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(Circulation. 1996;93:2052-2058.)
© 1996 American Heart Association, Inc.

Articles

Long-term Angiotensin-Converting Enzyme Inhibition With High-Dose Enalapril Retards Nitrate Tolerance in Large Epicardial Arteries and Prevents Rebound Coronary Vasoconstriction In Vivo

Thomas Münzel, MD; Eberhard Bassenge, MD

From the Medizinische Klinik III, Division of Cardiology (T.M.) and the Institute for Applied Physiology (E.B.), University of Freiburg (Germany).

Correspondence to Thomas Münzel, MD, Universitätsklinik Freiburg, Medizinische Klinik III, Hugstetterstr 55, 79106 Freiburg, Germany.

	Abstract

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Background Rebound myocardial ischemia develops in patients with unstable or stable angina pectoris after sudden cessation of nitroglycerin therapy. Long-term nitroglycerin infusion is associated with increases in plasma renin activity and catecholamine release rates, both of which may lead to excess angiotensin II and -adrenergic–mediated vasoconstriction, particularly on withdrawal of nitroglycerin.

Methods and Results Chronically instrumented dogs were treated for 5 days with nitroglycerin (1.5 µg·kg^-1·min^-1 IV) alone or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril (0.1 mg/kg two times daily or 1 mg/kg). With long-term nitroglycerin therapy, the left anterior circumflex artery was maximally dilated 4 hours after the start of nitroglycerin infusion (9.5±0.6%) and returned to baseline levels within the third day of treatment (baseline, 2.52±0.07 mm; day 3, 2.55±0.07 mm; P=NS), indicating a complete loss of nitroglycerin-induced coronary vasodilatation. Nitroglycerin infusion also was accompanied by a transient increase in plasma renin activity. Sudden withdrawal of nitroglycerin infusion caused a progressive constriction of the left anterior circumflex artery, which peaked 4 hours after nitroglycerin infusion cessation (-7.8±0.2%). This occurred in the absence of elevated plasma renin activity. Concomitant treatment with high-dose enalapril (1 mg·kg^-1·d^-1) markedly reduced the degree of tolerance and prevented the rebound constriction on cessation of nitroglycerin therapy.

Conclusions Long-term ACE inhibition with high-dose enalapril reduces nitroglycerin tolerance and prevents rebound vasoconstriction in coronary arteries. These phenomena were not associated with an activated circulating renin-angiotensin system. This observation suggests that during long-term nitroglycerin treatment, intrinsic abnormalities of the vascular smooth muscle may have developed that are suppressed by concomitant ACE inhibitor therapy. The present study also favors a combination of nitroglycerin and ACE inhibitors to maintain nitrate sensitivity of the vasculature during long-term nitroglycerin treatment.

Key Words: nitroglycerin • circulation • pharmacology

	Introduction

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The hemodynamic and anti-ischemic efficacies of nitroglycerin are blunted rapidly as a result of the development of tolerance.^{1 2} The underlying mechanisms responsible for nitrate tolerance probably are multifactorial and may include neurohormonal counterregulatory mechanisms,³ intravascular volume expansion,⁴ or properties intrinsic to the vasculature. Such intrinsic abnormalities may include desensitization of the target enzyme guanylyl cyclase⁵ or a decrease in nitroglycerin biotransformation.⁶ More recent experimental data demonstrated that tolerance is associated with enhanced vascular superoxide anion production⁷ and an enhanced propensity for vasoconstriction secondary to increased endothelin expression within the vascular smooth muscle.⁸ Importantly, nitroglycerin treatment is associated with increased circulating Ang II levels,³ which in turn may increase superoxide anion production and induce endothelin expression in cultured smooth muscle cells through activation of the angiotensin type 1 receptors.^{9 10 11} These observations suggest that cellular events leading to nitrate tolerance are mediated at least in part by Ang II.

