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PubMed1995

Failure of nitric oxide donors to alter arrhythmias induced by acute myocardial ischaemia or reperfusion in anaesthetized rats.

1. The aim of the present studies was to examine the effects of nitric oxide donors on arrhythmias induced by coronary artery occlusion and reperfusion, and on cardiac cyclic nucleotides. Experiments were performed in pentobarbitone-anaesthetized rats prepared for occlusion of the left coronary artery. 2. Sodium nitroprusside (0.1, 0.3 and 1 microgram kg-1 min-1) had no significant effects on the incidence of ventricular tachycardia, total ventricular fibrillation or the mortality resulting from 25 min of acute myocardial ischaemia when compared with values in controls. In addition, there was no alteration in the number of ventricular premature beats that occurred in survivors. 3. 3-Morpholinosydnonimine-N-ethylcarbamide (SIN-1, 10, 20 and 40 micrograms kg-1 min-1) caused marked hypotension but did not alter the incidence or severity of ischaemia-induced arrhythmias. In rats subject to abrupt reperfusion after 5 min of myocardial ischaemia, lower doses of SIN-1 (1, 3 and 10 micrograms kg-1 min-1) still caused significant reductions in systolic and diastolic blood pressure but were devoid of antiarrhythmic activity. 4. In separate experiments in sham-operated rats, sodium nitroprusside (1 microgram kg-1 min-1), isosorbide dinitrate (30 and 60 micrograms kg-1 min-1) and SIN-1 (20 and 40 micrograms kg-1 min-1) had no significant effects on cardiac cyclic GMP content. 5. These results indicate that nitric oxide donors do not alter arrhythmias induced by acute coronary artery occlusion or reperfusion in anaesthetized rats. Although increases in total cardiac cyclic GMP could not be detected, the results suggest that, at least in the rat, cyclic GMP does not influence these arrhythmias.

Anesthesia↗
PubMed1992

Development of nitrate tolerance and usefulness of pulse therapy in a patient with vasospastic angina.

In a 58-year-old man with vasospastic angina, we investigated the relationship between the antianginal effects of isosorbide dinitrate (ISDN) and plasma ISDN concentration. Despite adequate plasma ISDN levels, sustained therapy using ISDN tapes and oral ISDN (transcutaneously 160 mg and orally 100 mg ISDN day-1) failed to exhibit antianginal effects. However, pulse therapy using sublingual short-acting ISDN prevented anginal episodes, although the plasma ISDN levels were less than those of sustained therapy. Nitrate tolerance of the antianginal effects was avoided by creating an abrupt plasma ISDN concentration gradient using sublingual ISDN.

Administration, Oral↗
PubMed1987

Arterial dynamics, cardiac hypertrophy, and antihypertensive treatment.

The relationship between cardiac hypertrophy, ventricular function, and aortic volume distensibility was studied in men with sustained essential hypertension by echocardiography and determination of pulse-wave velocity. The more reduced the aortic distensibility, the higher was the blood pressure response to exercise and the greater were the degree of cardiac hypertrophy and the modifications in systolic time intervals. Changes in cardiac performance as determined by vasodilators equipotent in relation to blood pressure reduction were found to have markedly different effects on aortic distensibility; volume distensibility was unchanged by cadralazine but was improved by calcium entry blockers and isosorbide dinitrate. Our findings suggest that alterations in the buffering function of the large arteries, as indicated by decreased volume distensibility, participate in the increased afterload in patients with essential hypertension and thus influence the degree of cardiac hypertrophy and changes in cardiac function and selective use of antihypertensive drugs may influence cardiovascular morbidity and mortality by their differential effect on large-vessel distensibility.

Antihypertensive Agents↗
PubMed2003

Endothelial protection by pentaerithrityl trinitrate: bilirubin and carbon monoxide as possible mediators.

