evoked by the bronchoconstrictor methacholine and the dilators salbutamol, atrial natriuretic peptide and isosorbide dinitrate in isolated bovine bronchi. Cumulative concentration-response curves to methacholine (10(-9)-3 x 10(-4) M) were constructed in three oxygen tensions; hyperoxia (95%), normoxia (20%) and hypoxia (4% O2). Oxygen tensions of 20% and 4% each significantly enhanced contractions to methacholine compared to those in 95% O2. There was no significant difference, however, between responses in 20 and 4%. The ability of salbutamol, atrial natriuretic peptide and isosorbide dinitrate to reverse methacholine induced tone was also compared in the three oxygen tensions (95%, 20% and 4%). Lowering the oxygen tension from 95% enhanced the ability of each of the drugs to reverse contraction, however the pattern differed between drugs; salbutamol was more effective in 20% O2 than 4%, atrial natriuretic peptide was more effective in 4% than either 95 or 20% O2 and isosorbide dinitrate was more effective in both 4 and 20% than 95% O2. In conclusion, both bronchoconstrictor and bronchodilator responses in 95% O2 (hyperoxia) differed from those in 20% O2 (normoxia) and further changes occurred on moving to 4% (hypoxia), although the direction of the changes varied among the dilators. This suggests that the responses evoked by bronchodilators in 95% O2 may not necessarily predict those in the physiological range of oxygen tensions and that the relative effectiveness of bronchodilators may vary between normoxic and hypoxic conditions.

Adrenergic beta-Agonists↗
PubMed1997

Changing the oxygen tension alters the ability of bronchodilators to protect against methacholine-induced challenge in bovine isolated bronchial rings.

The ability of atrial natriuretic peptide, salbutamol, sodium nitroprusside and isosorbide dinitrate to protect against challenge with methacholine in bovine isolated bronchi was compared in different O2 tensions. Perfusing the Krebs-Henseleit solution with gas mixtures containing 95% O2 (hyperoxia), 20% O2 (approximately normoxia) and 0% O2 (hypoxia) produced O2 tensions in the organ-baths of 524, 147 and 26 mm Hg, respectively. In hyperoxia, pre-incubation of atrial natriuretic peptide at concentrations of 3 x 10(-7) M and 10(-6) M significantly attenuated responses to methacholine, whereas in normoxia, these concentrations of atrial natriuretic peptide had no effect. Furthermore, in hypoxia, 3 x 10(-7) M and 10(-6) M atrial natriuretic peptide significantly enhanced responses to methacholine. Salbutamol, at concentrations of 3 x 10(-7) M and 10(-6) M significantly attenuated responses to methacholine in hyperoxia, whereas in normoxia and hypoxia, pre-incubation of salbutamol did not alter the methacholine response. Pre-incubation of 10(-5) M sodium nitroprusside significantly attenuated methacholine-induced contractions in hyperoxia and when the oxygen tension in the gas mixture was lowered to 20% or 0%, the ability of sodium nitroprusside to protect against methacholine challenge was enhanced. In hyperoxia, isosorbide dinitrate, at the 10(-4) M level, evoked a rightward shift of the methacholine response curve. Lowering the oxygen tension to either 20% or 0% enhanced the protectant effect of isosorbide dinitrate, with the effect being greater in 20% O2. Thus, the effect of these bronchodilators on methacholine-induced challenge in hyperoxia O2 differed from those in normoxia and hypoxia, although the direction of the changes varied among the agents used. This suggests that the responses evoked by bronchodilators in 95% O2 may not necessarily predict those in the physiological range of oxygen tensions and that the relative effectiveness of bronchodilators may vary between normoxic and hypoxic conditions.

Albuterol↗