Another aspect of the organic nitrate therapy is the development of rebound ischemia on abrupt cessation of long-term therapy. This is associated with angina pectoris, myocardial infarction, and even sudden cardiac death.^{12 13 14} In patients with coronary artery disease, it generally is not possible to interpret whether recurrence of angina pectoris symptoms after nitroglycerin withdrawal reflects rebound constriction within the coronary circulation or whether this phenomenon is simply the consequence of cessation of an antianginal therapy.

On the basis of these considerations, we performed this study to directly analyze the consequences of sudden nitroglycerin withdrawal on large coronary conductance and resistance vessels and to address the possible role of the RAS in nitroglycerin tolerance and rebound phenomena. To perform these studies, we used a well-characterized animal model of nitrate tolerance and examined the effect of treatment with the non–sulfhydryl-containing ACE inhibitor enalapril.

	Methods

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Animals
Experiments were performed in trained mongrel dogs of either sex weighing 25 to 32 kg (average, 27±4 kg body wt). These dogs were used in different protocols without the same protocol being repeated in the same dog. For chronic instrumentation, the dogs underwent thoracotomy under pentobarbital anesthesia and sterile conditions. All dogs were instrumented for measurement of coronary flow and external epicardial artery diameter of the circumflex branch of the left coronary artery as described previously.^{15 16 17} Criteria for inclusion of these dogs were a minimal dilation of the LCx branch of at least 100 µm in response to an acute nitroglycerin challenge (0.4 mg IV). During thoracotomy, a polyethylene catheter was implanted in the pulmonary artery of each dog for long-term nitroglycerin infusion. Furthermore, a common carotid artery was translocated into a cutaneous loop at the ventral surface of the neck (for transcutaneous puncture); alternatively, a catheter was implanted in the aorta descendens for continuous arterial pressure recording. All cables and catheters were tunneled subcutaneously to the dog's back. Postoperatively, the dogs received antibiotics for 1 week, and the catheters were flushed daily. For long-term nitroglycerin application, a dosage of 1.5 µg·kg^-1·min^-1 was infused continuously over 5 days through a small infusion pump (model AS30C, Baxter). At the end of the experimental period, the dogs were killed with an overdose of pentobarbital.

Groups of Dogs and Experimental Protocols
Two groups were studied (see the Table). In group 1, designated the control group, the effects of nitroglycerin infusion and withdrawal on coronary and systemic hemodynamic parameters (group 1a) were examined. After a 2-week washout period, the effects of enalapril (1 mg/kg) on systemic and coronary hemodynamic parameters were studied (group 1b). Group 2 was designated the treatment group. In this group, we studied the effects of a combination therapy of nitroglycerin and either low-dose (0.2 mg/kg=0.1 mg/kg twice daily, group 2a) or high-dose (1.0 mg/kg, group 2b) enalapril on the development of tolerance and rebound. Similar to the experiments in group 1, the protocols using low- and high-dose enalapril were separated by a 2-week washout period.

View this table: [in this window] [in a new window]   Table 1.

Blood samples for determination of PRA were drawn before infusion (two control values), during long-term nitroglycerin infusion (4 hours; 1 to 5 days after the start of infusion), and during the withdrawal period (30 minutes; 2, 4, and 24 hours after nitroglycerin infusion was stopped). Blood samples were obtained at 9 AM before the systemic and coronary hemodynamic parameters were determined. Before the blood samples were collected, the dogs rested for at least 30 minutes. PRA and the ACE activity were determined as previously described.^{18 19}

In separate experiments, we examined the effects of 0.1 mg/kg enalapril on the Ang I pressor response in four conscious dogs. Increasing concentrations of Ang I (ranging from 10 to 1000 ng/kg bolus IV) were administered, and blood pressure was recorded. In these experiments, Ang I caused a concentration-dependent increase in mean arterial pressure. The area under the curve was integrated, and the data are presented as the pressure-time integral (millimeters of mercury times minutes). The pressure-time integral was determined before and 2 hours after administration of enalapril 0.1 mg/kg PO. Blood samples also were drawn before and after low-dose enalapril to determine the ACE activity before and after enalapril infusion.