Pentaerithrityl tetranitrate (PETN) is a long-acting donor of nitric oxide (NO) and has recently been characterized as an antianginal agent that, in contrast with other nitric acid esters, does not induce oxidative stress and is therefore free of tolerance. Moreover, animal experiments have revealed that PETN actively reduces oxygen radical formation in vivoand specifically prevents atherogenesis and endothelial dysfunction. Because heme oxygenase-1 (HO-1) has been described as an antiatherogenic and cytoprotective gene in the endothelium, our aim was to investigate the effect of the active PETN metabolite pentaerithrityl trinitrate (PETriN) on HO-1 expression and catalytic activity in endothelial cells. Endothelial cells derived from human umbilical vein were incubated with PETriN (0.01-1 mM) for 8 hr. PETriN increased HO-1 mRNA and protein levels in a concentration-dependent fashion up to 3-fold over basal levels. Elevation of HO-1 protein was accompanied by a marked increase in catalytic activity of the enzyme as reflected by enhanced formation of both carbon monoxide and the endogenous antioxidant, bilirubin. Pretreatment of endothelial cells with PETriN or bilirubin at low micromolar concentrations protected endothelial cells from hydrogen peroxide-mediated toxicity. HO-1 induction and endothelial protection by PETriN were not mimicked by isosorbide dinitrate, another long-acting nitrate. The present study demonstrates that the active PETN metabolite, PETriN, stimulates mRNA and protein expression as well as enzymatic activity of the antioxidant defense protein, HO-1, in endothelial cells. Increased HO-1 expression and ensuing formation of bilirubin and carbon monoxide may contribute to and explain the specific antioxidant and antiatherogenic actions of PETN.

Animals↗
PubMed1983

Nitrates in aortic valve disease: acute and chronic effects.

The beneficial effect of Nitroglycerin (NTG) on myocardial oxygen-supply-demand ratio in severe aortic stenosis has been already demonstrated. But the chronic administration of isosorbide dinitrate (ISDN) does not reduce the increase in left ventricular filling pressures during exercise. Therefore in severe aortic stenosis, the effects of chronic nitrate administration on left ventricular hemodynamics during exercise do not correspond to the beneficial acute effects of NTG. In aortic insufficiency, sublingual NTG has only minor effects on left ventricular volumes, heart rate and cardiac output. A moderate reduction in pressures results in a significant reduction of wall stress, while there is no major change in regurgitant fraction.

Aortic Valve Insufficiency↗
PubMed1987

Efficacy of a new calcium antagonist PN 200-110 (isradipine) in angina pectoris.

Angina pectoris is one of the major syndromes against which to test the therapeutic effectiveness of any new calcium antagonist. An interim analysis of the efficacy and safety of a new dihydropyridine calcium antagonist (PN 200-110 [isradipine]) in patients with confirmed coronary artery disease is reported. The study was carried out in 3 centers; 50 patients of an anticipated 96 have completed the double-blind comparative phases in 3 separate studies. Preliminary results from the placebo-controlled study indicate that PN 200-110 was significantly more effective than placebo in reducing the anginal attack rate and glyceryl trinitrate consumption in the 15 patients so far enrolled. Dose-response comparisons against nifedipine in 21 patients and against isosorbide dinitrate in 14 patients demonstrate that PN 200-110 has a similar antianginal efficacy profile to both drugs. No significant change in any of the monitored safety factors was noted in any of the patients taking PN 200-110. The side-effects profile compared favorably with that of nifedipine. These interim results suggest that PN 200-110 will prove to be an effective and safe drug for the treatment of angina pectoris.

Angina Pectoris↗
PubMed1976

Comparison of the coronary collateral circulation in dogs and baboons after coronary occlusion.

The relevance to man of experimental observations on coronary collateral blood flow (CCBF) in dogs has been questioned. The effect of 2 to 3 hour coronary occlusions in the anesthetized dog and a primate, the baboon, were therefore compared, with CCBF measured by injections of 85Kr distal to occlusion with precordial counting. Before killing, additional isotope was infused to compare inner/outer wall flow distribution and myocardial tissue samples were analyzed for electrolyte content. Effects of nitrates on hemodynamics and metabolism were also compared in dog and baboon. Similar values for CCBF and resistance following occlusions were found in dog and baboon (flow approximately 25 per cent control, calculated resistance increase four- to sevenfold). Greater subendocardial ischemia in both species was indicated by isotope distribution less to the inner wall, but electrolyte changes (k+ less and Na+ greater in the ischemic area compared to nonischemic) were similar transmurally in both species. Hemodynamic responses to nitrate infusion (isosorbide dinitrate) were similar, with increase in CCBF and decrease in resistance. In neither group were inner/outer wall isotope distribution or electrolyte changes influenced by nitrate. The coronary collateral response to occlusion is similar in dog and baboon in terms of both hemodynamics and metabolic changes. After 2 to 3 hours of coronary occlusion some hemodynamic benefit may be demonstrated with nitrates but no metabolic advantage, at least in the central area of ischemia.

