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Haemodynamic comparison of different routes of nitrate administration in postmyocardial infarction left ventricular failure.

An open randomised parallel group comparison of the haemodynamic effectiveness of three different routes of nitrate administration was undertaken in 36 male patients aged 40-69 years who had developed acute left ventricular failure within 18 h of the onset of myocardial infarction. All patients had electrocardiographic and serum cardiac enzyme changes compatible with transmural myocardial infarction and all had both radiographic and haemodynamic evidence of left ventricular failure. None were hypotensive, all were in sinus rhythm and none were receiving other cardioactive drugs. Control haemodynamic measurements were made over a period of one h, following which patients were randomised to receive either intravenous isosorbide dinitrate (mean dose 12.9 mg; range 7.7-14.9), buccal nitroglycerine (5 mg) or transdermal nitroglycerin (nitro TTS 10). The raised left heart filling pressure was reduced by all nitrate preparations but none significantly changed the heart rate or cardiac output. Systemic arterial pressure and vascular resistance were reduced by i.v. ISDN and buccal NTG but not by a transdermal NTG. The only adverse circulatory reaction was hypotension in the three patients following buccal NTG. Nitroglycerin by the transdermal route appears to be equally effective in reducing the raised left heart filling pressure in patients with postinfarction heart failure without the practical disadvantages of monitoring its intravenous administration or the potential hazard of hypotension with buccal NTG.

Administration, Buccal↗

Protective effect of enalapril on vascular reactivity of the rat aorta.

Cardiovascular complications are the major cause of morbidity and mortality in patients with diabetes mellitus (DM). Strategies that interrupt the renin-angiotensin system have been shown to reduce the ensuing threatening risk factors. The present study was carried out to investigate the effect of subchronic administration of enalapril on the aortic reactivity of streptozotocin (STZ)-diabetic rats. For this purpose, STZ-diabetic rats received enalapril (10 and 20 mg/kg ip) daily for 2 months. Contractile responses to phenylephrine (PE) and relaxation responses to acetylcholine (Ach) and isosorbide dinitrate (ISD) were obtained from aortic rings. Concentration-response curves from enalapril-treated diabetic (ED) rats to PE were attenuated as compared to vehicle-treated diabetics (VD), especially at a dose of 20 mg/kg for enalapril. In addition, endothelium-dependent relaxation responses induced by Ach was significantly higher in ED rats as compared to diabetic ones. The endothelium-independent relaxation responses for ISD were also found not to be significantly different among the groups. Therefore, subchronic treatment of diabetic rats with enalapril in a dose-dependent manner could prevent the functional changes in vascular reactivity in diabetic rats.

Acetylcholine↗

Importance of peak enzyme level and reinfarction while attempting to intervene myocardial infarction process.

Isosorbide dinitrate (ISDN) was tried in 27 patients, of which 4 patients with evidence of reinfarction were excluded in the course of the study, with acute myocardial infarction, with the aim of reduction of enzymatically estimated infarction size. The drug apparently seemed useless, when overall effects of the therapy was looked into. But in the group, where drug was administered before the occurrence of peak enzyme level (PEL), ISDN could reduce infarction size by 22.95% (p less than 0.01). Similarly when all the 12 cases of re-elevation of enzyme level (suggesting reinfarction) were excluded, the drug was found to reduce infarction size by 21.14% (p less than 0.01). Time of onset of therapy with respect to PEL and occurrence of reinfarction seemed to be important governing factors regulating the efficacy of drug therapy.

Humans↗

[Long-term effect of various nitrates in ischemic heart disease and latent heart failure].

In 24 patients (pts) with proven coronary artery disease, stable angina pectoris (AP) and elevated pulmonary artery pressure (PAP) during bicycle exercise, the acute and chronic (4 and 8 months) effects of several long-acting nitrates in different dosages: 50-300 mg pentaerythrityltetranitrate (PETN) or 40-120 mg isosorbide dinitrate (ISDN) were evaluated in comparison to sublingual nitroglycerin. Nitroglycerin was about 30%-40% more effective than PETN and ISDN with regard to pulmonary artery pressure at exercise. Beneficial effects of both long-acting nitrates were shown with regard to the number of anginal attacks, nitroglycerin consumption, and ST-segment depression both during short- and long-term treatment. Both nitrates decreased exercise pulmonary artery pressure by 15%-20%, at acute testing and during chronic therapy. There was no difference with respect to the long-term effects of both long-acting nitrates. However, more side-effects were observed during ISDN treatment. There were no signs of nitrate tolerance development with the therapy schedules under investigation.

