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PubMed1993

Detection of viable tissue in healed infarcted myocardium by dipyridamole thallium-201 reinjection and regional wall motion studies.

Reinjection imaging with thallium-201 (Tl-201) may provide a convenient method of assessing myocardial viability. Twenty patients with a previous Q-wave healed myocardial infarction were examined to evaluate the detection of viable tissue in infarcted segments. All patients underwent to evaluate the detection of viable tissue in infarcted segments. All patients underwent dipyridamole Tl-201 tomographic imaging with reinjection of 1 mCi of Tl-201 after redistribution. Radionuclide ventriculography was performed before and after administration of 5 mg of dinitrate isosorbide sublingually for regional wall motion analysis. Patients presented with 38 fixed defects, 12 of which demonstrated improved Tl-201 uptake on reinjection; 10 of 12 reinjection-reversible segments were hypokinetic or normal after administration of nitrates, whereas 22 of 26 nonreversible segments remained akinetic or dyskinetic (p < 0.001). Of 20 patients, 9 had reinjection-reversible segments; coronary angiography revealed a patent infarct-related artery or collaterals, or both, in 7 of these patients. The infarct-related artery was patent or collaterals were present, or both, in 4 of 11 patients who did not improve with reinjection. It is concluded that reinjection of Tl-201 during dipyridamole Tl-201 scintigraphy may frequently detect viable tissue in infarcted segments in patients with a Q-wave infarction. Segments with reinjection reversibility usually do not remain dyskinetic or akinetic after administration of nitrates and have some residual flow on coronary angiography.

Coronary Angiography↗
PubMed1991

The cardiovascular system and daily variation in response to antihypertensive and antianginal drugs: recent advances.

This review contains recent data on the pharmacokinetics and the hemodynamic effects on heart rate and blood pressure of three different groups of drugs (beta-blockers: propranolol; oral nitrates: isosorbide-dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN); calcium channel blockers: nifedipine) which were investigated in healthy volunteers or in hypertensive patients after drug application at different times of the day. In the case of IS-5-MN and nifedipine two different galenic formulations were studied. The results clearly demonstrate chronopharmacokinetics for propranolol, ISDN, and the immediate-release formulations of IS-5-MN and nifedipine, whereas no pharmacokinetic daily variations were observed with the sustained-release formulations. However, all drugs exhibited daily variations in their hemodynamic effects. These data greatly support the view that pharmacokinetics and drug effects should be studied simultaneously when chronopharmacologic studies are performed.

Adrenergic beta-Antagonists↗
PubMed1994

Risk of rebound phenomenon during nitrate withdrawal.

Organic nitrates are first-line drugs in the therapy and prevention of angina. These compounds, are acutely effective yet some formulations demonstrate a rapid decline in effect with chronic use. In this review the mechanisms of development of nitrate tolerance and the different strategies to prevent it are considered. If frequent dosing, high dosages and long acting preparations giving constant 24 h plasma GTN levels are more likely to cause tolerance, nitrate-low periods seem to be effective in restoring the drug's efficacy. Intermittent therapy with GTN patches, an effective way to prevent tolerance, raises the problem of the rebound phenomenon during the removal period. Considerable variations in its occurrence have been reported and in this review the factors that may influence the incidence of the rebound are discussed. The dangers of rebound can be lessened by concomitant anti-anginal drugs or avoiding any abrupt decline in blood nitrate concentrations. The use of beta-blockers or calcium channel blockers during intermittent therapy with GTN patches and oral preparations of isosorbide dinitrate or isosorbide 5-mononitrate seem to be effective for this purpose.

Angina Pectoris↗
PubMed2001

Reduction of organic nitrates catalysed by xanthine oxidoreductase under anaerobic conditions.

Xanthine oxidoreductase catalyses the anaerobic reduction of glyceryl trinitrate (GTN), isosorbide dinitrate and isosorbide mononitrate to inorganic nitrite using xanthine or NADH as reducing substrates. Reduction rates are much faster with xanthine as reducing substrate than with NADH. In the presence of xanthine, urate is produced in essentially 1:1 stoichiometric ratio with inorganic nitrite, further reduction of which is relatively slow. Organic nitrates were shown to interact with the FAD site of the enzyme. In the course of reduction of GTN, xanthine oxidoreductase was progressively inactivated by conversion to its desulpho form. It is proposed that xanthine oxidoreductase is one of several flavoenzymes that catalyse the conversion of organic nitrate to inorganic nitrite in vivo. Evidence for its further involvement in reduction of the resulting nitrite to nitric oxide is discussed.