Animals↗
PubMed2006

Specificity of vascular reactivity and remodeling after repeated endothelial injury in a swine model.

We investigated the difference in vascular responses and remodeling between coronary and iliac arteries after repeated endothelial denudation. Endothelial denudation of the left anterior descending coronary artery (LAD) and the right common iliac artery (RIA) was repeated 4 times twice a month using a Fogarty catheter in 21 pigs. Vascular responses to vasoactive drugs were evaluated as % luminal diameter changes on contrast angiography 2 weeks after the last denudation. Corresponding nondenuded sites, ie, the left circumflex coronary artery (LCX) and the left common iliac artery (LIA), were used as references. Acetylcholine (1 microg/kg) did not constrict the LCX (0 +/- 1%) and the LAD (1 +/- 1%, P < 0.05), whereas it constricted the RIA (20 +/- 6%) but not the LIA (-3 +/- 3%, P < 0.01). Alternatively, serotonin (10 microg/kg) constricted the LAD strikingly (88 +/- 5%, P < 0.01 versus LCX and RIA), as well as the RIA (35 +/- 10%, P < 0.05 versus LIA). Vasodilator responses to substance P and isosorbide dinitrate were not different after injury in both arteries. The intima-to-media ratio and adventitia-to-media ratio of the relevant site in cross section of tissue sample from LAD were greater than those from LCX, and were more prominent than those from RIA. The results show that vascular tone regulation after the endothelial injury and vascular remodeling might be altered in a vessel-specific manner.

Acetylcholine↗
PubMed1981

First data on effects and pharmacokinetics of isosorbide-5-mononitrate in normal man.

Isosorbide-5-mononitrate (IS-5-MN) 5, 10, 20, 30, 40 and 50 mg were administered orally to 2 healthy male volunteers. The pharmacological effect was determined using digital pulse plethysmography and the orthostatic tilting test, and at the same time side effects were monitored. The threshold of oral activity of IS-5-MN was found to be 5 mg. The maximum response was reached with doses of 20-30 mg. The duration of action of this dose was approximately 8 h. Higher doses did not lead to any further increase, but rather to a decrease in the pharmacological response, while the side-effects, such as headaches, dizziness and nausea, became more prominent. In a randomized, double-blind, three-way cross-over study in 11 female volunteers IS-5-MN 30 mg proved to be more potent with respect to pharmacological activity than sustained released ISDN 20 mg (isosorbide dinitrate), whereas there was no difference in side-effects. Thus, it can be estimated that IS-5-MN 20 mg is approximately equivalent to 20 mg sustained released ISDN. IS-5-MN is rapidly absorbed after oral administration and the maximum concentration in serum was reached 1.2 +/- 0.2 h after doses of 10 to 50 mg. The pharmacokinetics showed dose-linearity. The compound was eliminated with an average half life of 4.04 +/- 0.16 h, which is appropriate for a reasonably prolonged duration of action without the need for a sustained release formulation.

Adult↗
PubMed1992

Impaired endothelium-dependent cholinergic coronary vasodilation in patients with angina and normal coronary arteriograms.

The coronary vasomotor responses to selective infusion of graded concentrations (10(-6) to 10(-4) M) of acetylcholine into the left anterior descending artery were assessed by quantitative coronary arteriography in 24 patients with normal coronary arteriograms (12 patients with atypical symptoms and 12 patients with typical anginal pain) and 36 patients with coronary artery disease with different degrees of atherosclerosis of the left anterior descending artery. In the patients with normal coronary arteries and atypical chest pain, acetylcholine induced predominantly a vasodilator response, which was maximal during a 10(-5) M acetylcholine infusion. In contrast, in patients with coronary artery disease, acetylcholine caused dose-dependent vasoconstriction, which was observed even if the left anterior descending artery itself was smooth. Marked vasoconstriction was also induced in the patients with typical anginal pain and angiographically normal coronary arteries. In nine of these patients, this constrictor response was associated with anginal pain and electrocardiographic evidence of myocardial ischemia. Intracoronary administration of isosorbide dinitrate (1 mg) relieved the anginal pain and dilated all vessels. These data suggest that 1) patients with normal coronary arteriograms and angina pectoris manifest impairment of endothelium-dependent vasodilation similar to that observed in patients with overt coronary atherosclerosis; and 2) abnormal coronary vasoconstrictor responses resulting from this impairment may contribute to the pathogenesis of myocardial ischemia and angina in these patients.

