Search

During normal pregnancy, the maternal cardiovascular system undergoes important anatomic and functional modifications to establish a low-resistance, high-volume state to support fetal demands for nutrients and gas exchange.1 Cardiac output increases by as much as 30% to 40%, resulting from increases in stroke volume and, to a lesser extent, heart rate. Gestational hormones and alterations in the synthesis of, and reactivity to, vasoactive substances result in systemic vasodilatation.2 Despite increases in cardiac output, maternal blood pressure decreases because of a substantial reduction in systemic vascular resistance. Pregnancy is also associated with an increase in venous capacitance and a parallel large expansion of blood volume.3 The purpose of these maternal changes is to promote blood flow to the implantation site to optimize fetal growth, increase maternal renal excretory functions because of excess maternal, placental, and fetal metabolic demand, and to withstand hemorrhage at delivery. Hemodynamic and vascular adaptations that occur in normal pregnancy are disrupted in women who develop preeclampsia (PE), a hypertensive disorder that affects 2% to 8% of all pregnancies worldwide.4 PE is characterized by new-onset hypertension (blood pressure consistently >140/90 mm Hg) after 20 weeks of gestation, accompanied by evidence of organ injury (proteinuria, thrombocytopenia, renal or liver impairment, pulmonary edema, or cerebral/visual symptoms suggesting cerebral cortical dysfunction), as redefined by the American College of Obstetrics and Gynecology in 2013.5 PE can be subdivided into early-onset PE (before 34 weeks of gestation), the more severe subset of the disease with smaller birthweight neonates and a higher rate of recurrence, and late-onset PE (after 37 weeks of gestation).6 Once established, PE often advances until delivery and may persist for some time in the postpartum period.7–10 Recent population-based cohort studies have concluded that women with a history of PE are at …

We compared standard (0.6 mg/h) versus low-dose (0.05 mg/h) transdermal nitroglycerin (TGTN) on acute hemodynamic parameters, the development of tolerance, and endothelial function. Study 1 randomized six healthy volunteers to receive 0.6 mg/h or 0.05 mg/h TGTN in a crossover design study (6-day washout period) with measurements of heart rate, blood pressure, radial artery waveforms, and aortic augmentation index taken at baseline and 1, 2, and 3 hours after initial TGTN application. Study 2 enrolled 24 healthy volunteers to receive 400 μg of sublingual nitroglycerin spray followed by 400 μg of inhaled salbutamol 90 minutes later. Measurements of heart rate, blood pressure, radial artery waveforms as well as aortic augmentation index were taken at baseline and at 5, 10, and 20 minutes after each treatment. They were randomized to either 0.6 mg/h or 0.05 mg/h of TGTN, and the same measurements were repeated after 6 days. In Study 1, there was no significant difference in the response to both doses (analysis of variance, P < 0.05). In Study 2, the decrease in aortic augmentation index in response to sublingual nitroglycerin and salbutamol was attenuated after sustained therapy with 0.6 mg/h of TGTN (versus 0.05 mg/h, P < 0.05). This investigation documents that 0.05 mg/h TGTN has identical acute hemodynamic effects compared with 0.6-mg/h dose without causing tolerance or endothelial dysfunction.

Background There is limited evidence that the use of nitrates in acute decompensated heart failure early after presentation to a hospital can improve clinical outcomes. We aimed to determine whether early nitrate exposure is associated with improved survival in a large retrospective cohort study. Methods and Results We examined 11 078 acute decompensated heart failure patients who presented to emergency departments in Ontario, Canada, between 2004 and 2007, in the Enhanced Feedback For Effective Cardiac Treatment and the Emergency Heart failure Mortality Risk Grade studies. In propensity‐matched analyses, we examined the effect of nitrate administration in the acute emergency department setting for its impact on death at 7, 30, and 365 days. In propensity‐matched analyses, we found no difference in survival between those who received nitrates in the emergency department and the non‐nitrate comparator group. Hazard ratios for mortality were 0.76 (95% CI ; 0.51, 1.12) over 7 days, 0.97 (95% CI ; 0.77, 1.21) over 30 days, and 0.91 (95% CI ; 0.82, 1.02) over 1 year of follow‐up. There was no significant difference in survival or hospital length of stay between nitrate and non‐nitrate controls in extended follow‐up. There was also no significant effect of nitrates in subgroups stratified by presence of chest pain, troponin elevation, chronic nitrate use, and known coronary artery disease. Conclusions In acute decompensated heart failure, use of nitrates acutely in the emergency department setting was not associated with improvement in short‐term or near‐term survival. Our study does not support generalized use of nitrates when the primary goal of therapy is to reduce mortality.