Drugs
The drugs and intravenous solutions used were nitroglycerin (Pohl Boskamp) and enalapril (Merck, Sharp, and Dohme).

Statistical Analysis
All values are presented as mean±SEM. For comparison of coronary diameters to the baseline value within a protocol, a one-way ANOVA for multiple comparisons, followed by a t test with Bonferroni's correction for the numbers of comparison, was used. Ang I pressor responses before and after enalapril infusion were compared with a repeated measures ANOVA. A Scheffé post hoc test was used to examine differences between the dose responses when significance was indicated. A value of P<.05 was considered significant.

	Results

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Effects of Long-term Nitroglycerin Infusion and Withdrawal on Coronary and Systemic Hemodynamic Parameters in Chronically Instrumented Dogs
Within 4 hours of continuous nitroglycerin treatment, a significant increase in heart rate (from 85±5 to 94±6 beats per minute), a decrease in mean arterial pressure (from 99±1 to 90±2 mm Hg), an increase in coronary blood flow (from 25±2 to 30±2 mL/min), and an increase in LCx diameter of 10±0.2% (from 2.52±0.07 to 2.76±0.09 mm) occurred (Fig 1, all P<.05). Twenty-four hours after initiation of nitroglycerin infusion, coronary blood flow, heart rate, and mean arterial pressure returned to baseline, whereas the LCx remained nearly maximally dilated (Fig 1).

View larger version (24K): [in this window] [in a new window]   Figure 1. Plot of effects of long-term nitroglycerin (NTG) infusion (1.5 µg·kg-1·min-1; group 1a) and enalapril (1 mg/kg PO; group 1b) on coronary and systemic hemodynamic parameters of chronically instrumented dogs (n=6). Long-term nitroglycerin infusion resulted in a rapid development of tolerance within 2 to 3 days, and abrupt cessation of nitroglycerin therapy caused a rebound constriction in large coronary arteries. Treatment with high-dose enalapril (1 mg/kg PO) alone had no significant effects on coronary and systemic hemodynamic parameters. Data are expressed as mean±SEM. CDLCX indicates LCx diameter; MAP, mean arterial pressure; HR, heart rate; and CF, coronary flow. *P<.05 vs control values.

Similar to previous reports,^{16 17} LCx diameter returned to baseline within 2 to 3 days of continuous nitroglycerin treatment under ongoing nitroglycerin infusion, indicating the development of tolerance in epicardial conductance vessels.

In the early withdrawal phase (30 minutes after nitroglycerin infusion), we observed a transient increase in mean arterial pressure (from 96±3 to 106±3 mm Hg, P<.05) and a small but significant constriction of the LCx artery. Maximal constriction of the LCx was observed 4 hours after nitroglycerin infusion was stopped (-7.8±1%). Twenty-four hours after the cessation of nitroglycerin infusion, all coronary and systemic hemodynamic parameters did not differ significantly from values obtained before nitroglycerin infusion.

Effects of Long-term ACE Inhibitor Treatment on Coronary and Systemic Hemodynamic Parameters in Dogs With and Without Nitroglycerin Treatment
As Fig 1 shows, enalapril per se (1 mg/kg) had no significant effect on coronary artery diameter, coronary flow, and systemic hemodynamic parameters such as mean arterial pressure and heart rate. In dogs treated concomitantly with nitroglycerin and enalapril (1.0 mg/kg) for 5 days, the large coronary artery diameter remained significantly dilated throughout the entire nitroglycerin infusion period, although some degree of tolerance was observed on days 4 and 5 (LCx diameters were significantly smaller on days 4 and 5 compared with the 4-hour nitroglycerin infusion period). High-dose enalapril also prevented early rebound with respect to mean arterial pressure and prevented rebound constriction of large coronary arteries, whereas low-dose enalapril (0.2 mg/kg) was ineffective in preventing tolerance and rebound (Fig 2).

