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PubMed1975

Comparative vasodilator effects of nitroglycerin, pentaerythritol trinitrate and biometabolites, and other organic nitrates.

Previous studies in man have shown pentaerythritol (PE) trinitrate, given either sublingually or orally, produces a prolonged hypotensive effect. The coronary vasodilator and systemic vasodepressor activities of PE trinitrate and its metabolites, PE dinitrate, PE mononitrate and PE, were evaluated in dogs to determine whether the metabolites were active and contributory. Coronary vasodilator activity was estimated with a flow transducer placed on the left anterior descending artery, and reduction of arterial pressure was determined directly via the femoral artery. Quantitative comparisons were made from dose-response curves established for nitroglycerin (ng), PE nitrates, and other common organic nitrates after intrajugular administration. Increase of coronary blood flow and reduction of arterial pressure were proportionally related, and the proportionality was the same for all drugs. Relative to NG, the potency of PE trinitrate was about 20 percent, erythrityl tetranitrate 12 percent, and isosorbide dinitrate 3.5 percent. The ratios of vasodilator activity of PE trinitrate and its metabolities were: PE trinitrate 100; PE dinitrate 1.5; PE mononitrate 0.5; and PE O. Tachyphylaxis was observed after close-order injections of NG or PE trinitrate. In addition, there was cross tolerance between NG and PE trinitrate and also between PE trinitrate and its less active metabolites.

Animals↗
PubMed1987

Coronary artery infusion of neuropeptide Y in patients with angina pectoris.

Neuropeptide Y was infused into a coronary artery of 6 patients with typical angina but no significant coronary stenosis. 3 patients had transient myocardial ischaemia, shown by typical pain and electrocardiographic change, at doses of 0.2 pmol/kg per min in 2 patients and 1.0 pmol/kg per min in 1 patient. The arteriographic appearances suggested constriction of small vessels rather than constriction of epicardial coronary arteries. The ischaemia was completely reversed by intracoronary administration of isosorbide dinitrate with no adverse sequelae. This is the first demonstration of myocardial ischaemia in man induced by a peptide neurotransmitter.

Adult↗
PubMed1978

[Mode of action of cardiovascular drugs. Echocardiographic studies (author's transl)].

Echocardiography--combined with additional non-invasive methods--has proved a sensitive tool for measuring hemodynamic and left ventricular function parameters. This study was undertaken to measure by these methods the effect of digoxin, isoproterenol, of the beta-receptorblocker sotalol, sodium nitroprusside and isosorbide dinitrate on the hemodynamics and left ventricular contractility in various patients and normal volunteers. Besides the good reproducibility of results of recent invasive investigations, partly in animal experiments, new aspects about the mode of action of the individual substances were obtained.

Cardiovascular System↗
PubMed1984

Some pharmacological properties of organic nitrates.

The organic nitrates exert the same pharmacological actions. They differ in potency and in pharmacokinetics. They are more potent as dilators of veins than of arteries/arterioles and more potent as dilators of large arteries than of arterioles. This hemodynamic profile decreases heart work mainly by preload reduction but to some extent also by afterload reduction. The coronary flow is relatively improved and a redistribution to the ischemic myocardium takes place. The nitrates may facilitate the dissociation of oxygen from oxyhemoglobin and also may cause a more efficient energy metabolism. The basal mechanisms of action involve-SH groups and consecutively cyclic GMP. Glyceryl trinitrate is denitrated faster by the liver than is isosorbide dinitrate. The first pass metabolism is easily circumvented by sublingual and dermal application. Oral administration requires large dosages. Metabolites may contribute to the pharmacological activity. Plasma concentrations cannot be used to predict clinical effects of the nitrates.

Angina Pectoris↗
PubMed1984

Rebound of vasospastic angina after cessation of long-term treatment with nifedipine.