Background— Short term exposure to nitroglycerin (GTN) has protective properties that are similar to ischemic preconditioning. Whether other organic nitrates such as pentaerithrityl tetranitrate (PETN) and isosorbide mononitrate (ISMN) have similar protective effects has not been explored. Methods and Results— In a randomized, parallel, double blind, controlled trial, 37 healthy young volunteers received no therapy (n=10), transdermal GTN 1.2 mg for 2 hours (n=9), PETN 80 mg (n=9), or ISMN 40 mg (n=9). Twenty-four hours later, endothelium-dependent flow-mediated vasodilation (FMD) was measured before and after local exposure to ischemia and reperfusion (IR). In the no therapy group, IR blunted FMD (FMD after IR: 1.9±0.6%, P P P P =ns compared with no therapy). While it blocked the effect of GTN, Vitamin C (n=8) did not modify PETN preconditioning (FMD after IR: 6.3±0.9%, P =ns compared with before IR), showing that this phenomenon is not mediated by oxygen free radical production. In an effort to identify the mechanism of PETN preconditioning, isolated human endothelial cells were incubated with PETN, GTN, or ISMN. Only PETN induced expression of the genes encoding for heme oxygenase and ferritin, which have been involved in ischemic and pharmacological preconditioning. Conclusions— We show important differences among organic nitrates in their capacity to prevent IR-induced endothelial dysfunction. GTN and PETN, but not ISMN, have this preconditioning effect. The potential clinical implications of these data warrant further investigation.

Aim This study was designed to determine whether therapy with a diuretic has antianginal effects in patients with stable angina who are already treated with a traditional antianginal regimen. Methods and results Forty patients with chronic stable angina and normal left ventricular function were randomized in a double-blind, placebo-controlled study. Background antianginal therapy included beta blockers (n = 27), calcium channel antagonists (n = 18), and long-acting nitrates (n = 24). Of the patients 30% had diabetes and 75% had a history of hypertension. Patients were treated with a diuretic (hydrochlorothiazide 25 mg plus amiloride 5 mg) or placebo for 21 days. All patients underwent a treadmill exercise test before randomization and at day 21. The primary end point was the change in treadmill walking time until moderate angina. Diuretic therapy was associated with an increase in treadmill walking time of 63 +/- 17 seconds versus 19 +/- 9 seconds in the placebo group (P = 0.026) and reduced ST-segment depression (0.6 +/- 0.2 mm versus 0.1 +/- 0.2 mm (P = 0.03). There was a 25% increase in walking time in 8 patients (40%) treated with diuretic versus 1 patient (5%) in the placebo group (P = 0.02). The increases did not depend on changes in blood pressure or heart rate. Conclusion Therapy with hydrochlorothiazide plus amiloride has potent antianginal effects in patients with stable angina and preserved left ventricular function under treatment with standard antianginal therapy. Because most of the study patients had a history of hypertension the extrapolation of these findings to patients who did not have hypertension requires further investigation.

Nitric oxide synthase (NOS) uncoupling is a condition of increased production of superoxide anion associated with a decreased production of nitric oxide (NO) by this enzyme. Folic acid can prevent and/or reverse NOS uncoupling in the setting of diabetes, smoking, hypercholesterolemia, and nitrate tolerance. Whereas animal studies showed a protective effect of folic acid in ischemia and reperfusion (IR) injury, no study tested whether folic acid administration limits IR-induced endothelial dysfunction in humans. In a double-blind, parallel study, 20 healthy young male volunteers were randomized to receive folic acid, 10 mg/d for 7 days, or matching placebo. At the end of the treatment period, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR injury (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). There was no difference at baseline between groups in any variable. In the placebo group, IR significantly blunted FMD (before IR, 6.7+/-1.0%; after IR, 1.5+/-1.3%, P

