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PubMed1994

[Comparison of the effectiveness of olicard 40 retard and cardonit 40 prolongatum preparations in treatment of stable coronary heart disease].

The purpose of the work was a comparison of the effectiveness of representatives of two subgroups of nitrates: Olicard 40 (isosorbide mononitrate) and Cardonit 40 (isosorbide dinitrate) in the treatment of ischaemic heart disease. The studied group consisted of 52 patients with stable coronary heart disease who were given for 30 days according to "blind trial" rules either Cardonit 40 or Olicard 40 in single daily dose. The effects of the treatment were monitored, assessing the parameters during three exercise tests and two 24-hour records by the Holter method. The advantage of Olicard 40 was demonstrated, expressed by higher effectiveness in the treatment of coronary heart disease (especially its "silent" form) without development of tachyphylaxis and with lower per cent of adverse reactions.

Adult↗
PubMed1993

[Methodologic approaches to evaluation of interaction of anti-anginal agents in their combined use in patients with exercise-induced angina].

The paper shows methodological approaches to assessing the interaction (antagonism and synergism) of antianginal agents in their combination used in 15 patients with stable angina. Each patient underwent paired bicycle ergometry with placebo, isosorbide dinitrate, 10 mg (ID), nifedipine, 20 mg (N), propranolol, 40 mg (P), and a combination of the drugs: ID, 10 mg, +P, 40 mg; N, 20 mg, +P, 40 mg; ID, 10 mg+N, 20 mg. The results were processed by two-dimensional dispersion analysis. Based on the findings, it was concluded that the interaction of drugs in all combinations was statistically insignificant in patients. At the same time the developed individual criteria for assessing the interaction allowed patients both with synergic and antagonistic interaction of antianginal drugs to be revealed.

Angina Pectoris↗
PubMed1979

Nifedipine therapy for refractory coronary arterial spasm.

Nifedipine was evaluated in the management of eight patients with intractable coronary arterial spasm. All had Prinzmetal's variant angina, normal or mildly abnormal coronary arteriograms, and a positive ergonovine maleate provocative test. Anginal attacks occurred at least three times a week in all patients during isosorbide dinitrate therapy. All patients had a decrease in frequency of ischemic attacks with nifedipine. Seven patients underwent repeat Holter monitor evaluation, which confirmed the absence of ischemic changes while they were taking nifedipine. When nifedipine dosage was decreased.or therapy discontinued in six patients, all experienced a recurrence of anginal attacks. Two patients had minor side effects, which required a decrease in the dose of nifedipine. Nifedipine was well tolerated, and no major complications occurred with its use. Nifedipine appears to be effective in the management of patients with symptomatic coronary arterial spasm and normal or mildly abnormal coronary arteriograms. Our data justify further investigation of nifedipine for treatment of such patients.

Adult↗
PubMed1988

Effect of nipradilol, a new beta-blocker, on leukotriene D4-induced contraction in guinea pig tracheal smooth muscle.

The relaxant effect on smooth muscle of nitro compounds is suggested to be linked with the increase in the tissue level of cyclic GMP by activating guanylate cyclase. In this study, we investigated the effects of nipradilol, a new beta-blocker, which has NO2 residue in the molecular structure, and isosorbide dinitrate (ISDN) on guinea pig tracheal smooth muscle in comparison with the effect of propranolol. Nipradilol and ISDN showed dose-dependent relaxant effects on leukotriene (LT) D4-induced contraction of tracheal smooth muscle, though propranolol had no effect. 8-Bromo-cyclic GMP also showed a relaxant effect dose dependently. Nipradilol and ISDN elevated cyclic GMP levels in tracheal tissue dose dependently; however, propranolol caused no change in cyclic GMP levels. From these results, it is suggested that nipradilol relaxes LTD4-induced contraction of tracheal smooth muscle by increasing the tissue level of cyclic GMP.

Adrenergic beta-Antagonists↗
PubMed1986

Anion inhibition of the proton pump in rat liver multivesicular bodies.

