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[Effects of nitrates and beta-blockers on platelet aggregation in patients with coronary heart disease].

Our study aimed at evaluating an effect of the selected nitrates and beta adrenoceptor blockers on platelet aggregation in patients (pts) with coronary artery disease (CAD). The study included 168 male patients (M), aged between 33 and 72 years (mean age 51 +/- 7). 61 M given isosorbide dinitrate were divided into three groups: in the group I and II an effect of the drug on the platelet aggregation following a single 10 mg (I) and 20 mg (II) dose has been evaluated; in group III an effect of the drug after a two-week treatment has been evaluated. 14 male patients (group IV) were given 5-mononitrate 40 mg daily for two weeks. 85 male patients, treated with propranolol have also been divided into three groups. In group V and group VII an effect of propranolol on platelet aggregation following a single dose of 40 mg and 80 mg has been evaluated respectively. In the group VII an outcome of a two-week propranolol therapy has been assessed. Eleven patients (group VIII) received nadolol in a dose of 40-80 mg daily for two weeks. Platelet aggregation induced by adenosine diphosphate (ADP) in concentration of 1 mM/ml and 5 mM/ml (groups I, II, III, V, VI, VII) and only of 1 microM/ml (groups IV, VIII) was evaluated with Born's method. In patients with CAD only isosorbide dinitrate inhibits platelet aggregation. This effect has been noted following a single dose as well as a two-week treatment. Other drugs (5-mononitrate, propranolol, nadolol) transiently increase platelet aggregation, but became either ineffective after two-week therapy (5-mononitrate, nadolol) or increase (propranolol) platelet aggregation. Tendency to inhibit (sorbonit) or to increase (propranolol) platelet aggregation has been more pronounced with higher concentration of aggregating factor.

Adrenergic beta-Antagonists↗

[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↗

A clinical investigation on tong xin luo capsule in treatment of coronary heart disease with silent myocardial ischemia.

36 cases of coronary heart disease with silent myocardial ischemia (SMI) were treated sequentially with Tong Xin Luo (TXL) capsule and isosorbide dinitrate in random order. The results showed that both drugs were effective in decreasing episodes of SMI and shortening the duration of asymptomatic myocardial ischemia. TXL, however, was found with a better action and was superior to isosorbide dinitrate. It was also found that TXL could improve diastolic function of the left ventricle as well.

Adult↗

Long-term changes in the response of conductance and resistance coronary vessels to endothelium-dependent and independent vasodilators. A double-blind placebo-controlled study of the effect of a 6-month treatment with cilazapril.

BACKGROUND: The aim of this study was to assess the effect of a 6-month treatment with the inhibitor of the angiotensin-converting enzyme cilazapril on the response of conductance and resistance vessels to endothelium-dependent and independent vasodilators, in a randomized placebo-controlled parallel group single center study. METHODS: Quantitative angiographic and Doppler flow time-averaged peak velocity measurements were performed in an artery with < 30% diameter stenosis after sequential selective intracoronary injection of papaverine (7 mg), acetylcholine (0.036, 0.36 and 3.6 microg/ml at 2 ml/min) and isosorbide dinitrate. Repeated assessment was performed after a 6-month treatment with cilazapril 20 mg/day or placebo. Thirty-four patients were enrolled in the study undergoing elective percutaneous coronary interventions for stable angina. Main outcome measures were percent differences from baseline and absolute measurements of mean coronary cross-sectional area, coronary flow time-averaged peak velocity and flow resistance in the initial study and at follow-up for the placebo and the treated group. RESULTS: No significant differences between the placebo and the treated group were observed in the modifications of cross-sectional area after acetylcholine and isosorbide dinitrate and in the response of time-averaged peak velocity to papaverine. After the maximal concentration of acetylcholine a high but statistically not significant increase in flow and a decrease in flow resistance were observed in the treated group (medians: 45% increase vs 4% increase for coronary flow, and 44% decrease vs 1% increase for flow resistance in the cilazapril and in the treated group, respectively, p = NS). CONCLUSIONS: In patients with coronary artery disease, a 6-month treatment with 20 mg of cilazapril/day did not modify the response to endothelium-independent and dependent vasodilators of epicardial arteries without any significant stenoses but induced a consistent, although not significant, increase in flow and decrease in flow resistance after acetylcholine.