Adult↗

Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells.

Endothelium-derived relaxing factor has been recently identified as nitric oxide. The purpose of this study was to determine if vasodilator drugs that generate nitric oxide inhibit vascular smooth muscle mitogenesis and proliferation in culture. Three chemically dissimilar vasodilators, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and isosorbide dinitrate, dose-dependently inhibited serum-induced thymidine incorporation by rat aortic smooth muscle cells. Moreover, 8-bromo-cGMP mimicked the antimitogenic effect of the nitric oxide-generating drugs. The antimitogenic effect of S-nitroso-N-acetylpenicillamine was inhibited by hemoglobin and potentiated by superoxide dismutase, supporting the view that nitric oxide was the ultimate effector. Sodium nitroprusside and S-nitroso-N-acetylpenicillamine significantly decreased the proliferation of vascular smooth muscle cells. Moreover, the inhibition of mitogenesis and proliferation was shown to be independent of cell damage, as documented by several criteria of cell viability. These results suggest that endogenous nitric oxide may function as a modulator of vascular smooth muscle cell mitogenesis and proliferation, by a cGMP-mediated mechanism.

Animals↗

Continuous treatment with organic nitrate affects hepatic cytochrome P450.

We previously reported that cytochrome P450 (P450) is a key enzyme of organic nitrate biotransformation and that P450 levels of the heart and its vessels markedly decreased at the development of nitrate tolerance. Escape from tolerance of organic nitrate by induction of cytochrome P450. Most organic nitrates, including nitroglycerin (NTG), are metabolized in the liver, where nitric oxide (NO) is concomitantly produced from the organic nitrates. Therefore, organic nitrate administration may also affect hepatic P450 levels, since the liver is the major organ of P450-related metabolism. Male Wistar rats were intravenously administrated NTG or isosorbide dinitrate (ISDN) for 24-96 h. Hepatic P450 was drastically decreased after 48 h or 72 h of continuous NTG or ISDN infusion, when nitrate tolerance was observed, but it recovered 48 h after cessation of the drug administration. hemeoxygenase-1 (HO-1) was induced within 24 h of continuous NTG infusion, but it returned to normal levels 48 h after cessation of the NTG. The administration of sodium nitroprusside, an agent to which the animals showed no tolerance, did not induce HO-1 or P450 depletion as judged by SDS-PAGE in combination with Western-blotting. These results suggest that P450-dependent drug metabolism may be drastically affected after continuous organic nitrate administration.

Animals↗

Susceptibility to cerulein-induced pancreatitis in inducible nitric oxide synthase-deficient mice.

Production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been proposed as a pathogenic factor in acute pancreatitis, but its role has still not been fully examined. The present study explored the role of iNOS in cerulein-induced acute pancreatitis using iNOS-deficient mice. Twelve- to 14-week-old male mice (C57B1/6 and iNOS-deficient) were administered cerulein by intraperitoneal (i.p.) injection at hourly intervals for 7 hours and killed 24 hours later after the first dose. Pancreatic wet weight, pancreatic myeloperoxidase (MPO) activity, and levels of plasma nitrite and serum amylase were measured. In another experiment isosorbide dinitrate (an NO donor) was given by oral gavage every 6 hours for 24 hours beginning simultaneously with cerulein injections in iNOS-deficient mice. Cerulein administration dose-dependently increased pancreatic wet weight, myeloperoxidase activity, and levels of nitrite and amylase in C57B1/6 mice. These parameters (except nitrite levels) were significantly intensified in iNOS-deficient mice. At the dose employed, cerulein failed to increase nitrite levels in iNOS-deficient mice. The susceptibility to cerulein toxicity in iNOS-deficient mice was abolished by NO donor treatment. NO release from an iNOS source appears to play a protective role in cerulein-induced pancreatitis. At least in part, NO may prevent neutrophil accumulation after cerulein administration.

Acute Disease↗

Successful treatment of coronary artery spasm following coronary artery bypass grafting.

