Nitrate Therapy Research Articles

Hemodynamic resistance to intravenous nitroglycerin in severe congestive heart failure and restored response after diuresis

A wide variety of organic nitrate preparations are often used in the management of congestive heart failure (CHF). This class of drugs exerts a vasodilatory action, predominantly on the venous capacitance vessels, that leads to a reduced ventricular filling pressure and usually without an increase in cardiac output. 1,2 Two major problems exist that deter its widespread acceptance as an effective drug in CHF: the development of tolerance and hemodynamic resistance or primary drug failure. Tolerance is responsible for the loss of hemodynamic and clinical benefits after nitrate therapy has been initiated. 3–5 An absent or feeble hemodynamic response to nitrates, a relatively common occurrence, has been reported to occur in approximately ≥50% of treated patients. 6,7 However, nitrate resistance is not always apparent when intravenous nitroglycerin is used without hemodynamic monitoring. This study was designed for 2 purposes: (1) to substantiate previously described hemodynamic and clinical correlates of CHF predictive of resistance to intravenous nitroglycerin, 6,7 and (2) to determine whether hemodynamic modification using alternate drug therapy might restore responsiveness to nitroglycerin.

Anaesthetic management of a complex morbidly obese parturient

A case is presented of a morbidly obese parturient who had multiple medical problems. She had angina and was receiving nitrate therapy, had insulin-dependent diabetes mellitus, hypertension, asthma and benign intracranial hypertension (pseudotumour cerebri). Lumbar epidural analgesia was chosen for labour and delivery and resulted in an uneventful outcome.

Acute heart failure: determinants of outcome

We prospectively studied 69 consecutive patients hospitalized with a primary diagnosis of acute left ventricular failure so as to assess the impact of vasodilators on incidence and morbidity of acute symptomatic left ventricular failure. The determinants of duration of hospitalization, in-hospital mortality and symptomatic status 2 months after discharge were examined. There were 9 in-hospital deaths (13%), and survival at 60 days was 77%. Median duration of hospitalization was 9 days, and 33% of the surviving patients remained in New York Heart Association functional class III-IV 60 days subsequent to discharge. Of the patients, 49 (76%) had previously received treatment for left ventricular failure: 30 (61%) of these had received vasodilators, most commonly angiotensin converting enzyme inhibitors and nitrates. Ischaemic chest pain was present in 34 (49%) of the patients. Acute utilization of vasodilators (45% of patients) was largely limited to nitrate therapy associated with ischaemic chest pain ( P < 0.01). Multiple logistic regression revealed previous left ventricular failure, advanced age and hypokalaemia as significant correlates of prolonged hospitalization (> 9 days). Previous left ventricular failure was also predictive of persistent severe disability two months subsequent to discharge. No factor was a significant predictor of in-hospital death. Although preceding treatment with digoxin and incremental angiotensin converting enzyme inhibitor therapy tended to predict brief hospitalization, the parameter of acute ischaemia, other biochemical anomalies and modes of acute or chronic therapy were not significant correlates of any end point. We conclude that preceding disability, rather than mode of treatment, predicts an adverse outcome in acute left ventricular failure.

Update on Nitrate Therapy

The Journal of Clinical PharmacologyVolume 31, Issue 8 p. 697-701 Update on Nitrate Therapy Debbie Rinde—Hoffman MD, Debbie Rinde—Hoffman MD Division of Cardiology, University of South Florida, College of Medicine, and the James A. Haley, Veterans Administration Hospital, Tampa, Florida.Search for more papers by this authorStephen P. Glasser MD, Corresponding Author Stephen P. Glasser MD Division of Cardiology, University of South Florida, College of Medicine, and the James A. Haley, Veterans Administration Hospital, Tampa, Florida.Cardiovascular Unit for Research and Education (CURE), 3500 East Fletcher Avenue, Suite 218, Tampa, FL 33613.Search for more papers by this authorDonna K. Arnett MSPH, Donna K. Arnett MSPH Division of Cardiology, University of South Florida, College of Medicine, and the James A. Haley, Veterans Administration Hospital, Tampa, Florida.Search for more papers by this author Debbie Rinde—Hoffman MD, Debbie Rinde—Hoffman MD Division of Cardiology, University of South Florida, College of Medicine, and the James A. Haley, Veterans Administration Hospital, Tampa, Florida.Search for more papers by this authorStephen P. Glasser MD, Corresponding Author Stephen P. Glasser MD Division of Cardiology, University of South Florida, College of Medicine, and the James A. Haley, Veterans Administration Hospital, Tampa, Florida.Cardiovascular Unit for Research and Education (CURE), 3500 East Fletcher Avenue, Suite 218, Tampa, FL 33613.Search for more papers by this authorDonna K. Arnett MSPH, Donna K. Arnett MSPH Division of Cardiology, University of South Florida, College of Medicine, and the James A. Haley, Veterans Administration Hospital, Tampa, Florida.Search for more papers by this author First published: August 1991 https://doi.org/10.1002/j.1552-4604.1991.tb03762.xCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume31, Issue8August 1991Pages 697-701 RelatedInformation