Nitroglycerin (GTN) and other organic nitrates are important drugs commonly used in cardiovascular medicine, and, more recently, in obstetrics as tocolytic agents.1 The development of tolerance, ie, the reduction in effect or the requirement for higher doses that appears after continuous use,2 is a major factor limiting the efficacy of these drugs. Despite their clinical importance in the therapy of ischemic heart disease and heart failure, many aspects of the pharmacology of organic nitrates, including the mechanism(s) of tolerance, remain unclear. In the past decade, studies have demonstrated that organic nitrate therapy leads to complex interactions between the vasculature, neurohormones, and free oxygen radicals. In particular, the concept that GTN treatment causes increased vascular superoxide anion (·O2−) production, the mechanisms leading to this production, and the consequences of this phenomenon on endothelial function, have all been investigated. In the first part of this 2-part review, these recent findings, as well as the potential role of neurohormonal and autonomic abnormalities, will be described. In the second part, which will appear in the next issue of Circulation , we will propose a new, integrated view on the pathophysiology of nitrate tolerance. There is evidence from both animal and human studies that nitrate tolerance, especially when induced in vivo,3 is associated with an increased bioavailability of ·O2−, and that this process is responsible for the development of tolerance.4 Superoxide anion is normally scavenged by multiple intra- and extracellular mechanisms, including the enzyme superoxide dismutase (SOD). However, in higher concentrations, it can overcome these mechanisms and rapidly react with nitric oxide (NO), the active metabolite of GTN, to form peroxynitrite.5 This may reduce the bioavailability of GTN-derived NO, impairing its vasodilator activity (and that of other NO donors), and, possibly, directly counteract GTN-induced vasorelaxation, …

Flow mediated dilatation (FMD) is an accepted, non-invasive measure of endothelial function. FMD measures the capacity of the endothelium to respond to a stimulus but does not assess resting vascular tone. Prior to the measurement of FMD, the radial artery constricts as blood flow to the hand is interrupted, a phenomenon termed low-flow mediated constriction (FMC). The mechanisms of FMC remain poorly understood, however this measure is complementary to FMD. For example, exercise leads to vascular stimulation with an acute reduction in FMD but a reciprocal increase in FMC. It was hypothesized that interventions, which modify vascular nitric oxide bioavailability and alter endothelial function, impact FMC in normal subjects. The first protocol examined the impact of continuous therapy with transdermal nitroglycerin (GTN) on FMD and FMC (n = 18). After 5-7 days of GTN therapy, radial artery size was larger than before GTN (P < 0.01), FMD was reduced (P < 0.02, fig) but FMC was unchanged. In the second protocol (n = 8), vascular responses were assessed during sustained GTN therapy and 2 hours after GTN removal. FMD was blunted in the presence of GTN and remained blunted 2 hours after GTN removal (P < 0.01, fig), when vessel diameter had returned to baseline, but FMC was unchanged. In a third protocol (n = 14), the effect of inhaled salbutamol on vascular function was examined. Following stimulation with salbutamol, FMD was depressed (P < 0.02, fig) but FMC was not changed. These observations demonstrate that FMC does not change in response to sustained therapy with GTN, an intervention associated with marked abnormalities in endothelium dependent vasomotor responses, nor in response to beta-2 adrenergic receptor stimulation, an intervention known to acutely modify endothelial function. Both interventions are felt to mediate their effects through modification of nitric oxide bioavailability. Therefore, these findings confirm that FMC is not primarily dependent on nitric oxide.

Background Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective β-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional β 2 -adrenergic receptors. Methods and Results — Thirty-six patients with chronic heart failure were randomized to the nonselective β-blocker carvedilol or the selective β-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (−1.7±0.5 nmol/min, P P P Conclusions Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective β-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional β-adrenergic receptors.

Summary: Previous studies have shown that atrial natriuretic peptide (ANP) has relative sympathoinhibitory effects that are of potential benefit in patients with congestive heart failure (CHF). In this study, cardiac and systemic sympathetic responses to ANP were evaluated and compared with responses to sodium nitroprusside (SNP) in patients with CHF. Right- and left-heart hemodynamics were obtained simultaneously with cardiac (CANESP) and total body (TBNESP) norepinephrine spillover; these were measured by using the radiotracer technique. Reductions in arterial blood pressure and cardiac filling pressures were similar with both drugs. ANP and SNP caused a significant and similar increase in TBNESP. Mean values for CANESP did not change in either group, but the response of individual patients was dependent on the effect on diastolic blood pressure (r = −0.71, p < 0.01). These results do not provide evidence for a sympathoinhibitory effect of ANP, but suggest that in patients with CHF, cardiac sympathoexcitatory response to arterial baroreceptor unloading may be countered by a potential sympathoinhibitory effect caused by a reduction in cardiac filling pressures. In the setting of CHF, vasodilator therapy may decrease cardiac sympathetic activity if systemic hypotension is avoided.