Rat liver multivesicular bodies (MVB), as well as other hepatic subcellular organelles, are acidified by an electrogenic ATP-dependent proton pump that requires Cl- for maximal acidification (Van Dyke, R. W., Hornick, C. A., Belcher, J., Scharschmidt, B. F., and Havel, R.J. (1985) J. Biol. Chem. 260, 11021-11026), suggesting that Cl- serves as a permeable charge-compensating anion. However, we have observed that NO3- is unable to substitute for Cl-. This study was undertaken therefore to examine more closely the effects of Cl- on MVB acidification and to determine whether NO3- and other anions interact with the proton pump. ATP-dependent vesicle acidification and membrane potential (psi) were measured using the fluorescent dyes acridine orange and Oxonol V (bis(3-phenyl-5-oxoisoxasol-4-yl)pentamethine oxonol), respectively. Cl- both stimulated acidification (Km = 23.2 +/- 4.2 mM) and decreased psi (IC50 = 3.4 +/- 0.6 mM) in a concentration-dependent, nonlinear fashion. In the presence of saturating Cl- (100 mM), however, NO3- (shown to be more permeable than Cl-) and the impermeant anions SO4(2-) and PO4(2-), inhibited both ATP-dependent acidification and psi in a concentration-dependent manner. Other anions, including gluconate and HCO3-, had no effect. The inhibitory effect of NO3- was reversible. Neither SO4(2-) nor PO4(2-) appeared to block Cl- movement across the vesicle membrane as assessed by the ability of Cl- to decrease an established psi. In additional experiments, the effects of anions on relaxation of a previously established pH gradient were measured. Compared to Cl- or gluconate, NO3- had no significant effect on pH gradient relaxation, even when MVB were preloaded with NO3-, indicating that rapid cycling of NO3-/HNO3 across the MVB membrane does not occur. The organic nitrate, isosorbide dinitrate, also inhibited both acidification and psi and, similar to NO3-, had no effect on pH gradient relaxation. By contrast, NO2- potently inhibited both MVB acidification and psi but also rapidly relaxed a pre-established pH gradient, suggesting that NO2- increases MVB membrane proton permeability. Finally, MVB exhibited N-ethylmaleimide-sensitive ATPase activity that was inhibited 23.9% by NO3- (100 mM). In conclusion, although MVB are permeable to a variety of anions (Cl-, Br-, NO3-, NO2-), only Cl- and Br- support maximal rates of acidification by the proton pump.(ABSTRACT TRUNCATED AT 400 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

The effect of acute and chronic nitrate administration in precapillary and postcapillary pulmonary hypertension.

The effect of nitrates was monitored in 16 patients with precapillary, and in 12 patients with postcapillary pulmonary hypertension (PH). The patients had haemodynamic examination on acute administration of 10 mg of isosorbide nitrate (ID) in infusion and after 2-month therapy with 120 mg of isosorbide dinitrate retard daily. Acute ID administration decreased filling pressure of both ventricles, pulmonary and aortic pressure, pulmonary and systemic resistance and increased blood flow. No significant difference was found between the two types of PH. Long-term administration resulted in a statistically significant decrease in filling pressure (in both ventricles) and pulmonary pressure, even though the decrease was less pronounced than those seen following acute administration. Again, no statistical differences were noted between the two types of PH. While acute administration of nitrates decreases both preload and afterload, chronic administration decreases only preload. The implications of this finding for therapeutic practice are discussed.

Cardiomyopathy, Dilated↗
PubMed2000

A T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene and coronary arterial vasomotility.

In the endothelium, synthesis of nitric oxide (NO) from the amino acid L-arginine is catalyzed by the endothelial NO synthase (eNOS), and the continuously generated NO serves to maintain basal vascular tone. Recently, we discovered a T-786-->C mutation in the 5'-flanking region of the eNOS gene; this mutation reduced the promoter activity of the eNOS gene and was associated with coronary spasm. We examined the vasomotility of the epicardial coronary artery in subjects with and without T-736-->C mutation. We examined vasomotility in 32 consecutive subjects who were heterozygotes for the T-786-->C mutation and in 68 subjects without the T-786-->C mutation who had equivalent age, sex, and smoking status at the proximal and distal segments of the left descending coronary artery by performing quantitative coronary angiography. In subjects with the mutant allele (-786C allele), basal diameters of proximal and distal segments before intracoronary injection of acetylcholine (ACh) were less than diameters in subjects without the mutant allele (p <0.05), although there was no difference between subjects with and without the mutant allele in the diameters of coronary arteries after isosorbide dinitrate (ISDN) administration. When we compared the changes in diameters, both ACh-induced vasoconstriction and ISDN-induced vasodilatation in subjects with the mutant allele were significantly increased in the proximal (p <0.01, p <0.001, respectively) and distal segments (p <0.03, p <0.01, respectively). Taken together, these findings strongly suggest that the T-786-->C mutation increases the basal tone of the coronary artery, and enhances the response to the constrictor effects of ACh and the dilator effect of ISDN because of reducing the endothelial NO synthesis.