Transdermal nitrate therapy: bioavailability during exercise increases transiently after the daily change of patch.

Ten volunteers carried a 10 mg 24 h -1 transdermal glyceryl trinitrate (GTN) patch for 24 h before moderate exercise. Plasma GTN-concentration increased significantly (P less than 0.05) by 19% to peak value at 15 min. Two hours after patch renewal repeat exercise increased GTN concentration by 56% (P less than 0.001). The two nitrate-concentration curves differed significantly (P less than 0.0001). Thus, change of patch augmented nitrate availability during exercise.

Prevention of nitrate tolerance with angiotension converting enzyme inhibitors.

Activation of neurohumoral hormones or sulfhydryl group depletion may contribute to the development of nitroglycerin tolerance. In an attempt to prevent nitrate tolerance, this study evaluated the interaction of nitroglycerin with angiotensin converting enzyme (ACE) inhibitors with and without a sulfhydryl group. Thirty-four subjects were randomized to a 7-day regimen of enalapril 10 mg b.i.d., captopril 25 mg t.i.d., or placebo. Venodilator response to nitroglycerin was assessed with forearm plethysmography by measuring the change in venous volume after administration of 0.4 mg sublingual nitroglycerin. Plethysmographic measurements were obtained serially 1) at baseline, 2) after 4 days of ACE inhibitor or placebo, 3) 2 hours after application of a 10 mg/24 hr nitroglycerin patch, and 4) 74 hours after continuous nitropatch application. ACE inhibition alone caused no significant change in the response to sublingual nitroglycerin. Nitrate response remained unchanged after 2 hours ("acute") of nitropatch exposure in all three groups. After 74 hours ("chronic") of continuous nitropatch application, the venodilator response to sublingual nitroglycerin was reduced by 40% in the placebo group, 10% in the enalapril group, and 2% in the captopril group. This attenuation was significant only in the placebo group (p less than 0.01). Pairwise comparison of nitrate response between groups was significantly different between the captopril and placebo groups (p less than 0.01) and between the placebo and enalapril groups (p less than 0.05). Plasma renin levels increased equally in the enalapril and captopril groups. Body weight increased only in the placebo group, suggesting prevention of nitrate-induced volume expansion in the ACE inhibitor groups. This study demonstrates that ACE inhibitors may prevent nitrate tolerance to long-term nitrate therapy.

Hemodynamc benefit of nitrate therapy in patients with heart failure already treated with angiotensin converting enzyme inhibition

Hemodynamc benefit of nitrate therapy in patients with heart failure already treated with angiotensin converting enzyme inhibition

Diltiazem sustained release plus nitrates versus nitrate therapy alone for the treatment of stable angina pectoris

Diltiazem sustained release plus nitrates versus nitrate therapy alone for the treatment of stable angina pectoris

Prompt and persistent recovery of ventricular function and attenuation of ventricular geometry after late reperfusion and prolonged nitrate therapy in canine anterior myocardial infarction

Prompt and persistent recovery of ventricular function and attenuation of ventricular geometry after late reperfusion and prolonged nitrate therapy in canine anterior myocardial infarction

Nitrate Therapy in Heart Failure

Nitrates are drugs of first choice in patients with acute heart failure. Acute pulmonary edema can be successfully treated with single or repeated doses of sublingual nitroglycerin. In cases of prolonged acute heart failure, e.g. in the setting of acute myocardial infarction, nitroglycerin or isosorbide dinitrate can be given by the intravenous route for up to 24 h. Patients with acute myocardial infarction usually benefit from nitrate therapy if filling pressures are high and/or left ventricular function is compromised. Nitrate therapy can be considered safe if arterial blood pressure is maintained above 95 mm Hg. With these precautions nitrates can reduce infarct size and the incidence of complications as well as improve long-term prognosis. In the chronic treatment concern has risen with regard to possible nitrate tolerance. Thus, therapy schedules allowing for nitrate-poor phases are generally recommended. Therapy schedules with constant-rate delivery of drugs achieved with patches or intravenous administration of nitrates should be used with caution.

