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PubMed1976

Vasodilator therapy for chronic left ventricular failure.

The effects of chronic oral vasodilator therapy were studied in a group of patients with refractory congestive heart failure. Fifteen patients were treated acutely with intravenous sodium nitroprusside and sublingual isosorbide dinitrate. After continuous therapy with nitroprusside and isosorbide dinitrate for up to 72 hours the patients were then placed on isosorbide dinitrate and oral phenoxybenzamine. Hemodynamic responses to nitroprusside, isosorbide dinitrate, and phenoxybenzamine with isosorbide dinitrate were determined. After a mean follow-up of seven months, nine patients who were receiving isosorbide dinitrate and phenoxybenzamine underwent repeat hemodynamic studies. Beneficial effects of acute vasodilator therapy included a significant reduction in pulmonary capillary wedge pressure and systemic vascular resistance, and significant increases in cardiac index and stroke work index. Mean arterial blood pressure and heart rate were unchanged. During the period of chronic vasodilator administration, no other change in basic therapy with isosorbide dinitrate and phenoxybenzamine (3-21 months), the favorable effects observed acutely were maintained. All patients demonstrated symptomatic improvement with minimal side effects. The beneficial hemodynamic responses that are noted with acute vasodilator therapy in patients in advanced congestive heart failure are maintained with oral therapy on a chronic basis.

Adult↗
PubMed1993

Absence of desensitization to the relaxant activity of streptozotocin in isosorbide dinitrate-tolerant rat aorta.

The effect of in-vitro isosorbide dinitrate (ISDN)-induced tolerance on the vasodilatory actions of streptozotocin, a nitric oxide containing compound, and papaverine was studied in rat aortic strips precontracted by phenylephrine. Aortas made tolerant to ISDN remained fully responsive to streptozotocin but exhibited a greater response to low concentrations of papaverine compared with control strips. Methylene blue produced parallel displacement to the right of the relaxant concentration-effect curves of both ISDN and streptozotocin, whereas responses to only low concentrations of papaverine were significantly antagonized. These results indicate that the relaxant activity of streptozotocin is due to the stimulation of guanylate cyclase and impaired activity of this enzyme is not likely to be the operating mechanism for nitrate tolerance. It is also suggested that the vasodilating action of papaverine is partly dependent on the tissue cGMP level.

Animals↗
PubMed1999

The antioxidant defense protein ferritin is a novel and specific target for pentaerithrityl tetranitrate in endothelial cells.

The organic nitrate pentaerithrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In porcine aortic endothelial cells, a 24 h incubation with PETN (1-100 microM) or its metabolite pentaerithrityl trinitrate (PETriN) increased levels of the antioxidant protein ferritin up to three-fold over basal, whereas isosorbide dinitrate and isosorbide-5-mononitrate were without significant effect under these conditions. PETriN-induced ferritin expression was blocked by the NO scavenger PTIO but remained unaltered in the presence of ODQ, an inhibitor of soluble guanylyl cyclase. 8-Bromo cyclic GMP and dibutyryl cyclic GMP did not influence basal ferritin synthesis. The iron chelator desferrioxamine abolished ferritin induction by PETriN. Our results show that PETN or its active metabolite PETriN induce ferritin synthesis through NO- and iron-dependent but cyclic GMP-independent pathways. Increased activity of ferritin may contribute to, and at least in part explain, the specific antiatherogenic and antioxidant action of PETN.

Animals↗
PubMed1984

On the haemodynamic differences between sodium nitroprusside, nitroglycerin, and isosorbide nitrates. Comparison of their vasorelaxant effects in vitro and of their inactivation in vivo.

In organ bath studies, the sensitivity of isolated renal arteries and veins of the rabbit to sodium nitroprusside (SNP), nitroglycerin (GTN), and two isosorbide nitrates was compared. For isosorbide-dinitrate and isosorbide-5-mononitrate, a 7 to 20 times greater sensitivity of veins than of arteries was found explaining their known in vivo predilection for the capacitance vessels. To SNP and GTN, the immediate response was practically identical; a moderately greater sensitivity of the veins at threshold concentrations ( EC10 ), and a similar sensitivity of veins and arteries at the EC50 was observed with both drugs. However, on prolonged exposure (30 min), the relaxant response to GTN faded to a greater extent in arteries than in veins which may be a factor in the in vivo preference of GTN for the capacitance vessels. In anaesthetized rats, the hypotensive response to SNP and to GTN either infused i.v. or into the femoral artery, was compared. With GTN, the hypotensive response was the same by either route of administration. In contrast, the hypotensive response to SNP was considerably reduced on infusion into the femoral artery; an inactivation of SNP by 34% on passage through the hind-leg was calculated. The resulting decrease in venous over arterial blood levels of SNP could outweigh the somewhat greater sensitivity of veins than of arteries found in the organ bath, and may account for the balanced effect of SNP on resistance and capacitance vessels known to exist in vivo.