View larger version (27K): [in this window] [in a new window]   Figure 2. Plot of effects of long-term nitroglycerin (NTG) treatment (1.5 µg·kg-1·min-1) in combination with low- or high-dose enalapril (E; 0.2 mg/kg PO [group 2a] vs 1 mg/kg PO [group 2b]) on coronary and systemic hemodynamic parameters in chronically instrumented dogs (n=5). Concomitant treatment with high-dose enalapril retarded tolerance development and prevented rebound constriction after nitroglycerin was stopped, whereas low-dose enalapril was ineffective. Data are expressed as mean±SEM. Abbreviations as in Fig 1. *P<.05 vs control values.

Effects of Nitroglycerin Infusion and the Combination Therapy of Nitroglycerin and Enalapril (0.2 and 1 mg/kg) on PRA in Chronically Instrumented Dogs
In dogs treated with nitroglycerin alone (group 1a), initiation of nitroglycerin therapy was associated with a significant increase in PRA (from 0.40±0.08 to 1.24±0.16 ng·mL^-1·h^-1 [4-hour value]). During long-term infusion, PRA values constantly declined (Fig 3) and did not differ significantly from baseline at day 4 of nitroglycerin infusion.

View larger version (29K): [in this window] [in a new window]   Figure 3. Plot of effects of long-term nitroglycerin (NTG) treatment with and without enalapril (E; 0.2 and 1.0 mg/kg) on PRA in chronically instrumented dogs. High-dose but not low-dose enalapril effectively inhibited the circulating RAS as indicated by the persistent increases in PRA. Data are presented as mean±SEM. *P<.05 vs control values within the nitroglycerin infusion period.

In dogs treated with nitroglycerin and low-dose enalapril (group 2a), PRA peaked 4 hours after nitroglycerin infusion started (from 0.62±0.10 to 1.20±0.06 ng·mL^-1·h^-1, P<.05). As in dogs treated with nitroglycerin alone, PRA significantly declined steadily during nitroglycerin infusion and did not differ from baseline at day 4 of nitroglycerin infusion.

In dogs treated concomitantly with nitroglycerin and high-dose enalapril (group 2b), PRA values remained significantly elevated compared with dogs treated with nitroglycerin alone throughout the entire nitroglycerin infusion and withdrawal period, compatible with an effective ACE blockade.

The lack of significant effects of low-dose enalapril on PRA may indicate that the chosen concentration is too small to exert a significant inhibition of the ACE. To address this issue, we tested the effects of low-dose enalapril (2 hours after dosing) on the angiotensin-induced pressor action and ACE activity. As Fig 4 shows, enalapril (0.1 mg/kg) effectively shifted the dose pressor response to significantly higher Ang I concentrations and caused a significant inhibition of the ACE activity.

View larger version (17K): [in this window] [in a new window]   Figure 4. Left, Plot of effects of enalapril (E) 0.1 mg/kg PO on pressor actions of Ang I (AI in figure) in conscious dogs. For quantifications of the increase in mean arterial pressure in response to different concentrations of Ang I before and after enalapril infusion, the area under the mean arterial pressure curve above control mean arterial pressure was evaluated. Right, Effects of enalapril 0.1 mg/kg PO on ACE activity in the plasma. Data are expressed as mean±SEM. PTI indicates pressure-time integral.

	Discussion

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The new findings of the present study are that on abrupt cessation of a long-term nitroglycerin infusion, profound rebound constriction of large coronary arteries develops, which is prevented by concomitant treatment with high doses of a nonsulfhydryl containing an ACE inhibitor. The ACE inhibitor also reduced the degree of tolerance (as assessed by return of the coronary diameter toward baseline values).