Background —On the basis of the presence of β 2 -receptors within the sympathetic nervous system, β 2 -stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory β 2 -receptors are present in the human left ventricle. Methods and Results —The β 2 -agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no β-blocker therapy), group 2 (n=7, β 1 -selective blockade with atenolol), and group 3 (n=6, nonselective β-blockade with nadolol). Left ventricular +dP/dt in response to increasing concentrations of salbutamol was measured in all groups, and cardiac norepinephrine spillover was measured in group 1. There were no systemic hemodynamic changes in any group. Salbutamol resulted in a 44±6% increase in +dP/dt in group 1, a 25±6% increase in group 2 ( P P Conclusions —Evidence that salbutamol increased norepinephrine release from cardiac sympathetic nerves was provided by the observations that atenolol suppressed the salbutamol inotropic response, demonstrating that this response was mediated in part by β 1 -receptors and that salbutamol also resulted in an increase in cardiac norepinephrine spillover. This result provides in vivo evidence, in humans, for the role of sympathoexcitatory cardiac β 2 -receptors.

The pathophysiology of the cardiorenal syndrome remains poorly understood. Renal sympathetic activity is increased in heart failure. It contributes to the sodium avid state, renal vasoconstriction, and reduced glomerular filtration rate that is characteristic of a large number of heart failure patients. Dobutamine is commonly used in the treatment of decompensated heart failure. We used the norepinephrine spillover technique to examine the effects of dobutamine on renal sympathetic activity in human heart failure. Dobutamine was titrated to increase the peak positive rate of change in left ventricular pressure by 25%. In 11 patients with heart failure, dobutamine infusion reduced efferent renal sympathetic activity by 50% (P < 0.003). This sympatholytic response was associated with an 11% increase in renal plasma flow (P < 0.03) and a 12% increase in glomerular filtration rate (P < 0.04). These findings suggest that dobutamine infusion is acutely associated with a beneficial effect on renal function. This observation is potentially related to a renal sympatholytic response to ventricular mechanoreceptor activation associated with the inotropic effects of beta-adrenergic receptor stimulation.

Background Although there is indirect evidence of impaired baroreflex control of sympathetic outflow directed at heart muscle, the regulation of cardiac sympathetic activity in the setting of heart failure is largely unexplored. We used the norepinephrine spillover method to address the hypothesis that baroreflex control of cardiac sympathetic activity is reduced in heart failure. Methods and Results Twenty-three patients were studied, 17 in a group with heart failure and 6 in a group with normal ventricular function. In both groups, cardiac norepinephrine spillover was assessed in response to nitroprusside infused to steady-state conditions. Nitroprusside resulted in significant reductions in mean systemic arterial pressure (normal group, −15±3% [mean±SEM]; heart failure group, −13±1%) and mean pulmonary artery pressure (normal group, −25±10%; heart failure group, −29±4%). In response to nitroprusside, there was a 98±16% increase in cardiac norepinephrine spillover in the normal group (from 81±10 to 159±25 pmol/min, P P =NS), a response that was significantly smaller than that seen in the normal group. Conclusions In patients with heart failure compared with subjects with normal ventricular function, there was a significantly smaller increase in cardiac sympathetic activity in response to a steady-state infusion of nitroprusside. This result provides evidence for reduced baroreflex control of cardiac sympathetic activity in heart failure.