Chronotherapy in Coronary Heart Disease: Comparison of Two Nitrate Treatments

The purpose of this study was to assess the ischemic burden and the hemodynamic changes during daily activities in patients with coronary heart disease. Three exercise tests were performed during the day (10:00 a.m., 2:00 p.m., 6:00 p.m.), recording ST-segment depression, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output as well as heart rate and systemic blood pressure during placebo and nitrate therapy. With placebo as well as nitrate therapy there was a gradual increase of ischemia and preload and a decrease of cardiac output during the day. High nitrate concentrations led to a significant reduction of both preload and ST depression with a marked circadian phase dependency of cardiovascular effects.

A summary index for the assessment of quality of life in angina pectoris

When exploring the effects of anti-anginal therapy on quality of life (QL), it is essential to use concise, reliable, outcome measures which focus on those aspects of the disease which are affected by the anginal pain, and which are expected to be responsive to medical intervention. Analysis based on a single comprehensive index is preferable to the use of several indexes as it avoids the potential for conflicting inferences from multiple comparisons. In this paper, we describe the development of a QL index which summarizes the three questionnaires used in the North Karelian Quality of Life (KarQuol) study. The summary index (SI) will be used to compare transdermal and oral nitrate therapy in patients with angina pectoris, and represents the first stage in the construction of a disease-specific evaluative index for future trials.

Literature review and opinion

Sildenafil (Viagra) was studied in 2 randomized, double-blind, placebo-controlled trials with a 24-week follow-up for the dose-response study and a 12-week follow-up for the dose-escalation study. This multicenter study evaluated 861 men with a mean age of 58 who had erectile dysfunction lasting more than 6 months and who had a stable relationship with a woman for 6 or more months. Patients were excluded if they had anatomical defects, any sexual disorder, spinal injury, major psychiatric illness, poorly controlled diabetes, peptic ulcer disease, history of ethanol or substance abuse, recent stroke or myocardial infarction, or use of nitrate therapy. Of those enrolled, 87% completed the dose-response and 93% the dose-escalation part of this study. Men were to take either 25, 50, or 100 mg of sildenafil. In the dose-escalation study, men were assigned to take either a placebo or 50 mg of sildenafil; the dose could be doubled or reduced by 50% at each followup visit. Outcomes were ability to achieve penetration and maintain an erection. In addition, responses were recorded for erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Analysis was by an intention to treat. There was significantly improved ability to achieve penetration as compared to a placebo with a dose response relationship of 60, 84, and 100 percent for the 25, 50, and 100 mg doses, respectively. This relationship remained for the ability to maintain an erection as well as for all other areas assessed. In conclusion, men with erectile dysfunction may benefit from sildenafil.

Management of myocardial ischemia: Role of intermittent nitrate therapy

Tolerance to long-term nitrate therapy has now been documented in a large number of clinical studies. These trials have demonstrated attenuation of effect over time but a return of responsiveness with the start of nitrate-free intervals. Intermittent therapy prevents attenuation or tolerance when used as the initial treatment regimen. This strategy is appropriate for use with isosorbide dinitrate, as well as intravenous or transdermal nitroglycerin. Transmucosal nitroglycerin has not been associated with tolerance; the lack of such an effect may be a result of rapid increases and decreases in drug levels. In the future, sulfhydryl donors may also prove useful in prevention or reversal of nitrate tolerance.

Circadian Influence in Cardiovascular Disease (Part 1)

This department will offer stylized clinical presentations of current cardiovascular issues. Questions raised as a case history evolves highlight key elements that are elaborated upon in the discussions which follow.

Nitrate therapy in the elderly

Changes in the heart and blood vessels with age alter the response of the cardiovascular system to pharmacologic agents. Nitrate plasma half-life is longer and volume of distribution is larger in older persons. Apparently, these pharmacokinetic differences in older persons lead to increased venous smooth muscle responsivity to nitrates which, in turn, leads to greater reductions in central venous and pulmonary arterial pressures after nitrate administration. This is probably the explanation for the greater frequency of nitrate-induced severe hypotension and bradycardia in elderly patients with myocardial infarction compared with younger patients. Clinicians should be cognizant of the changes in the cardiovascular system which occur with age that sensitize the elderly patient to the action of organic nitrates. Initial dosages of nitrates should accordingly be less than in younger patients.