Acetylcholine↗

[Intravascular Doppler for the evaluation of renal blood flow: validation and demonstration of vessel reactivity].

AIM: To assess the feasibility and to demonstrate the potential clinical application of intravascular doppler in the evaluation of renal blood flow in patients with hypertension and normal renal arteries. MATERIALS AND METHODS: Intravascular doppler was used to measure renal blood flow in 19 patients (34 kidneys) during arteriography to rule out renovascular hypertension. Arteriography showed no evidence of renal artery stenosis in any patient. Hemodynamic parameters, renal artery diameter, and doppler measurements were undertaken at baseline, after injection of a bolus (10 ml) of normal (0.9%) saline, and after injection of isosorbide dinitrate (1 mg diluted in 10 ml normal saline). RESULTS: Repeated measurements of renal blood flow confirmed the reproducibility of the technique. Basal blood flow was similar in both right and left kidneys; injection of vehicle solution (10 ml normal saline) had no effect on doppler parameters. Injection of isosorbide dinitrate resulted in a significant increase in renal blood flow velocity reflecting an increase in renal blood flow; this demonstrates the existence of a renal flow reserve. The degree of increase in renal blood flow varied significantly between kidneys. CONCLUSIONS: Intravascular doppler is a safe, effective, and reproducible technique for measurement of renal blood flow. It allows evaluation of variations in renal blood flow in response to diverse vasoactive drugs or other vasomotor stimuli. The present study demonstrated the heterogenous response of renal blood flow in response to vasodilator stimuli.

Angiography↗

[Utility of echo enhancers in the study of pulmonary circulation time].

UNLABELLED: Pulmonary circulation time (PCT) varies under different clinical conditions. To evaluate the PCT, the persistence of contrast in both ventricles and the digital arterial saturation of oxygen with peripheral intravenous injection of microbubbles, were examined 14 patients. Groups: I normals, II left ventricular hypertrophy (EF > 50%), III with mitral stenosis and IV in congestive heart failure. In seven patients, isosorbide S/L was administered after the first injection. The transpulmonary transit in beats was 7.3 in normals, and larger in the others. The persistence of echo contrast in right chambers was 31 beats in group I, and larger in the other groups. In left chambers it was 20.6 beats in group I, and larger in others. There were no alterations with regards to peripheral arterial saturation of oxygen. AII patients with isosorbide presented shorter PCT and persistence of contrast in right chambers. CONCLUSIONS: There are differences in PCT among normals, patients with mitral stenosis and those with congestive heart failure. Prolonged persistence contrast in right chambers indicates abnormally slow transpulmonary transit. Patients with congestive heart failure and ventricular damage, have longer persistence of echo contrast. PCT studied with contrast is an easy means of evaluating some aspects of pulmonary circulation.

Contrast Media↗

Efficiency of NO donors in substituting impaired endogenous NO production: a functional and morphological study.

Two exogenous NO donors were used to act as substitutes for impaired endogenous nitric oxide (NO) production due to inhibition of NO synthase in rats. Six weeks' lasting inhibition of NO synthase by NG-nitro-L-arginine methyl ester (L-NAME) induced stabilized hypertension. Simultaneously administered isosorbide-5-mononitrate did not prevent the development of hypertension. Molsidomine, administered concomitantly with L-NAME, significantly attenuated the BP increase. However, BP was still found to be moderately increased compared to the initial values. Remarkable alterations in the geometry of the aorta, carotid and coronary artery found in NO-deficient hypertension were prevented in rats administered L-NAME plus molsidomine at the same time. In spite of 6 weeks' lasting inhibition of NOS, the NOS activators acetylcholine and bradykinin induced BP decrease; the maximum hypotensive value did not differ from the values recorded in the controls or in animals treated with L-NAME plus molsidomine. Notably enough, the hypotension was similar to that found in rats administered L-NAME alone for six weeks. After NO synthase inhibition, Isosorbide-5-mononitrate does not substitute and molsidomine substitute only partially the impaired endogenous NO production.