Anaerobiosis↗
PubMed1986

Nitrate tolerance in angina pectoris.

A review of the current literature concerning development of nitrate tolerance in the treatment of angina pectoris suggests that: development of nitrate tolerance is a clinical reality development of tolerance do not seem to differ for nitroglycerin, isosorbide-dinitrate or isosorbide-5-mononitrate a high nitrate dose seems to be more likely to induce tolerance a nitrate free interval during some part of the day or the night seems to restore vascular responsiveness by optimal use of different nitrate formulations the problem with development of tolerance may be reduced.

Angina Pectoris↗
PubMed1983

Baroreflex response and vasodilating drugs in essential hypertension.

Blood pressure, heart rate, and arterial diameter of the brachial artery were studied in patients with sustained essential hypertension before and after administration of three vasodilating drugs: dihydralazine, diltiazem, and dinitrate isosorbide (ISDN). The diameter of the brachial artery was measured using a pulsed Doppler device, enabling the angle between the ultrasound beam and the vessel axis to be evaluated with a precision inferior to 2 percent. The three drugs had similar effects in decreasing the blood pressure and the forearm vascular resistance. Dihydralazine reduced the arterial diameter (p less than 0.001) and increased heart rate. Diltiazem and ISDN increased markedly the arterial diameter (p less than 0.001) but did not change heart rate. Dihydralazine decreased the tangential tension of the arterial wall, while diltiazem and ISDN did not. The study provided evidence that, with vasodilating drugs, the changes in the caliber of peripheral large arteries, which are a determinant of wall arterial tension, can influence the baroreflex-mediated tachycardia caused by use of the drugs.

Adult↗
PubMed2006

[Did a reform strategy in drug management improve doctors' prescribing habits in Montenegro: the example for the cardiovascular drugs].

BACKGROUND/AIM: A comprehensive reform strategy in drug management has been applying for a few years in Montenegro in order to promote a rational use of drugs. The reform strategy covered: an information system named "The Control of Distribution and Use of Drugs", a new List of Essential Drugs (that are reimbursed by the Republic Fund for Health), legislative and regulatory measures in order to establish a better control of drug prescribing and more efficient processing of the prescriptions. The aim of this study was to evaluate the effects of the reform strategy on the doctors' prescribing habits and the subsequent use of cardiovascular drugs within the outpatient setting of Montenegro. METHODS: A retrospective-prospective pharmacoepidemiologic study included a sample of 100% of cardiovascular drugs that were taken with prescription from state pharmacies during 2000 and 2004. The results were presented by the number of defined daily doses (DDD) per 1000 inhabitants per day. All the drugs were classified according to the uniform anatomical-therapeutic-chemical (ATC) classification of the drugs. The Wilcoxon test for matched pairs was used in order to calculate the significance of difference in cardiovascular drugs utilization before and after the introduction of new measures. RESULTS: Although prescribing and the resulting outpatient use of cardiovascular drugs (ATC group C) that were reimbursed by the Republic Fund for Health was increased approximately by 13% in 2004 in comparison with 2000 (67.98 vs. 60.17 DDD/1000 inh./day), we did not find a statistically significant difference (p > 0.05). Prescribing of ACE inhibitors (C09A) increased approximately by 45% during the investigated period (15.30 vs. 22.17 DDD/1000 inh./day). The selection of drugs was also altered: cilazapril, ramipril and quinapril were left out, captopril and enalapril were more prescribed, and a newly-induded fosinopril was prescribed mostly (31.5%). Calcium-channel blockers (C08) were prescribed 33.7% more (7.12 vs. 9.52 DDD/1000 inh./day), mostly because of seven times higher prescribing of amlodipine in 2004. Pentaerythritol tetranitrate was left out, but isosorbide dinitrate and isosorbide mononitrate were prescribed more frequently. High-priced atorvastatin was replaced with the older simvastatin, that was prescribed three times more. CONCLUSION: The reform strategy in drug management mostly improved the doctors' prescribing habits and the subsequent use of cardiovascular drugs within the outpatient setting. For the most part, the noticed changes were in accordance with the actual recommendations, but some cases need additional measures. Regulatory policy, however, could not compensate for the continual education of doctors that prescribe drugs.