Animals↗
PubMed1994

Mechanisms of action of nitrates.

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.

Angina Pectoris↗
PubMed1996

Organic nitrates: new formulations and their clinical advantages.

The organic nitrates have been used for more than a century in the management of patients with myocardial ischemia. The most commonly used agents at this time include nitroglycerin, isosorbide dinitrate, and isosorbide-5-mononitrate. These agents all exert their therapeutic effects through biodegradation to nitric oxide, which stimulates guanylate cyclase in vascular smooth muscle cells with the production of cyclic guanosine monophosphate. The latter induces vasodilation by reducing the availability of ionized calcium to the contractile proteins. Tolerance to the organic nitrates occurs when the agents are administered in an attempt to provide therapeutic effects throughout 24 hours each day. There are probably several mechanisms responsible for nitrate tolerance, but there is no evidence at this time that concurrent medications will modify the development of tolerance. The only available method at this time is to give these agents intermittently to provide a period of washout. In so doing, it is possible to provide therapeutic nitrate effects for approximately 12 hours throughout each 24-hour period.

Cardiovascular Diseases↗
PubMed1986

[Dose-dependent serum concentration of ISDN and its metabolites following administration of ISDN-retard. Studies under steady-state conditions].

In a randomized cross-over trial of four groups of patients (total 49 patients) the serum concentrations of isosorbide dinitrate (ISDN), isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were measured under steady-state conditions after administration of 20, 40, 60 and 80 mg, respectively, of two ISDN preparations, the two being bioequivalent. At the studied dosage there was a linear relationship between dose and serum concentration of ISDN and its two metabolites in the proportion of 1:6:70. Because the serum concentration of IS-5-MN is so high under steady-state conditions, there is the potential problem of tolerance developing. The drug should therefore be administered at a lower dose twice daily.

Aged↗
PubMed1989

Effectiveness of interval nitrate therapy in angina pectoris.

Because of rapid tolerance development, the use of multiple daily doses of oral nitrates or continuous application of transdermal nitrate systems can no longer be considered justified. Only with an interval treatment, which prevents nitrate accumulation in the plasma such that, from low baseline values, renewed administration of the drug results in a marked increase in plasma concentration, is it possible to utilize the antianginal and antiischaemic effects of nitrates for meaningful long-term treatment. For isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin systems, interval treatment dosing regimens with maintained effectiveness documented in controlled studies have been delineated. To some degree, the principle of interval treatment can be achieved with continuously applied transdermal patches designed for discontinuous release of their content, which yield maintained though somewhat attenuated effects. Recent studies have shown that the tolerance to nitroglycerin, which develops within the first 12h of contact with currently available transdermal patches, can be prevented by gradually increasing the plasma concentration during this period of time. Evidence for clinically relevant rebound phenomena during interval treatment has not been observed.

Administration, Cutaneous↗
PubMed1990

Relaxation of bovine mesenteric arteries by glyceryl trinitrate and other nitro-compounds: evidence for partly different mechanisms of action.

The effect of pertussis toxin (PTX) and the cyclic GMP lowering agent LY83583 on the relaxatory response induced by glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN) and sodium nitroprusside (SNP) in bovine mesenteric artery (BMA) was investigated. Pretreatment with PTX (100 ng/ml; 2 hr induced a 100-fold right shift of the concentration-effect curve for GTN, while no effect on the relaxatory response elicited by ISDN, IS-5-MN or SNP was seen. The relaxatory effect of all the substances tested was markedly reduced by LY83583 (10 microM). The basal cGMP level as well as the GTN induced increase in cGMP were markedly reduced when BMA was exposed to LY83583. The substance also reduced the activation of soluble guanylate cyclase by SNP. Based on the different sensitivity towards PTX it is suggested that GTN induces vascular smooth muscle relaxation by a partly different mechanism than ISDN, IS-5-MN and SNP. As far as the GTN induced relaxation is concerned the sensitivity towards PTX indicates the involvement of regulatory component, possibly a G-protein. However, cyclic GMP seems to play a crucial role in mediating the relaxatory response of all the substances tested since the cGMP-lowering agent LY83583 markedly inhibited the relaxant response induced by all the vascular relaxant agents investigated.

Aminoquinolines↗
PubMed2000

[Nitrates in cardiology practice].