Acetylcholine↗

Total prevention of the development of in vitro tolerance to organic nitrates. Experiments with antioxidants.

The nearly total inhibition of development of pharmacological tolerance to an organic nitrate is reported here for the first time. The development of in vitro tolerance in the rabbit aorta to isosorbide-5-mononitrate (CAS 87-33-2) was potently inhibited by five structurally unrelated antioxidants--diaminodurol, ascorbic acid, potassium sulphite, pyrogallol and quercetin. Diaminodurol, ascorbic acid and potassium sulphite decreased, but quercetin increased, the spasmolytic activity of isosorbide-5-mononitrate. Diaminodurol, potassium sulphite, quercetin and ascorbic acid potently inhibited the spasmolytic activity of nitric oxide (NO). Quercetin also inhibited the development of in vitro tolerance to glyceryl trinitrate. It is suggested that tolerance to organic nitrates is the result of biochemical damage caused by a reactive intermediate such as NO. To test this possibility directly the effect of pretreatment with NO on the spasmolytic activity of glyceryl trinitrate (CAS 55-63-0) was examined. This pretreatment produced a small but significant tolerance to glyceryl trinitrate and to SIN-1 (3-morpholinosydnone imine), which also acts through guanylate cyclase. There was no effect on the activity of the unrelated vasodilators nitrendipine and theophylline. It is concluded that the reaction between NO and soluble quanylate cyclase is a real but minor cause of tolerance to organic nitrates. Other possible mechanisms of tolerance development are discussed.

Animals↗

Vasodilator therapy for acute heart failure: haemodynamic comparison of hydralazine/isosorbide, alpha-adrenoceptor blockade, and angiotensin-converting enzyme inhibition.

Haemodynamic comparison of three vasodilation regimens [intravenous (i.v.) hydralazine and isosorbide dinitrate (ISDN) combined, i.v. doxazosin, and i.v. enalaprilat] was undertaken in 36 patients with acute left ventricular (LV) failure due to recent myocardial infarction. Each regimen achieved similar reductions in pulmonary artery occluded pressure (PAOP, preload) and systemic arterial pressures (afterload), with increased cardiac and stroke volume (SV) indexes (p less than 0.01). Only the hydralazine and isosorbide combination induced resting tachycardia. Balanced vasodilatation after selective alpha-adrenoceptor blockade (doxazosin) and angiotensin-converting enzyme (ACE) inhibition (enalaprilat) without increase in heart rate (HR) suggests that these therapies may have definite haemodynamic advantages over the hydralazine/ISDN combination.

Adrenergic alpha-Antagonists↗

Vasomotor response to ergometrine and nitrates of saphenous vein grafts, internal mammary artery grafts, and grafted coronary arteries late after bypass surgery.