Cardiovascular Agents↗
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↗
PubMed1994

Relaxation of trabecular meshwork and ciliary muscle by release of nitric oxide.

PURPOSE: Recent evidence suggests that nitric oxide (NO) is a major messenger molecule regulating smooth muscle contractility. A role for NO in aqueous humor dynamics, and thus regulation of intraocular pressure, has been postulated. Recently, we described contractile properties of isolated bovine trabecular meshwork and ciliary muscle strips. To assess whether vasodilators contribute to the regulation of trabecular meshwork and ciliary muscle contractility, we measured the effect of various substances known to induce vasodilation by increasing intracellular cGMP production. METHODS: Measurements of isometric tension were performed on isolated bovine ciliary muscle and trabecular meshwork strips using a custom-built electromagnetic force-length transducer. The effects of a membrane-permeable cGMP and an inhibitor of nitric oxide formation (L-nitroarginine = L-NAG) were investigated. Organic nitrate (isosorbide dinitrate = ISDN, isosorbide-5-mononitrate = 5-ISMN) and non-nitrate (sodium nitroprusside = SNP, S-nitroso-N-acetyl penicillamine = SNAP) vasodilators were tested. RESULTS: Isolated strips were precontracted by carbachol 10(-6) mol/l for 30 minutes (100% carbachol maximal contraction). 8-bromo-cGMP 10(-4) mol/l evoked a relaxation to 86.7% +/- 1.4% (n = 8) in ciliary muscle and 58.6% +/- 5.4% (n = 7) in trabecular meshwork. Inhibition of NO-synthase by L-NAG increased the carbachol-induced contraction. The organic nitrovasodilators ISDN and 5-ISMN produced significant relaxations. The non-nitrates SNP and SNAP were the most potent relaxants. SNP 10(-4) mol/l relaxed the isolated ciliary muscle to 55.5% +/- 3.5% and the trabecular meshwork to 38.6% +/- 3.6%. ISDN and SNP were also tested on isolated strips without carbachol-induced precontraction. Both vasodilators had significant relaxing activity under these conditions. CONCLUSION: The data indicate that an increase of intracellular cGMP by application of cGMP and organic nitrate or non-nitrate vasodilators induces relaxation of the bovine trabecular meshwork and ciliary muscle. Thus, nitric oxide is a cotransmitter of smooth muscle relaxation in the chamber angle and may be involved in the regulation of aqueous humor dynamics.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

[Pharmacology of nitrates].

Nitrates (nitroglycerin, isosorbide dinitrate and isosorbide 5-mononitrate) are drugs used in the treatment of angina pectoris and in the prevention of myocardial ischaemia. By providing nitric oxide (NO), which, in turn, increases the level of cGMP and decreases (Ca)i, they induce effects of vasodilatation and anti-platelet aggregation. In patients suffering from endothelial dysfunction, they therefore act like exogenous NO providers. At low doses, they act as venous vasodilators by decreasing the tension (preload) and volume of the ventricle, as well as myocardial oxygen requirements (MVO2). The reduction of ventricular tension and volume also indirectly increases subendocardial blood flow. In the coronary vessels, they produce epicardial vasodilatation (all the more marked the smaller the calibre of the vessels), increase collateral blood flow and, through stenoses, induce reduction of coronary tone and the excess pressure due to vasospasm. At higher doses, the vasodilator effect is exerted on arteries and, although it reduces peripheral vascular resistance (afterload) and blood pressure, it can also produce reflex tachycardia which annihilates the reduction of MVO2. Finally, nitrates exert anti-platelet aggregation effects. All these properties account for the beneficial effects of nitrates in acute or chronic coronary ischaemic syndromes, in patients suffering from left ventricular dysfunction, during the acute phase of myocardial infarction and in post-myocardial infarction ventricular remodelling. There are many pharmaceutical formulations allowing administration of nitrates via a variety of routes. However, the efficacy of repeated nitrate administration is limited by the appearance of tolerance, which can be prevented by observing short periods without nitrates (8-24 hours). The use of sustained-release formulations, with a single daily dose, ensures a maximum anti-ischaemic effect, reduces the risk of tolerance and facilitates the patient's compliance with treatment, which makes it the treatment of choice in angina patients.