Nitrates have been applied in cardiology over one hundred years. They act via nitric oxide release. Nitric oxide is the same substance as endogenous endothelium-derived relaxing factor (EDRF). The most frequently used nitrates are nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate and similarly acting moledidomine. The wide range of actions results in antiischemic and antianginal effect. The inhibition of platelet a aggregation is important as well. Nitrates have no significant adverse effects. They are used in symptomatic treatment of nearly all forms of coronary heart disease. They improve prognosis of patients with heart failure and have favourable effects on early and late left ventricle remodeling post myocardial infarction as well as on incidence of silent ischemia. Nitrates are used both for acute (short-term) and for long-term therapy. The may latter lead to development of tolerance, which can be prevented or reversed with intermittent-dosing regimens.

Humans↗
PubMed1990

[Nitrates in the treatment of heart failure].

Organic nitrates were the first peripherally-active vasodilators to be used for the treatment of heart failure. Currently, three nitrate derivatives, glycerol trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate as well as the nitrate-like substance molsidomine are employed clinically. For treatment of heart failure, the decisive hemodynamic effect is a meaningful reduction in ventricular filling pressures with maintenance or even a slight increase in cardiac output. The individual response to nitrates is variable. An important indicator for the effect achievable for a certain dose or for the necessary dosage to affect a defined reduction in ventricular filling pressures, is the magnitude of right atrial pressure. It can be assumed that the latter statement is also valid for the nitrate-like substance molsidomine. An inherent problem with any long-term treatment with nitrates is the incurrence of tolerance. This can be expected with any dosing regimen which leads to nitrate cumulation in the plasma or to nearly-constant, high, plasma concentrations as rendered by multiple daily administration of orally-active nitrates or with continuous transdermal or intravenous nitrate administration. The cause of nitrate tolerance is regarded as an insufficient or absent stimulation of guanylate cyclase and, consequently, inadequate generation of cyclic GMP due to availability of thiol substrate. Since the nitrate-like substance molsidomine appears to be able to stimulate guanylate cyclase independent of thiol groups, tolerance development may not be a limiting factor with this agent. Comparable reduction of diastolic pulmonary artery pressure after acute administration and at the end of one week of treatment with 4 mg molsidomine four times daily has been reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationship, Drug↗
PubMed1989

[Long-term therapy with nitrates. How can continuous effectiveness be achieved?].

Due to rapidly occurring tolerance, "continuous" administration of nitrates can no longer be considered justified. The development of tolerance can be avoided and, thus, the antiischemic effect maintained during long-term treatment only by providing a nitrate-free interval. Dosing regimens with documented effectiveness in long-term controlled studies are available for both isosorbide dinitrate and isosorbide 5-mononitrate as well as for transdermal nitroglycerin systems.

Administration, Cutaneous↗
PubMed1983

In vivo and in vitro studies to elucidate the hemodynamic differences of sodium nitroprusside, nitroglycerin, and two isosorbide nitrates.

In isolated renal veins of the rabbit, isosorbide dinitrate and isosorbide-5-mononitrate were seven to twenty times more potent as relaxants than in renal arteries which explains their predilection for the capacitance vascular bed in vivo. For sodium nitroprusside (SNP) and nitroglycerin (NTG), the sensitivity was slightly greater in veins at threshold concentrations (EC10), but similar in veins and arteries at higher concentrations (EC50). After 30 min of exposure, the relaxant effect to NTG faded partially in arteries, but not in veins, which may underlie its preference for the capacitance vessels in vivo. In anaesthetized rats, SNP and NTG were infused i.v. or into the femoral artery. The hypotensive response to NTG was the same by either route of infusion, whereas that to SNP was considerably lower on infusion into the femoral artery; a 34% inactivation of SNP on passage through the hind leg was calculated. The result decrease in venous over arterial blood levels of SNP at a somewhat greater sensitivity of veins than of arteries may account for the balanced effect of SNP on resistance and capacitance vessels in vivo.

Animals↗
PubMed1995

The rationale for nitrates in angina pectoris.

Organic nitrates are among the oldest drugs used in the management of patients with ischemic heart disease. The most frequently used nitrates are nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate. Their duration of action can be influenced by choice of substance, frequency of administration, formulation (eg, extended release) and route of administration. As well as providing effective treatment of acute angina, nitrates produce a long term prophylactic effect. Stable plasma nitroglycerin levels lasting longer than 10 to 12 h are not desirable due to the rapid development of tolerance. Simple, well-designed dosing schedules can avoid tolerance and rebound phenomena and can improve patient compliance.

Angina Pectoris↗
PubMed1995

The role of nitrates in coronary heart disease.