The beneficial effect of calcium antagonists in the treatment of vasospastic angina is now well recognized. Although withdrawal symptoms have been reported following abrupt cessation of therapy with some cardiovascular drugs, there is no detailed report on similar complications of the cessation of therapy with calcium antagonists. In a 4-month period eight patients with well documented and well controlled vasospastic angina experienced a marked increase in the frequency and duration of anginal episodes at rest following the involuntary cessation of treatment with nifedipine, 10 to 20 mg four times a day. The increase began within 2 to 5 days after the cessation of treatment. Substitute therapy with isosorbide dinitrate, 30 mg, and verapamil, 80 to 120 mg, each four times a day, was effective in all cases. Although the mechanism responsible for this rebound phenomenon is not known, awareness of its existence is essential considering the widespread use of calcium antagonists.

Adult↗
PubMed1981

Ergometric and hemodynamic studies on a new cardiotonic agent AR-L 115 BS.

The cardiotonic agent, 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazol[4,5-b]pyridine (AR-L 115BS), increases cardiac contractility and lowers cardiac pre- and afterload. These properties were shown to favourably influence hemodynamics at rest and under exercise in patients with coronary heart disease and angina pectoris. Although it reduces pre- and afterload, unlike isosorbide dinitrate it does not improve exercise tolerance in symptom limited ergometry. There was, however, no worsening of exercise tolerance. It appears that the decrease in oxygen consumption due to a decreased pre- and afterload is compensated for by an increase in oxygen requirement during contractility.

Angina Pectoris↗
PubMed1980

Chromosome aberrations induced by clinical medicines.

Inducibility of chromosome aberrations of cultured mammalian cells was examined on 11 clinical medicines which are used for a long term mainly in the field of internal medicine. P-aminosalicilic acid, isonicotinic acidhydrazid, streptomycin A, hydralazine hydrochloride methimazole and theophylline induced definite increase of chromosome aberrations. Among them P-aminosalicilic acid was a little weak in its effect. The effects of rifamycin SV, aminophylline and isosorbide dinitrate were judged as suspicious, because only a slight increase of the aberrations were caused. Reserpine and propylthiouracil induced little chromosome aberrations. Effective concentrations of these medicines in our chromosome test were compared with their maximum blood concentrations in clinical use in human quoted from the published papers. Their ratios by isonicotinic acid hydrazid, streptomycin A, methimazole, theophylline and issorbide dinitrate were very high and those by others were relatively low. Because p-aminosalicilic acid, rifamycin SV, hydralazine hydrochloride and aminophylline were positive or suspicious in our chromosome test, further pursue for the safety evaluation seems necessary.

Aminophylline↗
PubMed2002

Involvement of nitric oxide on prolactin release induced by immobilization stress in rats.

The nitric oxide (NO) has important participation in the control of hypothalamic-pituitary axis. The authors investigated the effect of NO donor, isosorbide dinitrate (ISDN), on prolactin (PRL) release induced by immobilization stress (IS) in male rats. Pretreatment with the NO donor, ISDN (2.5; 5 and 10 mg/kg), inhibited about 60-85% of the PRL response to IS. It is concluded that NO does participate in the regulation of PRL response to IS.

Animals↗
PubMed1994

Function of the peripheral serotoninergic pathways in migraine: a proposal for an experimental model.

We propose a model for assessing the function of 5HT receptors in migraine by evaluating their expression on monocytes by means of double-labeling fluorocytometry (CD14-positive cells FITC-labeled). This model demonstrates that during headache induced in migraine without aura sufferers given isosorbide dinitrate followed by sumatriptan treatment 5HT expression on monocytes progressively increases. This increase may be due to the activation of 5HT turnover and to the increased availability of 5HT displaced by sumatriptan from cerebrovascular receptors during head pain.

Adult↗
PubMed1995

Loss of flow-dependent coronary artery dilatation in patients with hypertension.