Nitroglycerin Rebound
Early reports found a substantial increase in mortality in workers exposed to nitroglycerin compared with age-matched control subjects. Ischemic periods usually occurred at nitrate-free intervals in workers having years of nitroglycerin exposure. These individuals had manifest objective evidence of atheromatous disease at autopsy.²⁰ Similar rebound phenomena also were reported to occur after cessation of prolonged therapy with nitroglycerin or sodium nitroprusside infusion,^{12 21} oral therapy with isosorbide dinitrate,¹⁴ or nitroglycerin patches^{13 22} in patients with coronary artery disease or heart failure. The underlying mechanisms, however, remain poorly defined. Sudden withdrawal of nitroprusside in patients has been shown to cause an early hemodynamic rebound,²¹ a phenomenon observed in an experimental model of heart failure²³ after sudden withdrawal of nitroglycerin. Similarly, in the current studies, mean arterial pressure was significantly increased 30 minutes after nitroglycerin cessation compared with baseline values. Although the mechanisms underlying this early rebound remain obscure, it seems likely that because of the short elimination half-life of nitroglycerin (minutes), the vasorelaxant effects may be removed so rapidly that the counterregulatory vasoconstrictor effects, which are still operative, become unopposed.²³

This early rebound phenomenon, however, does not explain clinical observations of recurrence of angina in patients with coronary artery disease 3 to 4 hours after interruption of nitroglycerin therapy,²² even in the absence of significant changes in systemic hemodynamics¹² and circulating vasoconstrictor forces. With the present studies, we demonstrated that sudden cessation of long-term nitroglycerin treatment leads to a rebound constriction of large coronary arteries that peaked 4 hours after the nitroglycerin infusion was stopped. The maximal constriction of the outer LCx diameter averaged 8%. Taking into account a ratio of wall thickness to diameter of 1:4, this would mean a reduction in cross-sectional area by 50%. Although it may be difficult to extrapolate this observation to the clinical situation, a marked increase in large coronary artery tone after nitroglycerin withdrawal could indeed represent a pathophysiological mechanism responsible for ischemic periods in patients, eg, with eccentric coronary artery stenosis. The observed increase in large artery tone with a peak 4 hours after cessation of nitroglycerin therapy would also explain recent observations demonstrating that a nitrate-free interval after transdermal nitroglycerin therapy was associated with a marked decrease in anginal threshold for 4 to 6 hours after patch removal.²⁴

In contrast to large coronary artery constriction, we could not detect a significant change in coronary blood flow after cessation of nitroglycerin therapy. This finding suggests a different susceptibility of large conductance and small resistance vessels to develop rebound. Previous reports showed that in contrast to large arteries, arterioles cannot metabolize nitroglycerin into its vasoactive metabolite nitric oxide.^{25 26} Furthermore, clinical and experimental studies demonstrated that in the setting of tolerance in large arterial conductance vessels, the arteriolar responsiveness to nitroglycerin is retained.^{27 28} Thus, it is reasonable to conclude that only vessel segments that can biotransform nitroglycerin develop an increase in tone after cessation of long-term nitroglycerin exposure. Studies of the coronary resistance vessels are further confounded by the propensity of these vessels to be modulated predominantly by autoregulation.

Role of the RAS in Tolerance and Rebound
In the present study, chronic nitroglycerin infusion was associated with an activation of the circulating RAS. Values for PRA of dogs treated with nitroglycerin alone peaked 4 hours after initiation of nitroglycerin infusion, indicating maximal neurohormonal stimulation during the early nitroglycerin infusion phase (Fig 3). During long-term infusion, PRA gradually declined and by day 4 did not differ from baseline. The transient nature of the activation of the circulating RAS may be explained by the well-known development of systemic hemodynamic tolerance within 24 to 48 hours of continuous nitroglycerin treatment, resulting in less baroreflex stimulation and a subsequently attenuated neurohormonal response.