Acetylcholine↗
PubMed1986

[Clinico-pharmacological study of a new Russian anti-angina preparation dinitrosorbilong].

Eighty patients with ischemic heart disease and stable angina pectoris of effort were examined for the efficacy of dinitrosorbilong (DNL), a new long-acting drug based on isosorbide dinitrate (ID). The anti-ischemic effect of DNL appraised with the aid of repeated exercise lasted about 8h, which was on the average 4 h longer as compared with the duration of the anti-ischemic effect of ID tablets. The regular intake of DNL favoured an appreciable decrease in the number of angina pectoris attacks making it possible to lower nitroglycerin consumption. DNL was well tolerated by the patients.

Administration, Oral↗
PubMed1982

Diltiazem for long-term therapy of coronary arterial spasm.

The first 36 patients with coronary arterial spasm treated with diltiazem and followed up at the Stanford University Coronary Artery Spasm Clinic for 6 months or longer are described. There were 13 men and 23 women with a mean age of 50.2 years; the mean duration of angina was 36.1 months. All patients had angina at rest with a good or fail response to sublingual nitroglycerin. During a mean of 17.5 months of diltiazem therapy, the frequency of angina was reduced from a mean of 21.5 to 1.3 attacks/week. This 94 percent reduction in pain frequency occurred when either 240 or 360 mg of diltiazem was administered daily. Sixteen patients required the addition of isosorbide dinitrate to achieve a painfree state. Pain breakthrough occurred a mean of 1.7 times during the 17.5 month follow-up period but tended to be of short duration. Six patients had trace to 1+ pedal edema and no other adverse effects occurred. It is concluded that diltiazem is highly effective and well tolerated for the long-term prophylaxis and treatment of angina in patients with coronary spasm.

Adult↗
PubMed1985

Large vessel coronary vasospasm: diagnosis, natural history and treatment.

The diagnosis of coronary artery spasm is confirmed by angiography, for example, change in caliber of the coronary arteries plus evidence of ischemia. The prevalence and contribution of coronary artery spasm in the individual patient with symptoms of ischemic heart disease is not known and depends on how the condition is defined. The prognosis of patients with coronary artery spasm appears to depend on the presence or absence of severe coronary atherosclerosis, that is, those with severe disease have a worse prognosis. Nitrates should be used to initiate therapy in all patients with this problem. Intravenous nitrates have proven useful in patients whose symptoms are difficult to control and who require hospitalization. beta blockers used alone may be detrimental in patients with coronary artery spasm, but studies supporting the detrimental effects are few. The combination of nitrates, beta blockers and nifedipine has proved effective therapy for many patients with recurrent angina at rest, possibly related to coronary artery spasm. Several open-label and double-blind placebo control trials have shown that all of the calcium antagonists are effective short-term agents for patients with proven coronary artery spasm. When nifedipine was compared with isosorbide dinitrate in a randomized crossover, double-blind trial in patients with coronary artery spasm, both drugs were shown to be efficacious and neither was superior. The traditional alpha-blocking agents have not been shown to be an effective therapy, but a recent study of prazosin, a selective alpha blocker, revealed excellent results in patients whose conditions were resistant to therapy with traditional calcium blockers, beta blockers and, in 1 case, phenoxybenzamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1988

Effects of nifedipine and nitrates on coronary vasomotion.

The diameter changes of angiographically normal coronary arteries following vasodilator drugs were studied in 41 patients. In group 1 (22 patients) angiograms and plasma levels were obtained before as well as 10, 20 and 30 minutes after 20 mg nifedipine s.l. (15 patients) or placebo (7 patients). A cluster analysis allowed a classification of patients into group A (N = 4) and B (N = 11) according to the slope of plasma level increase. Plasma levels A versus B were 27.8 +/- 9.8/13.5 +/- 4.5 ng ml-1; P less than 0.05; 54.0 +/- 11.7/21.7 +/- 6.6 ng ml-1; P less than 0.001; 79.1 +/- 9.3/28 +/- 9.8 ng ml-1; P less than 0.001. Corresponding diameter changes A versus B were: 7.3 +/- 5.1%/-5.6 +/- 9.0%; P less than 0.01; 11.4 +/- 4.1%/-4.5 +/- 11.3%; P less than 0.01; 14.5 +/- 5.9%/0.5 +/- 13.6%; P less than 0.05. In group 2 (N = 19) angiograms were obtained before as well as 2, 4, 7 and 15 minutes after administration of 10 mg isosorbide dinitrate (N = 9) or placebo (N = 10). Coronary dilation ISDN versus placebo was: 2.4 +/- 3.6%/0.9 +/- 4.0%; NS; 10.6 +/- 5.1%/3.1 +/- 3.8%; P less than 0.001; 12.3 +/- 5.9%/-0.3 +/- 6.4%; P less than 0.005; 10.5 +/- 6.5%/-4.0 +/- 7.7%; P less than 0.005. These data indicate that the interindividual variations of changes in coronary lumen size are due to different slopes of plasma level increase, most likely due to different rates of drug absorption after sublingual administration of nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Sublingual↗
PubMed1980