5' Flanking Region↗
PubMed2001

Methylene blue abolishes aortal tone impairment induced by liver ischemia-reperfusion in a dose response manner: an isolated-perfused double-organ rat model study.

Liver ischemia-reperfusion (IR) generates remote organ reperfusion injury attributable to oxidative mediators. We tested the protective properties of methylene blue (MB) on aortal dysfunction. An ex vivo rat liver-aortal ring model was used to study the results of aortal exposure to post-ischemia (IR) hepatic effluent and its response to phenylephrine and isosorbide dinitrate in the absence or presence of increasing concentrations of MB in the effluent. Aortal incubation with IR effluents resulted in abnormal contraction. Ring's response to the vasoactive drugs was abnormally weak both during and following this exposure. Return to stabilization tone was irregular. MB (1.28 mM) best avoided overall dysfunction; 0.86 mM was partially effective, and 0.42 mM was ineffective. Nitrite/nitrate levels were similar to controls in the only IR 1.28 mM perfusate. Liver IR interferes with aortal tone and its response to vasoactive drugs, probably via oxidative interaction with nitric oxide. MB reverses these effects in a dose-dependent fashion.

Acetylcholine↗
PubMed1987

Oral isosorbide-5-mononitrate: pharmacokinetics and clinical efficacy.

Isosorbide-5-mononitrate is a longer acting active metabolite than the parent drug, isosorbide dinitrate (ISDN), with a half-life of around 4 hours. In coronary heart disease, myocardial infarction and in heart failure it causes a typical nitrate action on the central hemodynamics, but due to a complete systemic availability with high and predictable systemic drug levels, a drug action with a lower interindividual variability than with ISDN is to be expected. There is a close correlation between serum level and effect. The antianginal exercise tolerance increasing and unwanted effects as well as the development of tolerance to the drug action are comparable with those of ISDN. This naturally long-acting metabolite in ISDN works usually with a standard dosage of 20 mg twice daily.

Administration, Oral↗
PubMed2002

Congestive heart failure: what should be the initial therapy and why?

Left ventricular systolic dysfunction is associated with neurohormonal activation which contributes to progressive ventricular remodeling and worsening clinical heart failure. Renin-angiotensin-aldosterone and sympathetic nervous systems are activated, not only in patients with clinically overt heart failure, but also in patients with asymptomatic or minimally symptomatic left ventricular systolic dysfunction. Activation of the angiotensin and adrenergic systems produces deleterious effects on systemic and coronary hemodynamics, promotes myocyte hypertrophy and fibroblast growth, and myocyte necrosis and apoptosis. Thus, therapy of heart failure should consist of pharmacologic agents not only to relieve symptoms but also to prevent and attenuate ventricular remodeling and progressive heart failure, thereby improving prognosis. In patients who are symptomatic, ACE inhibitors along with digitalis and diuretics as initial therapy (triple therapy) have the greater potential to improve exercise tolerance and decrease the incidence of treatment failure compared with diuretics alone or a combination of diuretics and digitalis. Diuretics alone should not be considered for long-term therapy as plasma renin activity, angiotensin II, aldosterone, norepinephrine and vasopressin levels may increase. ACE inhibitors decrease mortality in patients with heart failure resulting from left ventricular systolic dysfunction. The results of presently available studies indicate that angiotensin II receptor blockers (ARBs) do not provide any advantage over ACE inhibitors regarding survival benefit but may be better tolerated. Long-term adrenergic inhibition with the use of ss-adrenoceptor antagonists added to ACE inhibitors is associated with attenuation of ventricular remodeling, improvement in ventricular function and clinical class and survival of patients with symptomatic systolic left ventricular failure. Thus, initial pharmacotherapy for systolic heart failure should consist of: maximal tolerated dosages of ACE inhibitors;ARBs if ACE inhibitors are not tolerated because of intractable cough or angioedema;adequate dosages of hydralazine and isosorbide dinitrate if ACE inhibitors or ARBs are not tolerated; relatively low dosages of digoxin (serum concentrations of < or = 1.0 ng/dl) if not contraindicated; and diuretics to relieve congestive symptoms. Addition of spironolactone to ACE inhibitors can result in a significant reduction in the risk of sudden death in patients with symptomatic severe heart failure. Myocardial infarction resulting from ischemic heart disease is the most common cause of systolic left ventricular failure and the therapeutic modalities with potential to reduce the risks of myocardial infraction, such as risk factor modification, adequate control of diabetes and hypertension, antiplatelet agents and lipid-lowering agents, should also be included in the initial therapy.

Adrenergic Antagonists↗
PubMed1987

The Frankfurt experience in restenosis after coronary angioplasty.