By comparing the time course of activation of the RAS during long-term nitroglycerin infusion with the time course of tolerance development in large coronary arteries, we established a maximal dilation of the circumflex branch 4 and 24 hours after initiation of nitroglycerin infusion, despite a markedly stimulated RAS. This indicates that during the early nitroglycerin infusion period, increased levels of circulating Ang II cannot override nitroglycerin-induced coronary vasodilation. Within 2 to 3 days of continuous nitroglycerin treatment, however, tolerance developed in large epicardial arteries, although PRA at this time was significantly less compared with the 4-hour-infusion values. Furthermore, maximal coronary artery constriction during the withdrawal period (4 hours after nitroglycerin infusion was stopped) occurred even without signs of an activation of the circulating RAS. These findings clearly demonstrate that activation of the circulating RAS is not a prerequisite for nitroglycerin tolerance and rebound.

More likely, intrinsic abnormalities of the tolerant vasculature itself may have emerged including, eg, an increase in sensitivity to circulating vasoconstrictors, activation of the local RAS, or attenuation of nitroglycerin action caused by an impaired intracellular nitroglycerin biotransformation.

Recent experimental and clinical data from our group indicate that long-term nitroglycerin therapy is associated with a marked increase in sensitivity to circulating vasoconstrictors.^{8 29} We also established an increase in sensitivity to the direct protein kinase C activator phorbolester 12,13 dibutyrate⁸ and an induction of endothelin-1 expression in the vascular media of nitrate-tolerant aorta. From these observations, we proposed that autocrine-produced endothelin-1 may serve as a priming stimulus for protein kinase C activation, which in turn mediates hypersensitivity to almost all vasoconstrictor stimuli.⁸ Interestingly, in cultured smooth muscle cells, low concentrations of Ang II induced expression of preproendothelin mRNA through stimulation of the Ang type 1 receptor in a protein kinase C–dependent fashion.⁹ Ang II also facilitates norepinephrine release rates from nerve endings and enhances the already-augmented sympathetic activity during nitroglycerin infusion.^{28 30} In addition, preliminary data indicate that concomitant treatment with the Ang II receptor antagonist losartan (angiotensin type 1 receptor) but not concomitant treatment with ß-blockers (unpublished observations) completely prevents tolerance development and an increase in sensitivity to vasoconstrictors.³¹ Therefore, an Ang II–endothelin-1–mediated increase in sensitivity to vasoconstrictors could explain at least in part the progressive loss of nitroglycerin coronary vasodilator effect during long-term infusion. It could also represent a potential mechanism for the observed coronary rebound constriction and the development of hemodynamic tolerance even in the absence of an activated circulating RAS.³² An increase in vascular ACE activity in response to long-term nitroglycerin treatment is not very likely because increased circulating Ang II levels inhibit rather than stimulate through a negative feedback the activity and expression of the vascular ACE.³³

The present data are similar to those from previous investigations, showing that tolerance has different effects in different vascular beds.^{17 28} High-dose enalapril caused a sustained epicardial artery dilation for several days, but mean arterial pressure and heart rate responses were no different in low-dose enalapril or control groups. Furthermore, tolerance to the circumflex dilation in dogs treated with high-dose enalapril is rather substantial by days 4 and 5, rather close to control levels. The absence of adverse rebound phenomena suggests that tolerance is not complete. Thus, partial tolerance (and dependence) is present by day 5 in the high-dose group. This may suggest that other mechanisms such as enhanced inactivation of nitric oxide by endothelium-derived vasoconstrictor factors (eg, vascular superoxide anions)⁷ or an impairment of intracellular nitroglycerin biotransformation itself³⁴ may come into play, thereby limiting the nitroglycerin coronary vasodilative effects during long-term administration.

From our observations, however, we cannot conclude entirely that the beneficial effects of ACE inhibition on tolerance and rebound are secondary to an additional endothelium-derived nitric oxide–mediated vasodilator stimulus. The ACE is identical to kininase II, an enzyme involved in the breakdown of the endothelium-dependent vasodilator bradykinin.^{35 36} Therefore, long-term ACE inhibition during nitroglycerin infusion may be associated with an accumulation of locally generated kinins, which in turn may activate endothelium-mediated vasodilator effects.