Heart Diseases↗
PubMed1977

[Effectiveness of nifedipine on exercise tolerance in patients with angina pectoris. Comparison with a nitroderivative and a beta-blocking agent].

The effect of nifedipine on effort angina was investigated by means of exercise tests with bycicle ergometer and compared, in the same patients, with the effects of a nitroderivative and a betablocking agent. Five patients with stable effort angina entered the study, after an hemodynamic and contrasto-graphic control. According to the protocol of a latin square 5 X 5, all the patients received in a random sequence the following treatments: placebo, 1 c. orally; isosorbide dinitrate, 5 mg sublingually; propranolol, 40 mg orally; nifedipine, 10 mg sublingually; nifedipine, 10 mg orally. No significant change of any of the considered parameters was observed after the placebo. Isosorbide dinitrate and nifedipine produced significant increases of the duration of work before appearance of pain and EKG positivity, and of total work performed before anginal pain. Only the duration of work before EKG positivity was improved by propranolol. The comparisons between treatments showed no significant difference of the effects of the administered doses of isosorbide dinitrate and nifedipine. The improvements observed after propranolol were significantly lower than that observed after isosorbide dinitrate and oral nifedipine. On the basis of the observed changes of cardiac rate, maximal arterial pressure, ejection time index and triple product, the authors evaluate the possible mechanism of action of nifedipine.

Adolescent↗
PubMed1978

Nitrate therapy for congestive heart failure.

A randomized double-blind crossover trial included 16 patients with severe congestive heart failure who received isosorbide dinitrate or placebo for eight weeks, and then the opposite treatment for eight more weeks. All patients received their usual maintenance therapy with digitalis and diuretics. Seven morbid events occurred during 85 patient-weeks of isosorbide dinitrate therapy compared with 17 during 76 patient-weeks of placebo. Severity of congestive heart failure improved in all eight patients who received isosorbide dinitrate compared with two patients who showed improvement and five whose symptoms became worse with placebo. No significant differences in physical findings, cardiac dimensions, or resting hemodynamics were observed. Maximal exercise duration increased significantly by 2.54 minutes with isosorbide dinitrate therapy, and rose insignificantly by 1.24 minutes with placebo. This preliminary trial suggests that long-term vasodilator therapy may be clinically beneficial in congestive heart failure.

Adult↗
PubMed1983

Newer aspects of the pharmacokinetics of organic nitrates.

Plasma drug and metabolite concentrations were measured after single oral doses of 40 mg sustained-release 14C-isosorbide dinitrate to humans. The bioavailability of isosorbide dinitrate from this sustained-release formulation was about 90% of that from a standard formulation. The pharmacokinetics of isosorbide-5-mononitrate were studied in humans after intravenous infusion (8 mg/h) and oral doses of 20 mg. The systemic availability of the drug after oral doses was 93%, its systemic clearance was 127 ml/min, its volume of distribution was 48.5 liters and its half-life was 4.4 h.

Biological Availability↗
PubMed1981

[Treatment of congestive cardiac failure with vasodilators (author's transl)].

The possibility of development of tolerance of treatment with vasodilators was investigated in 16 patients with severe chronic congestive cardiac failure. Independent of the primary site of action, the first application of a vasodilator resulted in lowering of pulmonary artery pressure by about 30% (isosorbide dinitrate 40 mg orally in delay-action form and 5 mg sublingually, prazosin 2 mg, dihydralazine 75 mg). Only dihydralazine reduced systemic resistance acutely by 42% and increased cardiac minute volume by 66%. After treatment for 12 days with isosorbide dinitrate delay-action (three times 20 mg), prazosin (three times 2 mg) or dihydralazine (three times 75 mg), there was persistent lowering of the pulmonary artery pressure 16 hours after cessation of treatment only after isosorbide dinitrate (-29%) and dihydralazine (-27%). A decrease of systemic resistance by 11% and an increase of cardiac minute volume by 20% were seen only after dihydralazine. An additional acute application of isosorbide dinitrate or dihydralazine resulted in a further decrease of pulmonary artery pressure (-25% and -11%, respectively). An additional decrease of systemic resistance (-23%) and increase of cardiac minute volume (+18%) were again only seen with dihydralazine. In contrast to the first medication there was no significant change of the pulmonary artery pressure after treatment with prazosin for 12 days.