The organic nitrates are a safe and effective choice for the management of ischemic syndromes related to coronary heart disease. Although the anti-ischemic effects of these compounds have been recognized for more than a century, the mechanisms by which they exert their beneficial effects are still being delineated. In addition to their well-established venodilative activity, nitrates are now known to cause vasorelaxation of coronary arteries, coronary stenoses, and coronary collateral vessels and to prevent episodic coronary constriction. An antiplatelet effect has also been hypothesized. The three nitrate compounds currently available in the United States--nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate--are provided in a variety of dosage forms, including sublingual, transmucosal, oral, and transdermal preparations. The rapid- but short-acting nitrate preparations are useful in arresting and preventing acute attacks of angina pectoris, whereas longer-acting oral and transdermal formulations are indicated for the relief of chronic symptomatic and asymptomatic ischemia. The intermittent nitrate dosing regimens introduced in recent years have reduced the likelihood of tolerance, which greatly limited the usefulness of long-acting nitrates in the past. Intravenous infusion of nitroglycerin is particularly appropriate for the management of unstable angina and the early complications of acute myocardial infarction. Preliminary evidence suggests that intravenous nitroglycerin may also be beneficial in preventing postinfarction ventricular remodeling, although it cannot yet be recommended for this purpose.

Angina Pectoris↗
PubMed1983

Concentration and time-dependent relationships between isosorbide dinitrate-induced relaxation and formation of cyclic GMP in coronary arterial smooth muscle.

This study is based on the hypothesis that isosorbide dinitrate (ISDN)-induced relaxation of coronary arterial smooth muscle is causally linked to formation of cyclic (c) GMP. The hypothesis requires the extent of relaxation to be correlated to both time-and concentration-dependent increases in coronary content of cGMP. Accordingly, studies were performed with bovine coronary arterial strips to determine the relationships among isometric force and coronary content of cGMP and cAMP with respect to time of exposure to and concentration of ISDN. Cyclic nucleotide levels were determined by radioimmunoassay. No change in cAMP levels was observed during ISDN-induced relaxation of KCl contracted strips. In sharp contrast, cGMP levels increased significantly with time of exposure and concentration of ISDN stimulation. Moreover, the addition of methylene blue, a reported inhibitor of guanylate cyclase, to the bathing medium significantly inhibited the relaxation and cGMP increase during ISDN stimulation. In addition, prolonged exposure to ISDN resulted in a redevelopment of force with a parallel decrease in cGMP content. The increase in cGMP during ISDN stimulation also occurs in the absence of depolarization by KCl and in an essentially Ca++-free medium. These data support the hypothesis that the relaxation of coronary arterial strips in response to ISDN stimulation is causally linked to cGMP.

Animals↗
PubMed1986

Sarcolemmal dependence of isosorbide dinitrate-induced relaxation of aortic smooth muscle.

Studies were conducted to determine if ISDN antagonizes the contractile responses to calcium of chemically-skinned aortic smooth muscle preparations. Isosorbide dinitrate relaxed intact aortic smooth muscle segments in a dose-dependent manner (0.01-100 microM). At all concentrations tested, ISDN was unable to relax triton-skinned smooth muscle preparations. However, the tension development of skinned preparations was inhibited by trifluoperazine (10 microM), a calmodulin antagonist. These results suggest that the relaxation of intact aortic smooth muscle preparations induced by ISDN is not related to an interference with calmodulin-dependent contractile events.

Animals↗
PubMed1977

[Sublingual isosorbide dinitrate-induced severe hypotension, bradycardia and prelypothymia in patients with acute myocardial infarction (author's transl)].

100 patients with acute myocardial infarction were given 5 mg of sublingual isosorbide dinitrate within 36 hours by the onset of their symptoms. 86 patients did not show any unusual effect after the administration of the drug; their heart rate was only slightly increased and their arterial pressure slightly reduced. 14 patients developed severe systemic arterial hypotension, associated with absolute or relative bradycardia, within 30 minutes of receiving the drug. All the patients complained of fainting and sweating, 1 patient developed a syncope. Symptoms were relieved by raising patients legs in 10 cases, by 0.5 mg Atropina e.v. in 4 cases, 1 case required also external cardiac massage. There was no significant difference between the two groups as regard to the location of myocardial infarction nor to the functional class (according to Killip classification). Possible mechanism producing bradycardia, hypotension and lipothymia after nitrates administration are considered. A vagally mediate reflex possibly elicited by a fall in venous return is the most acceptable hypothesis. The study emphasizes the importance of carefull observation of patients receiving sublingual nitrates during acute myocardial infarction, and the rapid response of bradycardia, hypotension and lipothymia following nitrates administration, to a simple therapy, which avoids other potentially hazardous treatments.

Aged↗