A case of coronary artery spasm developed 6 hours after myocardial revascularization inducing both hemodynamic and electrocardiographic changes, is reported. The spasm was documented by coronary angiography, and it was not reversed by intracoronary infusion of isosorbide dinitrate. Intravenous infusion of nifedipine (initial dose of 0.0104 mg/min to final dose of 0.0208 mg/min), along with infusion of glyceronitrate (1.0 micrograms/kg/min) was able to significantly improve hemodynamic impairment and to reverse electrocardiographic changes in 12 hours. Coronary angiography, repeated in postoperative day 3, after 48 hours of continuous nifedipine infusion, showed a resolution of coronary spasm. There was no evidence of myocardial infarction as resulted from total CPK and MB isoenzyme release. Nifedipine infusion was gradually reduced as oral administration of slow release nifedipine (40 mg twice daily) was started. The combined intravenous infusion of glyceronitrate and nifedipine seems to be able to control and overcome coronary artery spasm following coronary surgery.

Coronary Angiography↗

Early vasoreactive profile of skeletonized versus pedicled internal thoracic artery grafts.

BACKGROUND: No data are available on the early vasoreactive profile of skeletonized internal thoracic artery grafts. METHODS: Fifteen patients undergoing primary isolated coronary artery bypass grafting were randomly assigned to receive a skeletonized or pedicled internal thoracic artery graft. On the second postoperative day all patients were subjected to follow-up angiography and endovascular infusion of serotonin, acetylcholine, and isosorbide dinitrate. RESULTS: Internal thoracic artery grafts were widely patent in all cases. Mean diameters of the internal thoracic artery were 1.95 +/- 0.17 mm in the pedicled group and 2.26 +/- 0.40 mm in the skeletonized group. After serotonin challenge, mean internal thoracic artery diameters were reduced to 1.44 +/- 0.34 mm and 1.64 +/- 0.14 mm, respectively; acetylcholine challenge lead to a moderate degree of vasoconstriction (1.55 +/- 0.59 mm in the pedicled group and 1.84 +/- 0.15 mm in the skeletonized group). No statistically significant difference was evident between the two groups at any step. CONCLUSION: Skeletonization does not affect the early vasoreactive profile of internal thoracic artery grafts used for surgical myocardial revascularization.

Acetylcholine↗

[Determination of isosorbide-5-mononitrate in plasma by GC-ECD and study on its pharmacokinetics in ten volunteers].

A rapid, accurate and sensitive gas chromatographic method was developed for the determination of isosorbide-5-mononitrate(5-ISMN) in 0.5 ml plasma. The instrument was equipped with 5% SE-30 glass packed column (2 m x 3 mm) and electron-capture detector. Isosorbide dinitrate (ISDN) was used as internal standard. The plasma was extracted with a mixture of ethyl ether and n-hexane (4:1) to give mean recoveries of 100.1% of 5-ISMN. The extracts reacted with trifluoroacetic anhydride and the derivatives were analyzed. The calibration curves were linear over a wide range of concentrations (20-800 ng.ml-1), and the detection limit of 5-ISMN was 2.0 ng.ml-1. The precisions (RSD%, n = 5) of within-day and day-to-day were less than 4% and 6.5%, respectively. The pharmacokinetic characteristics of 5-ISMN in ten human volunteers after a single oral dose of 20 mg 5-ISMN were investigated. The concentration-time curve was fitted to a one-compartment model.

Adult↗

[Effect of beta-adrenergic blockaders and nitrates on left ventricular diastolic function in patients with ischemic heart disease].

By means of M-type electrocardiography the anapriline (propranolol--40 mg) and nitrosorbide (isosorbide dinitrate--10 mg) action on the left ventricular diastolic function was studied in the conditions of acute experiment in 55 patients with stable stenocardia. It was established that anapriline lengthens the diastole (at the expense of diastasis), decreases the myocardial relaxation speed and the fast filling and causes an increase of the telediastolic volume. Nitrosorbide decreases the filling velocity in the three diastolic phases without changing its duration and leads to a decrease of the telediastolic volume. In the combination of the two drugs anaprilin acts mainly on the duration, volume and speed indices of the left ventricular diastolic function while nitrosorbide acts mainly on the venous flow towards the heart and reduces the unfavourable action of anapriline on myocardial relaxation.

Administration, Oral↗

[Dinitrosorbilong--a new Soviet anti-angina preparation. Its comparative pharmacodynamic, pharmacokinetic and clinical study].