Adult↗
PubMed1980

[Orally active vasodilators in the management of chronic treatment-resistant cardiac failure (author's transl)].

The acute haemodynamic effects of 40 mg isosorbide dinitrate (10 subjects), 4 mg prazosin (20 subjects) and 50 mg dihydralazine (8 subjects) were compared in 24 patients with the clinical picture of chronic therapy-resistant cardiac failure (NY Heart Association stages III-IV). There was a fall in left-ventricular filling pressure of about 15% and right-atrial mean pressure of 21 and 24%, respectively, with isosorbide dinitrate and prazosin, while there was no change with dihydralazine. Cardiac output rose by 23% with dihydralazine and 20% with prazosin, but remained unchanged with isosorbide dinitrate. These data indicate that a reduction in pulmonary and systemic-venous congestion due to chronic decompensated cardiac failure can be achieved with isosorbide dinitrate and prazosin, while cardiac output can be improved only with prazosin and dihydralazine.

Adult↗
PubMed1994

Vasodilators in heart failure. Conclusions from V-HeFT II and rationale for V-HeFT III.

The Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT I and II) provided information about heart failure treated with conventional therapy, and evaluated the long term efficacy of vasodilators. In V-HeFT I, the combination of hydralazine and isosorbide dinitrate provided a beneficial effect on prognosis in heart failure. V-HeFT II demonstrated that enalapril had a more favourable effect on 2-year survival than a combination of hydralazine plus isosorbide dinitrate. However, the hydralazine-isosorbide dinitrate combination exerted the most favourable short term impact on exercise performance and left ventricular ejection fraction. The V-HeFT studies showed that, although not all vasodilators are alike, their differing effects might be beneficial when used in combination. Determination of the potential additive effect of the calcium antagonist felodipine, a vasodilator, when used in combination with an ACE inhibitor, is the major goal of V-HeFT III.

Clinical Trials as Topic↗
PubMed1982

Hemodynamic effects of vasodilator therapy in severe left heart failure combined with large atrial septal defects.

Two patients presented with severe left heart failure and large secundum atrial septal defects without severe pulmonary hypertension. The acute hemodynamic effects of two commonly used vasodilator agents, isosorbide dinitrate and hydralazine, are described. Although isosorbide dinitrate improved systemic forward cardiac output, it also increased left-to-right intracardiac shunting in both patients. On the other hand, hydralazine dramatically improved systemic toward output and concomitantly diminished left-to-right shunt flow in each patient (43 and 21 percent). The complexities of combined severe left ventricular failure and a large atrial septal defect with left-to-right shunting, and the importance of extensive hemodynamic monitoring at the time of pharmacologic intervention, are discussed.

Blood Pressure↗
PubMed2003

[Nitrates in therapy of effort angina in hypotensive patients].

A randomized single blind cross-over trial with placebo lead-in has been conducted in 71 anginal patients with arterial hypotension (group 1) and 38 ischemic heart disease patients with normal arterial pressure (group 2) to compare efficacy of therapy with isosorbide dinitrate (ID), sustac-forte (SF), isosorbide dinitrate retard (IDR) and trinitrolong (TN). Paired bicycle exercises revealed that in group 1 patients ID was low effective in 49%, SF--in 61%, IDR was highly effective in 97% and TN--in 96%. In group 1 tolerance to antianginal effect of ID, SF and IDR shown by stress myocardial scintigraphy with Tl-199 developed earlier--in 2-4 weeks in 63-70% patients (versus 22-27% in group 2; p < 0.01). Recovery of ID, SF, IDR effect required prolongation of the drug withdrawal period to 8-16 days (versus 3-5 days in group 2; p < 0.05). TN therapy remained effective for 3 months. Resistance to ID, SF in group 1 was relative and depended on dosage form of nitrates.

Angina Pectoris↗