Three hundred and thirty-three of 356 patients underwent angiographic follow-up from 1 to 18 months (mean 5.6 months) after percutaneous transluminal coronary angioplasty (PTCA). This is a reangiography rate of 94%. Recurrence rate after the first PTCA was 15% (n = 289). Restenosis rate was defined as an increase from immediate post-PTCA stenosis of more than 30%, or the loss of at least half of the initial gain in luminal diameter. Patients who needed a second angioplasty due to restenosis (n = 30) had a restenosis rate of 33%. Patients with angioplasty in the aortocoronary bypass (n = 14) had a restenosis rate of 45%. All patients were treated before, during and at least 4 to 6 months after the procedure with 60 to 100 mg of isosorbide dinitrate daily plus 160 to 360 mg of verapamil or 100 to 150 mg of gallopamil and 1.5 g of acetylsalicylic acid. In a second retrospective study 111 of 399 patients had the acetylsalicylic acid therapy discontinued or decreased. Forty-two of them developed restenosis (38%), whereas only 49 of 288 patients who continued to receive 1.5 g aspirin developed restenosis (17%). The restenosis rate was 32% in those who received the reduced dose of aspirin. Thus, a large dose of acetylsalicylic acid given before, during and 4 to 6 months after the procedure seems to be necessary to achieve a low rate of restenosis after PTCA.

Angioplasty, Balloon↗
PubMed2004

The inhibitory effect of sodium nitroprusside on HIF-1 activation is not dependent on nitric oxide-soluble guanylyl cyclase pathway.

Adaptation to hypoxia and maintenance of O(2) homeostasis involve a wide range of responses that occur at different organizational levels in the body. One of the most important transcription factors that activate the expression of O(2)-regulated genes is hypoxia-inducible factor 1 (HIF-1). Nitric oxide (NO) mediates a variety of biological effects including relaxation of blood vessels and cytotoxicity of activated macrophages. We investigated the effect of the clinically used nitrates nitroglycerin (NTG), isosorbide dinitrate (ISDN), and sodium nitroprusside (SNP) on HIF-1-mediated transcriptional responses to hypoxia. We demonstrate that among the three nitrates, only SNP inhibits HIF-1 activation in response to hypoxia. In contrast, NTG or ISDN does not affect HIF-1 activity. SNP inhibits the accumulation of HIF-1alpha, the regulatory subunit of HIF-1, and the transcriptional activation of HIF-1alpha via a mechanism that is not dependent on either NO or soluble guanylate cyclase.

Animals↗
PubMed1993

[Vasodilator therapy in cardiac failure].

In recent years, vasodilator drugs are considered a standard therapy for patients with symptomatic heart failure. Isosorbide dinitrate, venodilator, shows a striking fall in cardiac filling pressure. Hydralazine, arterially active vasodilator, decreases afterload and increases cardiac output. The combined use of nitrates and hydralazine shows synergistic effect in increasing cardiac output, lowering cardiac filling pressure and improving exercise tolerance and life expectancy. Prazosin showed no favourable effect on survival in a V-HeFT trial. Although calcium antagonists have been expected to improve hemodynamics in the patients with heart failure, there have been no controlled large trial to prove that the hemodynamic effect is accompanied by any improvement in exercise tolerance or quality of life. At the present, it is considered to be reasonable to use nitrates and hydralazine combined with ACE inhibitors, in patients with chronic heart failure.

Adrenergic beta-Antagonists↗
PubMed1994

Effects of a novel, selective and potent phosphodiesterase type V inhibitor, E4021, on myocardial ischemia in guinea pigs.