High- Versus Low-Dose Enalapril
Enalapril in a concentration of 1.0 mg/kg retarded tolerance, prevented rebound coronary rebound constriction, and led to consistently elevated PRA values compatible with an effective inhibition of the ACE. In contrast, the PRA profile of dogs treated with low-dose enalapril did not differ from that obtained from dogs treated with nitroglycerin alone. Although low-dose enalapril significantly inhibited the Ang I pressor response 2 hours after dosing, the chosen concentration apparently still was too small to cause a continuous inhibition of the ACE for a 12-hour period. Therefore, it is tempting to speculate that a persistent inhibition of the Ang II formation might be a prerequisite for the observed beneficial effects of high-dose enalapril on tolerance development and rebound. Furthermore, the demonstration of positive effects of ACE inhibitors, even in the absence of a functional sulfhydryl group, suggests that in agreement with previous observations, sulfhydryl group depletion is not the decisive mechanism responsible for nitrate tolerance.^{15 16 37 38}

Study Limitations
The results of this study may be limited by the observation that attenuation of the coronary effects of nitroglycerin is observed with high-dose enalapril only over the 5-day test period. The slope of the curves does not suggest a plateau effect but may suggest that "full tolerance" might have been reached within a few more days. Furthermore, the effective enalapril concentration was on a milligram-per-body-weight basis that was rather large compared with conventional human dosing. Similarly, the nitroglycerin concentration required to cause a maximal dilation of large coronary arteries in dogs is threefold larger compared with concentrations required to maximally dilate human coronary arteries.³⁹ Therefore, it seems difficult to extrapolate the relevance of drug doses between different species, especially when body surface areas are different.

Conflicting Role of ACE Inhibitors in Nitrate Tolerance
Although the data presented indicate a positive effect of ACE inhibition on tolerance and rebound, the existing literature concerning the usefulness of ACE inhibitors in preventing tolerance is quite contradictory. Although several groups reported that ACE inhibition reversed tolerance or prevented the development of tolerance when given concomitantly with nitroglycerin,^{37 40 41} other groups failed to reproduce these observations.^{42 43} Although it is almost impossible to explain the different efficacies of ACE inhibitors in these particular studies in preventing or reversing tolerance, it is quite possible that, for example, the use of higher concentrations of ACE inhibitors may have influenced the different outcomes of these studies.^{40 42}

Clinical Implications
The data presented may have important clinical implications. Rebound constriction of large coronary arteries may represent a potential mechanism responsible for recurrence of angina pectoris symptoms during nitroglycerin withdrawal periods in patients with stable or unstable angina and may explain the angina symptoms in and sudden deaths of munition workers. Withdrawal symptoms after nitrate therapy have been observed in patients treated with nitrates alone,²⁴ whereas concomitant ß-blocker therapy prevented postnitroglycerin rebound,⁴⁴ probably by attenuating the nitroglycerin-induced hypersensitivity to catecholamines. These findings, together with our recent observations in animal studies,⁸ encourage the standard practice of treating angina with a combination of long-acting nitrates and a ß-blocker. Furthermore, the impressive positive effects of enalapril on tolerance and rebound favor a combination therapy of nitrates and ß-blockers with high rather than low doses of ACE inhibitors; however, this issue has to be addressed by well-designed clinical research trials.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme Ang = angiotensin LCx = left anterior circumflex artery PRA = plasma renin activity RAS = renin-angiotensin system

	Acknowledgments

 
This study was supported by DFG grant Ba 408/13-2. We also appreciate the technical assistance provided by Olaf Sommer and Helmut Siegel.

Received August 17, 1995; revision received October 20, 1995; accepted November 9, 1995.

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