Effects of chronic glyceryl trinitrate on left ventricular haemodynamics in a rat model of congestive heart failure: demonstration of a simple animal model for the study of in vivo nitrate tolerance

The aim of the study was to investigate the problem of pharmacological tolerance to nitrate therapy in congestive heart failure, using an animal model. The effects of chronic glyceryl trinitrate infusions were studied in a rat model of congestive heart failure, induced by myocardial infarction, wherein surgical procedures have been developed to permit continuous monitoring of ventricular pressures in conscious animals for up to 4-5 d. male Sprague-Dawley rats were used, weight 300-325 g, n = 3-7 per experiment. Glyceryl trinitrate infusion (18 micrograms.kg-1.min-1) in rats with congestive heart failure caused by a 28.5(SEM 3.5)% infarction induced a rapid fall in left ventricular end diastolic pressure from 12.0(0.8) mm Hg to a peak effect of 5.5(0.6) mm Hg within 30 min (n = 7), but rapid attenuation developed beginning about 4 h after the start of the infusion. Complete abolition of the haemodynamic effects of glyceryl trinitrate was observed after 8 h of infusion. After a 12 h wash out period, responsiveness to a new infusion of glyceryl trinitrate (same dose) was restored. Withdrawal of nitrovasodilator dose led to rapid return to baseline left ventricular end diastolic pressure values. Infusion of vehicle to control animals (infarct size not different from treatment group) caused no haemodynamic effects. The haemodynamic changes caused by glyceryl trinitrate resemble those seen in man and suggest a possible use for this animal model in examining the mechanisms of nitrate action and tolerance.

Circadian Variation of Cardiac Performance in Coronary Heart Disease

To study the circadian variation of cardiac performance in patients with coronary heart disease, three exercise tests on a bicycle crgometer were performed during the active part of the day (10 a.m., 2 p.m. and 6 p.m.), recording ST-segment depression and pulmonary capillary wedge pressure. Ten male patients with angiographically documented coronary heart disease underwent bicycle ergometry during placebo and during nitrate therapy (placebo controlled, double-blind crossover 2 × 20 mg IS-5-MN and 1 × 120 mg ISDN sustained release). During placebo as well as during nitrate therapy there was a gradual decrease of cardiac performance during the day, documented by the increase in ST-depression and pulmonary capillary wedge pressure at equal work loads. High nitrate concns led to a significant reduction of both ST-depression and preload with a marked circadian-phase dependency of cardiovascular effects.

Circadian Variation of Cardiac Performance in Coronary Heart Disease

To study the circadian variation of cardiac performance in patients with coronary heart disease, three exercise tests on a bicycle ergometer were performed during the active part of the day (10 a.m., 2 p.m. and 6 p.m.), recording ST-segment depression and pulmonary capillary wedge pressure. Ten male patients with angiographically documented coronary heart disease underwent bicycle ergometry during placebo and during nitrate therapy (placebo controlled, double-blind crossover 2 x 20 mg IS-5-MN and 1 x 120 mg ISDN sustained release). During placebo as well as during nitrate therapy there was a gradual decrease of cardiac performance during the day, documented by the increase in ST-depression and pulmonary capillary wedge pressure at equal work loads. High nitrate concns led to a significant reduction of both ST-depression and preload with a marked circadian-phase dependency of cardiovascular effects.

Nitrate Therapy for Left Ventricular Failure Complicating Acute Myocardial Infarction: A Haemodynamic Comparison of Intravenous, Buccal, and Transdermal Delivery Systems

The haemodynamic effects of three different methods of nitrate administration [intravenous (i.v.) isosorbide dinitrate (ISDN) and buccal and transdermal nitroglycerin (NTG)] were evaluated in 36 patients with acute left ventricular failure due to a recent myocardial infarction. Similar reductions in pulmonary artery occluded pressure (p less than 0.01) followed all three regimens without change in heart rate and cardiac and stroke volume indices. Significant reductions in systemic arterial pressure and vascular resistance followed both ISDN and buccal NTG but not transdermal NTG. A disadvantage of the buccal NTG delivery was an abrupt and, on occasion, inappropriate reduction in blood pressure. The more gradual and controlled reduction of systemic blood pressure with substantial falls in pulmonary artery occluded pressure following ISDN infusion suggest that in the context of myocardial infarction this method of nitrate delivery may have safety advantages; however, when invasive haemodynamic monitoring facilities are not available, transdermal delivery may offer a practical alternative.