BACKGROUND: In vitro studies have shown that the vasomotor response of internal mammary artery to vasoactive agents differs from that of saphenous vein. METHODS AND RESULTS: To assess whether the response in vivo to methylergometrine and to nitrates differs in saphenous vein grafts, internal mammary artery grafts, and coronary arteries, 25 patients were studied more than 6 months (range, 6-96 months) after surgery. Angiograms of saphenous vein grafts (n = 11) or mammary artery grafts (n = 14) were obtained in basal conditions, after intravenous infusion of 0.4 mg methylergometrine, and after intragraft infusion of 1 mg isosorbide dinitrate. Computerized quantitative angiography was used to assess the changes in luminal diameter of the bypass graft and of the grafted coronary artery (n = 11). Methylergometrine reduced the diameter of saphenous vein grafts by 6.9 +/- 7.4%, from 3.26 +/- 0.71 to 3.05 +/- 0.76 mm (p < 0.01), and that of grafted coronary arteries by 9.3 +/- 7.2% (NS compared with saphenous vein grafts), from 2.08 +/- 0.49 to 1.89 +/- 0.49 mm (p < 0.005). The diameter of internal mammary artery grafts did not change significantly, from 3.27 +/- 0.42 to 3.25 +/- 0.44 mm (-0.3 +/- 5.1%, p < 0.02 compared with saphenous vein grafts and p < 0.002 compared with coronary arteries). After isosorbide dinitrate, the diameter of both grafted coronary arteries and mammary artery grafts increased significantly (respectively to 2.46 +/- 0.62 mm and 3.44 +/- 0.43 mm), the vasodilatation being greater (p < 0.002) in coronary arteries (+17.8 +/- 9.8% in proportion to basal diameter, p < 0.001) than in mammary grafts (+5.5 +/- 3.3%, p < 0.001). The diameter of saphenous vein grafts returned to control values (3.28 +/- 0.70 mm, NS compared with basal); the changes in luminal diameter after nitrates (+0.7 +/- 3.1%, NS) were significantly smaller than for mammary artery grafts (p < 0.01) and for grafted coronary arteries (p < 0.001). CONCLUSIONS: Unlike internal mammary artery grafts, saphenous vein grafts constrict in response to methylergometrine and do not dilate in response to nitrates. These differences in vasomotor response could reflect heterogeneity in the sensitivity of vascular smooth muscle to these agents or differences in the basal level of vasomotor tone.

Cardiac Catheterization↗

Vasodilator therapy enhances neutrophil tissue migration.

Very little is known about the effect of vasoactive substances on migration of polymorphonuclear neutrophils in vivo. We evaluated the effect of oral treatment with isosorbide dinitrate on neutrophil migration into a sterile skin inflammatory focus in man with the use of "skin chamber technique". Isosorbide dinitrate increased the number of neutrophils harvested in the chamber as well as the "granulocyte clearance". Thus, vasoactive agent may increase neutrophil extravasation and subsequent tissue migration.

Administration, Oral↗

[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↗

[Inhibition of adenosine deaminase activity by drugs influencing the cardiovascular system].

Adenosine deaminase (ADA) is an unique enzyme which catalyzes conversion of adenosine and 2'-deoxyadenosine to inosine and 2'-deoxyinosine respectively. One of physiological roles of this enzyme is modulation of its substrate--adenosine concentration (both intracellular and extraectocellular). In presented work the influence of acetylsalicylic acid, metoprolol, simvastatin, isosorbide mononitrate and molsidomine on total activity of adenosine deaminase and its isoenzymes--ADA1 and ADA2 in vivo was studied. We have affirmed that simvastatin decreased of tADA activity by 50%, acetylsalicylic acid by 34%, metoprolol by 29.1% and isosorbide mononitrate by 19.3%. Only after molsidomine administration were no significant changes in ADA activity observed. The result showed that the decline of ADA activity was mainly due to marked decrease in ADA2 isoenzyme.

Adenosine↗

Pharmacokinetic/pharmacodynamic relationship of the duration of vasodilating action of organic mononitrates in rats.

Conflicting information existed regarding the relevance of pharmacokinetics in relation to the duration of action of organic nitrates. We examined this question using three geometric isomers of organic mononitrates, L-isoidide mononitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate, which produce no active metabolites but possess diverse biological half-lives (T1/2). These compounds were given i.v. to rats at doses which were predetermined to produce equal peak effects on pulse pressure. The relationship between percentage change in pulse pressure and plasma mononitrate level could be described by the classical Hill equation, with similar slope but different EC50 values. A duration of action, defined as the time taken for the pulse pressure to change from -30% to -20% from base line, was measured experimentally. Theoretical analysis suggests that a linear relationship should exist between this duration of action and T1/2/slope, and this was indeed observed (r = 0.99, P less than .01, n = 12), affirming the dependency of pulse pressure pharmacodynamics on the pharmacokinetics of organic mononitrates. Pharmacokinetic modeling of the in vivo time-dependent hemodynamic effects further indicated that the blood compartment data were more consistent with a mechanism of mononitrate action that involves metabolic activation to form nitric oxide and cyclic GMP, rather than direct receptor activation. Using this pharmacodynamic model, the in vivo half-lives of nitric oxide and cGMP were estimated to be 1.6 and 2.0 min, respectively.