BACKGROUND: Abnormal endothelium-dependent coronary response to acetylcholine has been shown in patients with essential hypertension. We tested the hypothesis that flow-dependent dilatation, which has been shown in normal human coronary arteries, is impaired in hypertensive patients. METHODS AND RESULTS: The coronary vasomotor response to maximal increase of blood flow induced by papaverine was studied in 10 control subjects and in 14 hypertensive patients with no other risk factors and angiographically normal coronary arteries. After the injection of papaverine in the midportion of the left anterior descending coronary artery (LAD), the diameter of the proximal LAD (LAD1) was measured by quantitative angiography, whereas that of the proximal circumflex artery (LCx) served as control segment. Estimates of coronary blood flow in the distal LAD (LAD2) were calculated by intracoronary Doppler flow velocity measurements. An increase in LAD2 blood flow of 521 +/- 41% (P < .001) in control subjects was associated with a 17.0 +/- 3.3% dilatation of the LAD1 (P < .001) and with no significant change in the diameter of the LCx. In hypertensive patients, despite a comparable increase in LAD2 blood flow of 406 +/- 32% (P < .001), the LAD1 failed to dilate (-0.4 +/- 0.6%, NS). The dilative response to isosorbide dinitrate was similar in control subjects and hypertensive patients (30.0 +/- 4.1%, P < .001 and 21.9 +/- 1.9%, P < .001, respectively). CONCLUSIONS: Thus, the flow-mediated coronary dilatation is lost in hypertensive patients, and this may impair normal dilatation observed in response to an increase in myocardial metabolic demand.

Adult↗
PubMed1980

Coronary spasm management with verapamil (Isoptin).

Because of recurrent chest pain, 17 patients with documented spasm in coronary arteries without severe atherosclerotic obstructions were treated with verapamil in an open trial, using doses of 120 mg/day to 480 mg/day (mean, 240 mg/day). Thirteen patients received additional oral isosorbide dinitrate (30 mg/day). Eleven patients became asymptomatic, and four experienced marked reduction in frequency of attacks (one to four a month). While two patients did not respond, in most patients verapamil was effective in preventing attacks of angina due to coronary spasm.

Administration, Oral↗
PubMed1981

[Clinical, angiographic and therapeutic aspects of variant angina (author's transl)].

A report is given on seven patients with Prinzmetal's variant angina. Rest angina occurred in all patients. In contrast, exertional angina was observed only on patients with significant (greater than 70%) coronary stenosis. Likewise, electrocardiographic changes (negative T) were only demonstrable in patients with severe coronary obstruction. The coronary angiogram was normal in one patient, demonstrated insignificant lesions in two and significant stenosis in four cases. In patients with insignificant coronary lesions obstructive coronary spasm was provoked by ergonovine maleate and this group responded well to a combination of nifedipine and isosorbide dinitrate therapy. The patients with significant coronary stenosis were free from pain after coronary bypass surgery; one of these suffered a perioperative anterior myocardial infarction. On the basis of these observations promising therapy is possible if the coronary morphology is known.

Adrenergic beta-Antagonists↗
PubMed1993

1,4:3,6-Dianhydrohexitol nitrate derivatives. II. Synthesis and antianginal activity of aryl- or arylcarbonylpiperazine derivatives.

A series of 5-(4-aryl- or 4-arylcarbonylpiperazin-1-yl)-5-deoxy-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared in order to obtain orally active, nitrate-type vasodilators with reduced side effects. Our drug design was based on a small reduction in the lipophilicity compared to that of 5-deoxy-5-[4-(3-phenylthiopropyl)piperazin-1-yl]-1,4: 3,6-dianhydro-L-iditol 2-nitrate (1, KF14124). Compounds 4h (aryl = benzimidazol-2-yl), 4i (arylcarbonyl = nicotinoyl), and 4w (arylcarbonyl = 3-furoyl) showed potent anti-ischemic activity in a lysine-vasopressin-induced angina pectoris model (rats), and their structure-activity relationships are discussed. Compound 4i exhibited potent vasodilation of the coronary artery in anesthetized dogs and also exhibited potent preload reduction in a heart failure model (dogs) as compared with isosorbide dinitrate (2), nicorandil (3), and KF14124 (1). Furthermore, 4i showed much weaker acute lethal toxicity and less central nervous system depression than 1 in mice. Thus, 4i (KW-3196) is under development as a vasodilator and a drug for treating angina pectoris.

Angina Pectoris↗
PubMed1994

[The evaluation of the hemodynamic effects of captopril one year after a myocardial infarct].

In the present study, the authors evaluate the haemodynamic effects of continuous captopril therapy during one-year after a first anterior myocardial infarction (MI). Haemodynamic measurements are made during the first 48 hours after de MI and repeated one year later. Patients are divided in two groups: The first group had therapy with acetylsalicylic acid (ASA) and isosorbide dinitrate (ISDNI) and the second group had therapy with ASA, ISDNI and captopril. From their results the authors conclude that captopril helps peripheral resistances elevations, and that this is one of the mechanisms by which it can have a favourable effect after an anterior MI.