Influence of vasodilator therapy on prognosis of acute myocardial infarction in the aged patients. A comparative study between vasodilator-treated group and group treated without vasodilator.

Influence of vasodilator therapy on prognosis of acute myocardial infarction complicated by left heart failure (in Killip classes II and III) was studied in 22 aged patients (mean age; 75.7 years). The patients were retrospectively divided into 2 groups: Group I; 12 patients were treated with isosorbide dinitrate and/or chlorpromazine and Group II; 10 patients were treated with other conventional medical measures. Initial hemodynamic changes on admission were not significantly different between 2 groups. With these treatments mortality rate within 2 weeks of treatment was lower in Group I than in Group II (p less than 0.01), however, cumulative cardiac mortality rate within 18 months did not differ significantly. The present study demonstrated beneficial influence of vasodilator therapy on early prognosis in aged patients, but failed to show prolonged influence on later mortality.

Age Factors↗
PubMed1992

[Nitrate derivatives and coronary vasomotricity].

The action of nitrate derivatives on the coronary arterioles is weak and very short lasting which avoids the phenomenon of a coronary steal syndrome. Investigations of the epicardial coronary vessels require vasoconstriction stress tests, usually using ergometrine, and vasodilatation tests, mainly using isosorbide dinitrate (ISDN). The combination of the two tests allows evaluation of global coronary vasomotricity which is less than 100% variation of diameter. In coronary spasm, ISDN relieves the stenosis in less than 2 minutes in nearly all cases. An infusion of ISDN also prevents most cases of arterial spasm. In effort angina, it has been possible to demonstrate paradoxal vasoconstriction during exercise due to endothelial dysfunction. The direct action of nitrate derivatives on smooth muscle which is not endothelium dependent, prevents the vasoconstriction and increases oxygen supply during exercise.

Coronary Artery Disease↗
PubMed1994

[Gas chromatographic method with EC detection to determine isosorbide-5-mononitrate (IS-5-MN) in human serum and its pharmacokinetic parameters].

A simple, sensitive and precise capillary GC-ECD method was developed for the determination of isosorbide-5-mononitrate in human serum. Pharmacokinetic parameters of the drug was obtained from the human serum level-time curve measured. Serum samples were extracted with a mixture of ethyl ether-ethyl acetate (4:1), the upper phase was collected and evaporated to about 100 microliters under a gentle nitrogen stream. Isosorbide dinitrate was used as internal standard. With a human serum sample size of 200 microliters, the detection limit of IS-5-MN was found to be about 5 ng/ml, and the absolute recovery from 74% to 85%. The within-day and between-day relative standard deviation were less than 7% and 9%, respectively. This method was applied to the pharmacokinetic studies of IS-5-MN tablets from two different sources. Two sets of t1/2 (Ke), Tmax and AUC values obtained from 8 volunteers were tested statistically and no significant difference was found.

Chromatography, Gas↗
PubMed1984

Effect of transluminal coronary recanalization on left ventricular regional wall motion and clinical course in acute myocardial infarction.

We performed percutaneous transluminal coronary recanalization (PTCR) in 90 patients within 12 hours of onset of acute myocardial infarction (AMI). Fifty seven patients had total occlusion and 33 patients had subtotal occlusion of the involved coronary artery. Reopening of the occluded coronary artery by injection of isosorbide dinitrate (ISDN) was achieved in 24.4%. Continuous infusion of Urokinase was effective in 82.7%. Comparison of conventional therapy with PTCR showed that ejection fraction was higher in patients with PTCR than in those with conventional therapy, and that wall motion shortening was better in the former than in the latter. Relationship of regional wall motion shortening to the time interval from the onset of AMI showed that wall motion shortening was better it recanalized within 3 hours to and was fine within 6 hours, but poor after 6 hours of onset of AMI.

Adult↗