Background β-Blockers may reduce cardiac sympathetic activity in patients with heart failure by antagonizing β-adrenergic receptors that facilitate sympathetic outflow to the heart. To explore this possible effect of β-blockade, we measured cardiac norepinephrine spillover responses in patients with heart failure after the acute administration of either propranolol, a nonselective β-blocker, or metoprolol, a β 1 -selective agent. Methods and Results Eighteen patients were studied. Repeated intravenous doses of propranolol (0.5 mg; nine patients; left ventricular ejection fraction, 14±2%) or metoprolol (1.0 mg; nine patients; left ventricular ejection fraction, 18±2%) were administered until one of the following end points was reached: a 15% decrease in heart rate, left ventricular +dP/dt, or mean arterial blood pressure or a 5 mm Hg increase in left ventricular end-diastolic pressure. Propranolol (mean dose, 2.0 mg) and metoprolol (mean dose, 3.6 mg) caused similar reductions in heart rate, +dP/dt, and coronary sinus plasma flow. Cardiac norepinephrine spillover was reduced after propranolol (277±55 to 262±53 pmol/min, P P P Conclusions The administration of a β 1 -selective antagonist was associated with increased cardiac norepinephrine spillover. In contrast, the administration of a nonselective β-blocker until similar hemodynamic end points were reached caused a reduction in norepinephrine spillover. This suggests that in patients with heart failure, nonselective β-blockade may have favorable inhibitory effects on cardiac sympathetic activity.

Background Therapy with diuretics has been reported to prevent the development of nitrate tolerance. Importantly, diuretics may have independent antianginal effects through their effects on intravascular volume. The present investigation was designed to determine whether diuretic therapy could prevent the development of tolerance to continuous transdermal nitroglycerin. The study was also designed to examine whether diuretic therapy has an independent antianginal effect. Methods and Results Twelve patients with chronic stable angina were studied in a randomized, double-blind, crossover trial. Patients received diuretic (hydrochlorothiazide plus amiloride) or placebo for 14 to 20 days. During each double-blind treatment period, patients underwent treadmill exercise testing on three separate occasions. The first exercise testing was performed after 7 to 10 days of single-blind, placebo transdermal nitroglycerin therapy. Subsequently, exercise testing was repeated on the first day of active transdermal nitroglycerin therapy and following 7 to 10 days of continuous transdermal nitroglycerin application. Therapy with a diuretic was associated with an increase in exercise capacity but had no effect on nitroglycerin tolerance. During therapy with placebo transdermal nitroglycerin, diuretic therapy caused an increase in treadmill walking time to the development of moderate angina compared with placebo (371±26 versus 288±16 seconds, diuretic versus placebo, P Conclusions The results of this study demonstrate that therapy with a diuretic has no effect on the development of tolerance to continuous transdermal nitroglycerin. Interestingly, diuretic therapy itself has important antianginal effects and improves exercise capacity in patients with stable angina.

Background There are α-adrenergic receptors on human myocardium that exert positive inotropic effects. The effect of α-adrenergic receptor blockade on human left ventricular (LV) performance has not been fully explored. Although α-adrenergic receptor blockade might have effects on LV function that are mediated via blockade of postsynaptic myocardial α-adrenergic receptors, it is also possible that blockade of presynaptic α 2 -adrenergic receptors and subsequent increased release of norepinephrine would have effects on LV performance. In the present study, we explored the effects of nonselective α-adrenergic receptor blockade on LV performance and transcardiac norepinephrine concentrations in a group of patients with normal LV function and in a group of patients with congestive heart failure secondary to dilated cardiomyopathy. Methods and Results Using an intracoronary drug infusion technique, we administered the nonselective α-adrenergic antagonist phentolamine to 13 patients with normal LV function and 19 patients with congestive heart failure secondary to dilated cardiomyopathy. With a high-fidelity LV catheter, the systolic (+dP/dt) and diastolic (−dP/dt and Tau) LV function responses to intracoronary infusion of phentolamine (0.2 mg/min×5 minutes) were assessed. In 8 patients with normal ventricular function and 10 patients with congestive heart failure, arterial and coronary sinus blood samples were drawn to determine the effects of phentolamine on catecholamine concentrations. Phentolamine had no measurable effect on LV performance or catecholamine concentrations in the normal ventricular function group. In patients with congestive heart failure, intracoronary phentolamine caused a significant increase in +dP/dt and the rate of isovolumic LV relaxation (−dP/dt and Tau). These hemodynamic effects were accompanied by a significant increase in coronary sinus norepinephrine concentration but no change in arterial norepinephrine concentration. Conclusions Myocardial α-adrenergic receptor blockade causes significant inotropic and lusitropic effects in the failing but not the nonfailing human LV. These effects appear to be mediated by increased release of norepinephrine from cardiac nerves secondary to blockade of presynaptic α 2 -adrenergic receptors. Differences in the responses of the failing and nonfailing human LV appear to reflect the higher level of sympathetic activation that is seen in the group with congestive heart failure. This suggests that the presynaptic α 2 -adrenergic receptor exerts a tonic inhibitory effect on the release of norepinephrine from cardiac nerves in patients with congestive heart failure.