The anti-ischemic effects of a new, selective and potent cyclic 3',5'-guanosine monophosphate-specific phosphodiesterase (phosphodiesterase type V) inhibitor, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl ]piperidine-4- carboxylate (E4021), in a vasopressin-induced guinea pig anginal model were examined and compared with those of coronary vasodilators with a guanylate cyclase-activating action. An intravenous injection of vasopressin (0.2 IU/kg) into anesthetized guinea pigs produced ST segment elevation on the electrocardiogram (an index of myocardial ischemia) of 0.28 +/- 0.02 mV (n = 10) from the baseline within 30 s. E4021 administered intravenously at doses of 0.03 and 0.1 mg/kg, 5 min before the injection of vasopressin, significantly inhibited the ST segment elevation to 0.15 +/- 0.03 mV (n = 6, P < 0.01) and 0.17 +/- 0.02 mV (n = 6, P < 0.01), respectively. Three guanylate cyclase activators, isosorbide dinitrate (0.1 mg/kg), nicorandil (0.1 mg/kg), and FK409 (0.3 mg/kg), also significantly reduced the ST segment elevation to 0.18 +/- 0.03, 0.11 +/- 0.02 and 0.17 +/- 0.02 mV, respectively. In a second experiment, E4021 was administered intraduodenally 30 min before the injection of vasopressin to examine its oral effectiveness. Intraduodenal E4021, at doses of 1.0 and 3.0 mg/kg, also significantly inhibited the ST segment elevation to 0.16 +/- 0.02 mV (n = 6, P < 0.01) and 0.13 +/- 0.02 mV (n = 6, P < 0.01), respectively. It is concluded that the potent phosphodiesterase type V inhibitor, E4021, administered intravenously or intraduodenally, ameliorated myocardial ischemia similarly to guanylate cyclase activators. Thus, E4021 may be an orally effective drug in the treatment of angina pectoris.

Animals↗
PubMed1980

Hemodynamic effects of nitrates in chronic heart failure and myocardial infarction.

The peripheral venodilation, principal effect of NTG and nitrates may cause a significant reduction in pulmonary venous pressure and, therefore, improve the symptoms of pulmonary venous congestion. Hemodynamic effects o high doses of oral isosorbide dinitrate in patients with chronic heart failure (N - 13). (Formula: see text). The other mechanism by which nitrates can potentially improve cardiac performance in patients with heart failure due to obstructive coronary artery disease is by relieving myocardial ischemia which tends to improve global myocardial function. Nitroglycerin or nitrates improve systolic motion of the ischemic but viable myocardial segments improved segmental wall motion consequent on relief of regional myocardial ischemia is probably related to a decrease in the determinants in oxygen demand rather than an increase in regional myocardial blood flow. An increase in collateral blood flow, however, may be contributory. Effects of nitrates on coronary dynamics and myocardial metabolism. (Formula: see text). These findings suggest with nitrates cardiac performance improves with decreased metabolic cost.

Chronic Disease↗
PubMed1994

Sodium nitroprusside modulates NMDA response in the rat supraoptic neurons in vitro.

The modulatory effects of NO on N-methyl-D-aspartate (NMDA)-induced response in neurons of the supraoptic nucleus (SON) were studied by intracellular recording and radioimmunoassay of cyclic nucleotides using the rat brain slice preparation. Depolarization induced by 100 microM NMDA was reduced by application of 1 to 3 mM of the NO-donors, sodium nitroprusside, and isosorbide dinitrate in all 8 neurons and in 6 of 10 neurons, respectively. The scavenger for NO, hemoglobin, and the inhibitor of NO synthase, NG-nitro-L-arginine (LNNA) enhanced the NMDA-induced depolarization in four neurons and two of three neurons, respectively. Intracellular cGMP accumulation induced by NMDA was significantly diminished by LNNA. However, NMDA-induced depolarization was not affected by either the protein kinase inhibitor, N-[2-(methylamino)ethyl]-5- isoquinolinesulfonamide dihydrochloride (H-8), or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). These results indicate that NO reduces NMDA-induced depolarization in a manner that is independent of cGMP and may control the activity of the SON neurons through NMDA receptors.

Animals↗
PubMed2004

Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery.

We have recently demonstrated that fasudil, a Rho-kinase inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the inhibitory effect of fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosorbide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

[Long-term nitrate therapy in coronary heart disease--loss of effect by developing tolerance].

The therapeutic efficiency of the long-term nitrates in coronary heart disease with exercise-induced heart insufficiency is recently more frequently called in question by observations of a nitrate tolerance. In own long-term studies on 34 patients with coronary heart disease with clinical and haemodynamic evidence (pathologic increase of the end-diastolic pressure of the pulmonary arteries under ergometric load) of an exercise-induced heart insufficiency the efficacy of pentaerythril tetranitrate (PETN) and isosorbide dinitrate (ISDN) in chronic dosage titration use was tested. The oral nitrate therapy evoked a clear decrease of the end-diastolic pressure of the pulmonary arteries. The reduction of the values of the pressure of the pulmonary arteries was correlated with adequate clinical findings (significant decrease of the frequency of pectanginous attacks and of the sublingual need of GTN, regression of the ST segment depression). The own results with particular valuation of the microcatherisation of the right heart on exertion plead against a clinically remarkable nitrate tolerance and confirm the efficiency of the at present usual basic medicamentous therapy in patients with coronary heart disease and exercise-induced heart insufficiency.

Angina Pectoris↗