Adult↗
PubMed2000

Nitric oxide protects against contrast media-increased pulmonary vascular permeability in rats.

RATIONALE AND OBJECTIVES: Nitric oxide (NO) regulation of endothelial function is involved in the development of acute lung injury. The role of NO in contrast media-induced increases in pulmonary vascular permeability was investigated in a rat model. METHODS: Nonionic (iohexol) and ionic (ioxaglate) contrast media were intravenously injected at 1.5 mL/min in rats. Pulmonary vascular permeability was evaluated by measuring the amount of Evans blue dye uptake as a quantitative marker of albumin extravasation in lung tissue. RESULTS: Intravenous injections of contrast media at doses of 4 and 6 g I/kg induced a dose-dependent increase in pulmonary vascular permeability. L-Arginine (an NO synthase substrate) and N(G)-nitro-L-arginine (L-NNA) (an NO synthase inhibitor) prevented and aggravated, respectively, the increase in pulmonary vascular permeability induced by the contrast medium. An aggravating action of L-NNA was confirmed by morphological and histological observations, this action being blocked by L-arginine (300 mg/kg) but not by D-arginine. Isosorbide dinitrate (1-20 mg/kg), an NO donor, had a dose-dependent protective effect on ioxaglate-increased vascular permeability. CONCLUSIONS: Our experimental findings suggest that contrast media at high doses produce pulmonary edema by inhibiting endothelial NO production, and nitrovasodilators protect against this adverse effect in rats.

Animals↗
PubMed1981

Treadmill exercise protocols to demonstrate effectiveness of nitrate drugs in relief of angina pectoris; duration of action and degree of functional enhancement.

During constant uninterrupted exercise with mild angina present, either placebo, nitroglycerin, isosorbide dinitrate or erythrityl trinitrate was given by buccal membrane absorption. Placebo produced no relief and exercise had to be stopped. Nitroglycerin produced rapid complete relief and the long-acting drugs effected relief more slowly but of long duration as shown on repetitive walks as long as 3 h after drug administration.

Angina Pectoris↗
PubMed1998

Collateral flow detected by a Doppler guide wire in a case of vasospastic angina.

We could detect recruitable backward collateral flow in systole and diastole by using a Doppler guide wire during coronary artery spasm in a 42-year-old female among 20 patients with documented variant angina. The electrocardiogram (ECG) showed no ST-segment deviation, although she had chest pain and her coronary angiography showed a totally occluded right coronary artery. After administration of isosorbide dinitrate (ISDN) the collateral flow disappeared and the flow pattern recovered to normal. The good collateral flow pattern in patient with totally occluded coronary artery due to spasm was indicated to relieve myocardial ischemia, even when the patient felt chest pain.

Adult↗
PubMed2004

[Rest angina caused by coronary spasm].

HISTORY AND PHYSICAL EXAMINATION: A 70-year-old woman with recurrent angina at rest and dyspnea was admitted for coronary angiography. Prior to the admission an ECG showed new negative T-waves in the precordial leads, which have completely disappeared the day after. Clinical examination revealed a low systolic murmur over the aortic valve and a low murmur over the left groin artery. The other examination findings were normal. INVESTIGATIONS: Exercise ECG revealed no signs of ischemia. In the coronary angiography a plaque in the left circumflex artery without significant lumen reduction could be detected. Intracoronary administration of acetylcholine induced a spasm in the left circumflex artery with total lumen occlusion with reproduction of intense chest pain. After injection of nitroglycerin coronary spasm and chest pain were reversible TREATMENT AND CLINICAL COURSE: After the diagnosis of vasospastic angina pectoris medical treatment with isosorbide dinitrate and amlodipine was initiated. Additionally ACE- and CSE-inhibitors were prescribed to improve endothelial dysfunction. After one year the patient was free of symptoms. CONCLUSION: Coronary spasm can cause angina at rest. After confirmation of diagnosis an appropriate medical therapy could be applied and other unnecessary examinations including further coronary angiographies could be prevented.

Aged↗