Background Intermittent transdermal nitroglycerin therapy is effective in the treatment of stable angina and prevents the development of tolerance. Previous investigations have suggested that removal of nitroglycerin patches may be associated with a decrease in anginal threshold. This study examines the effect of nitroglycerin patch removal on anginal threshold in a group of patients with stable angina. Methods and Results Twelve patients with stable angina were enrolled in a randomized, double-blind, placebo-controlled, crossover study. These patients had reproducible treadmill walking times and were taking no other long-acting antianginal medications or vasodilators. They received 0.8 mg/h transdermal nitroglycerin or wore a matching placebo patch for 5 to 7 days and then crossed over to the other treatment arm of the study. Transdermal nitroglycerin was applied at 8:00 pm and removed at 8:00 am each day. On the last day of each treatment period, patients underwent treadmill exercise testing at 8:00 am (before patch removal) and at 2, 4, and 6 hours after patch removal. The primary end point was the treadmill walking time until moderate angina (P2). Other end points included the treadmill walking time until onset of angina (P1), the amount of ST segment depression at P1 and P2, and treadmill walking time until the development of 1 mm ST depression. Heart rate, systolic blood pressure, and the rate-pressure product were determined at rest before exercise and at P1 and P2. At 8:00 am P1 and P2 were not significantly affected by active nitroglycerin compared with placebo, indicating the development of tolerance. Removal of the active transdermal nitroglycerin patch was associated with a significant decrease in the time to P1 at 2, 4, and 6 hours after patch removal compared with placebo. There was also a decrease in the time to P2 after active patch removal that was statistically significant compared with placebo at 2 and 4 hours and was of borderline significance at 6 hours. There were no differences in heart rate, blood pressure, or amount of ST segment depression at either P1 or P2 after active compared with placebo patch removal. Conclusions In patients with stable angina pectoris, intermittent transdermal nitroglycerin therapy is associated with a decrease in anginal threshold for 4 to 6 hours after patch removal. Although the cause of this phenomenon remains uncertain, it may be due to counterregulatory responses that develop during nitroglycerin patch application.

BACKGROUND The morning increase in asymptomatic ambulatory ischemia may be due to heightened coronary tone, increased physical activity, or both. If ambulatory ischemia is primarily due to physical activity, then alterations in the schedule of physical activity should be reflected in a corresponding alteration in the occurrence of ischemia. This study was designed to examine the relation between activity patterns and the frequency of ambulatory ischemic episodes and the effect of nadolol on these relations. METHODS AND RESULTS A double-blind, randomized, placebo-controlled, crossover trial of nadolol versus placebo was performed in 20 patients with stable coronary artery disease. At the end of each 2-week treatment phase, patients were hospitalized for 48 hours. In the hospital, there was a regular activity day (awaken and assume normal activities at 8:00 AM) and a delayed activity day (awaken at 8:00 AM, arise at 10:00 AM, and begin normal activity at noon). Ambulatory ECG monitoring was performed throughout the hospitalization. On the regular activity day, there was a morning increase in heart rate and in the number of ischemic episodes during therapy with placebo that began at 8:00 AM. In contrast, on the delayed activity day, there was a 4-hour phase shift of the increases in heart rate and the increase in ischemic episodes (ie, at noon) corresponding to the onset of physical activities. Therapy with nadolol caused a 50% reduction in the total number of ischemic episodes (129 versus 65, placebo versus nadolol; P < .02). During nadolol therapy, there was no discernible circadian peak in the number of ischemic episodes on either activity day. During placebo treatment, 87% of ischemic episodes were preceded by an increase in heart rate > or = 5 beats per minute. Although nadolol caused a significant reduction in the total number of episodes preceded by a heart rate increase compared with placebo (99 versus 38 episodes, P < .04), this therapy was associated with a significant increase in the number of episodes not associated with a heart rate increase (15 versus 21 episodes, P < .002). CONCLUSIONS The morning increase in ambulatory ischemic episodes is due to physical activity patterns. The majority of ischemic episodes are preceded by a heart rate increase, and it is these episodes that are primarily responsible for the morning increase in ischemia. Therapy with nadolol caused a reduction in the total number of ischemic episodes solely by reducing those episodes preceded by a heart rate increase. In contrast, nadolol caused a significant increase in the number of ischemic episodes not associated with a heart rate increase, perhaps in part because it potentiated coronary vasoconstriction.