The efficacy of dinitrosorbilong (DNL)--a new long-acting isosorbid dinitrate (IDN) preparation applied to the gum--was evaluated in 72 coronary patients with stable angina of effort. Repeated treadmill tests revealed antianginal effect of DNL exceeding 8 hours. The degree and duration of DNL action significantly surpassed those of conventional oral IDN tablets and of some other long-acting IDN preparations. The results of pharmacokinetic studies show that DNL bioavailability is 491 +/- 240% as compared to conventional oral IDN tablets. Regular 7-day DNL administration resulted in a significant decrease in the frequency of anginal attacks and in the daily consumption of nitroglycerin tablets as compared not only to the control period but also to the period of conventional IDN tablet therapy.

Angina Pectoris↗

Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations.

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac disorder impairing the ability of the ventricles to fill with or eject blood. The approach to pharmacologic treatment has become a combined preventive and symptomatic management strategy. Ideally, treatment should be initiated in patients at risk, preventing disease progression. In patients who have progressed to symptomatic left ventricular dysfunction, certain therapies have been demonstrated to improve survival, decrease hospitalizations, and reduce symptoms. The mainstay therapies are angiotensin-converting enzyme (ACE) inhibitors and beta-blockers (bisoprolol, carvedilol, and metoprolol XL/CR), with diuretics to control fluid balance. In patients who cannot tolerate ACE inhibitors because of angioedema or severe cough, valsartan can be substituted. Valsartan should not be added in patients already taking an ACE inhibitor and a beta-blocker. Spironolactone is recommended in patients who have New York Heart Association (NYHA) class III to IV symptoms despite maximal therapies with ACE inhibitors, beta-blockers, diuretics, and digoxin. Low-dose digoxin, yielding a serum concentration <1 ng/mL can be added to improve symptoms and, possibly, mortality. The combination of hydralazine and isosorbide dinitrate might be useful in patients (especially in African Americans) who cannot tolerate ACE inhibitors or valsartan because of hypotension or renal dysfunction. Calcium antagonists, with the exception of amlodipine, oral or intravenous inotropes, and vasodilators, should be avoided in HF with reduced systolic function. Amiodarone should be used only if patients have a history of sudden death, or a history of ventricular fibrillation or sustained ventricular tachycardia, and should be used in conjunction with an implantable defibrillator [corrected]. Finally, anticoagulation is recommended only in patients who have concomitant atrial fibrillation or a previous history of cerebral or systemic emboli.

Adrenergic beta-Antagonists↗

Time sequence of anginal pain.

We studied 187 patients with angina at rest in order to evaluate the circadian rhythm of chest pain attacks. All subjects were followed for 7 days in absence of therapy (placebo period) and then with therapy (nifedipine, metoprolol, or isosorbide dinitrate). During the placebo period (1309 days) 1466 attacks were recorded, on an average of 1.1 per day. Most episodes occurred between 5 and 8 A.M. The incidence of chest pain attacks was much lower between 9 A.M. and 4 P.M. During the period with therapy, a reduction of painful episodes was observed, while the diurnal distribution remained unchanged. Furthermore, we studied the relationship between circadian distribution of anginal attacks and the extension of coronary damage in the 76 patients who underwent coronary angiography. Alterations of diurnal distribution of chest pain attacks were noted in subjects with normal coronary arteries and those with one-vessel and two-vessel disease. Patients with three-vessel disease or left main coronary artery stenosis showed more uniform distribution of their attacks.

Adult↗

Comparison of epicardial coronary artery tone and reactivity in Prinzmetal's variant angina and chronic stable angina pectoris.