Animals↗

[Clinical study on "sini" decoction on treating stenocardia for coronary heart disease].

OBJECTIVE: To observe clinical effect of "Sini" decoction on stenocardia for coronary heart disease. METHODS: 65 cases of stenocardia for CHD with deficiency of yang or cold syndrome were randomly divided into" Sini" decoction therapeutic group and isosorbide dinitrate controll group. Drug effects of the two groups were compared by clinical symptoms, electrocardiogram (ECG), myocardial oxygen consumption and cardiac function. RESULTS: "Sini" decoction had better effects on reducing myocardial oxygen consumption and improving cardiac function isosorbide dimitrate, and similar to improving clinical symptoms and ECG, decreasing frequency of stenocardia and dose of nitroglycerin on stenocardia for coronary heart disease. CONCLUSION: "Sini" decoction can treat stenocardia for CHD with deficiency of yang or cold syndrome.

Aged↗

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↗

Effect of preload and heart rate manipulation on Doppler transmitral flow velocity pattern: search for load--independent parameters.

Pulsed Doppler transmitral flow-velocity provides a non-invasive method for serial evaluation of diastolic function. However confounding influence of loading conditions and heart rate on transmitral flow makes many conclusions suspect. To study the effect of preload, various parameters of Doppler mitral spectrum were studied in 11 patients with stable effort angina, angiographic coronary artery disease and intact global and segmental systolic function, before and after administration of sublingual isosorbide dinitrate (group 1). Following isosorbide dinitrate administration, there was a significant increase in heart rate (p less than 0.001), decrease in left ventricular end-diastolic volume (p less than 0.01), no change in left ventricular ejection fraction and systolic blood pressure. Peak E velocity, E velocity-time integral, E/A velocity time integrals ratio, acceleration and deceleration rates and diastolic filling period were significantly reduced whereas peak A velocity, A velocity time integral, acceleration and deceleration times and atrial filling period were unchanged. In 10 age-matched patients (group 2), atrial pacing performed to achieve similar degree of increase in heart rate as in group 1 (10 +/- 1 vs 12. +/- 4, p = NS), resulted in a decrease in E velocity time integral, E/A velocity time integrals ratio and diastolic filling period (p less than 0.01) without any significant change in any other parameter. Absolute A velocity time integral, acceleration and deceleration times are the only parameters of transmitral diastolic flow-velocity profile which are relatively independent of preload and heart rate provided the change is small.

Administration, Sublingual↗

Lessons from V-HeFT: questions for V-HeFT II and the future therapy of heart failure.

V-HeFT, the first mortality trial in patients with heart failure, has provided important insights regarding trial design, including patient selection and efficacy criteria. Planning of V-HeFT II, the trial comparing hydralazine-isosorbide dinitrate and enalapril, has raised additional issues regarding the power to detect mortality effects and the relative value of non-mortality endpoints for efficacy. V-HeFT has demonstrated that some vasodilator regimens can prolong life in heart failure. Hydralazine + isosorbide dinitrate reduced mortality by 27% compared to placebo in patients treated with digoxin and diuretics. The possibility of a non-vasodilator mechanism for long-term benefit of these interventions is raised by the apparently poor relationship between the magnitude of vasodilation and the favorable long-term effects. These issues need to be explored in subsequent trials. In future long-term trials, however, the need for background therapy with drugs that have been effective in reducing mortality will make the identification of life prolongation from new therapies more difficult to demonstrate.

Enalapril↗

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