Nitroglycerin (NTG) and other organic nitrates continue to be important drugs that are often used in cardiovascular medicine. All organic nitrates undergo denitrification, releasing nitric oxide (NO) through a biotransformation process that remains poorly understood to date. NO activates the enzyme soluble guanylyl cyclase in smooth muscle cells, causing increased levels of the second messenger cGMP. Finally, cGMP activates a cGMP-dependent protein kinase. This enzyme mediates vasorelaxation through inhibitory phosphorylation of different proteins involved in the regulation of intracellular Ca2+ levels. See p 2338 All of the organic nitrates have potent short-term vascular, hemodynamic, and clinical effects. A critical limitation in their clinical application is the development of tolerance, whereby their initial effects are rapidly lost during sustained administration. Although there seems to be little doubt that NO, or some NO adjunct, mediates the pharmacodynamic effect of nitrates, the mechanism(s) underlying the development of tolerance remain an important and vexing problem for cardiovascular pharmacology. The phenomenon of nitrate tolerance has been recognized for more than a century and has been intensely investigated for 3 decades. Despite these efforts, a unifying hypothesis concerning the mechanism of tolerance continues to be elusive. Initial investigations focused on abnormalities in biotransformation and denitrification of organic nitrates. Almost 30 years ago, Needleman and Johnson1 proposed that tolerance might result from impaired nitrate metabolism caused by the reduced bioavailability of sulfhydryl groups. Although sulfhydryl depletion is no longer thought to play a causal role in tolerance,2 abnormalities in nitrate biotransformation remain the subject of active investigation.3 Importantly, investigations in this area are severely limited by our poor understanding of the biotransformation pathway and by significant analytical problems in quantifying NO and/or NO adjunct production rates. Approximately 10 years ago, research in the field of nitrate tolerance shifted toward the description of systemic, …

The organic nitrates are widely used in the management of coronary artery disease. They are given not only to patients with stable angina pectoris, but also to those with unstable angina, acute myocardial infarction, and heart failure. Although they are effective for the treatment of these disorders, their therapeutic value is compromised by the rapid development of tolerance during sustained therapy. This review will be limited to the use of organic nitrates in patients with chronic stable angina pectoris, but many of the principles enunciated are relevant to other clinical situations. In 1879 Murrell reported that a 1 percent solution . . .

Cyclic AMP plays a central role in modulating systolic and diastolic myocardial function. Consequently, the adrenergic nervous system, acting through myocardial beta-adrenergic receptors, very likely plays a significant role in regulating left ventricular systolic and diastolic function. Theoretically, beta-adrenergic agonists and antagonists may further modify myocardial systolic and diastolic function. Although the effects of beta-adrenergic agents are clearly demonstrable in vitro, it has been more difficult to evaluate the direct myocardial effects of beta-adrenergic agents in patients. These difficulties are related both to technical aspects of the measurement of systolic and diastolic parameters and to the potentially confounding effects of secondary nonmyocardial drug actions and reflex-mediated changes in myocardial and/or vascular adrenergic activity. A number of strategies for evaluating the direct myocardial actions of beta-adrenergic agents are discussed. Two promising approaches are the use of direct intracoronary drug infusion and the analysis of left ventricular pressure-volume relationships. The positive inotropic action of beta-adrenergic agonists is substantially attenuated in many patients with left ventricular failure due to end-organ desensitization of the beta-adrenergic pathway. Nevertheless, a beta-adrenergic agonist may still cause a substantial improvement in left ventricular pump function in such patients. There is less information available regarding the effect of beta-adrenergic agonists on myocardial relaxation. Preliminary data from the intracoronary infusion of dobutamine suggest that isovolumic relaxation is accelerated. Conversely, preliminary data suggest that a beta-adrenergic antagonist, esmolol, causes a slowing of isovolumic myocardial relaxation. Further studies will be needed to determine whether these drug effects result in a significant alteration in hemodynamic performance during diastole, and to evaluate the possibility that beta-adrenergic-mediated myocardial relaxation is attenuated in patients with heart failure.