It has been suggested that a generalized coronary vasomotion disorder is present in variant angina and that evaluation of baseline coronary artery tone may be useful for predicting the occurrence of coronary artery spasm. The vasomotor response of angiographically normal proximal and distal coronary artery segments was studied in 9 patients with atypical chest pain and normal coronary arteriograms (control group), 13 patients with active variant angina and 41 patients with chronic stable angina. Ergonovine (intravenous, 100 to 300 micrograms, or intracoronary, 8 to 20 micrograms, was administered to all 22 patients in the control and variant angina groups and to 11 of the 41 patients with chronic stable angina. All patients also received intracoronary isosorbide dinitrate (1 to 2 mg). Computerized coronary artery diameter measurement of angiographically normal segments was carried out before and after ergonovine and nitrate administration. Mean baseline intraluminal diameter of proximal and distal coronary segments was not significantly different in control patients and those with variant angina (nonspastic segments only) or coronary artery disease (proximal 2.89 +/- 0.15, 2.83 +/- 0.14 and 2.82 +/- 0.09 mm; distal 1.60 +/- 0.08, 1.63 +/- 0.07 and 1.62 +/- 0.06 mm, respectively). After ergonovine, proximal segments constricted by 10 +/- 2%, 15 +/- 3% and 11 +/- 4% and distal segments by 11 +/- 3%, 11 +/- 2% and 14 +/- 3% in control, variant angina and coronary artery disease groups, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Dose-dependent haemodynamic response to prenalterol in patients with congestive heart failure.

The effect of three doses of prenalterol, 12.5, 25 and 50 micrograms, on cardiac index (CI), pulmonary artery pressure (PAP), heart rate (HR), and stroke volume index (SVI) was investigated in 18 patients with congestive heart failure (CHF). Twelve patients received only prenalterol, while 6 patients received prenalterol 1 hour after an oral dose of hydralazine and isosorbid dinitrate. In 7 out of 12 patients a dose-dependent increase in HR was observed. The response of HR was inversely correlated to resting catecholamine levels; patients with high resting catecholamines--these are patients with severe CHF--did not show any increase in HR. CI increased in 8 out of 12 patients (average 1 . 1/min m) and SVI in 5 out of 12 patients. This inconsistent response was not dependent on left ventricular ejection fraction or plasma catecholamines at rest. Pretreatment with vasodilators did not improve the haemodynamic response to prenalterol. Four out of 17 patients demonstrated an increase in severity of arrhythmias suggestive of arrhythmogenic properties of prenalterol.

Administration, Oral↗

Role of collateral flow in a pharmacological stress test (a combination of low-dose dobutamine and a vasodilator) as a predictor of wall motion reversibility.

The role of collateral flow was evaluated in a pharmacological stress test [a combination of low-dose dobutamine (DOB) and a vasodilator] as a predictor of wall motion reversibility at rest after percutaneous transluminal coronary angioplasty (PTCA) using ultrafast computed tomography (UFCT). Segments with wall motion abnormalities before PTCA were divided into two groups; ie, either with or without collateral flow. Patients were scanned at rest for baseline and again after 5 min of intravenous administration of 4 micrograms/kg per min of DOB after nitroglycerin (0.3 mg sublingually) or isosorbide dinitrate (2.5 mg bolus intravenous injection). Three months after PTCA, patients were scanned again and wall motion was compared with the previous findings. In collateral-dependent segments, the sensitivity of the pharmacological stress test as a predictor of wall motion reversibility was 87.5% and the specificity was 83.3%. In collateral-independent segments, the sensitivity was only 41.7%, while the specificity was 95.2%. Our findings demonstrate that the pharmacological stress test we used satisfactorily predicted wall motion reversibility in collateral-dependent segments, but tended to underestimate wall motion reversibility in collateral-independent segments. Therefore, collateral flow may be an important factor in accurately predicting wall motion reversibility by this pharmacological stress test.

Adolescent↗

Application of a combination of sublingually administered vasodilating drugs for rapid action on pulmonary hypertension in patients with cardiac asthma and with pulmonary oedema.

Eight patients with pulmonary oedema and 6 patients with cardiac asthma (primary disease: in 7 patients acute myocardial infarction, in 6--hypertension, in 1--mitral defect) were given sublingually a combination of 0.5 mg nitroglycerin, 10 mg Isodinit (isosorbid dinitrate) and 4 mg Sidnofarm (molsidomine) in powder form. This resulted in a rapid, pronounced and protracted reduction of dyspnoea, pulmonary congestion, respiration rate, and heart rate in the course of a four-hour observation rate, in more than 80% of cases. In patients with high blood pressure it dropped by 27% vs. the initial level; in patients with hypotension the change was only minimal. Pulmonary diastolic pressure began to drop from the 3rd minute after administration of the agents and the maximal decrease was attained after 30 min (34% of the initial value); even 4 hours after administration the values were below the initial level. The mentioned drug combination appears to be valuable especially in the first stage of treatment of cardiac asthma and pulmonary oedema.

Administration, Oral↗