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Effects of Epanolol, a Selective β1-Blocker with Intrinsic Sympathomimetic Activity, in Patients with Ischemic Left Ventricular Dysfunction

Van Den Heuvel, *†; van der Ent, Martin*; van Veldhuisen, Dirk J.; Kruijssen, Dick A.C.M.*; Bartels, G. Louis; Remme, Willem J.*

Journal of Cardiovascular Pharmacology: April 1998 - Volume 31 - Issue 4 - p 506-512
Article

Recently, different β-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective β1-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 ± 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 ± 0.04). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 ± 164 pg/ml for patients with LV dysfunction vs. 637 ± 41 pg/ml for normal subjects; p < 0.05). A similar effect was observed for angiotensin II. Further, in the LV-dysfunction group, coronary sinus blood flow increased less, and coronary vascular resistance decreased less (both values, p < 0.05). Despite the fact that the increase in double product was decreased to a similar extent in both groups, ischemia was reduced only in normal LV function (p < 0.05). In ischemic LV dysfunction, neurohumoral activation after epanolol may impair adequate coronary flow response, and this may limit its antiischemic properties. Because of the small size of the study, no definitive inference on the clinical benefit of epanolol in patients with ischemic LV function can be made from this study.

*Sticares Cardiovascular Research Foundation, Rotterdam, and Thoraxcenter, Department of Cardiology, University Hospital, Groningen, The Netherlands

Received April 29, 1997; revision accepted September 19, 1997.

Address correspondence and reprint requests to Dr. A. F. M. van den Heuvel at Department of Cardiology/Thoraxcenter, University Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.

β-Blockers have recently received widespread attention as potentially useful drugs in chronic heart failure (CHF; 1-3). The selective β1-blockers metoprolol and bisoprolol were found to be effective in patients with idiopathic dilated cardiomyopathy (1,2). Carvedilol, which is a nonselective β-blocker with additional α1-blocking effects, was recently found to reduce mortality in an unselected population with CHF, which also included patients with ischemic CHF (3). The importance of these additional properties of β-blockers in patients with CHF is, however, unclear, and may possibly be related to the severity of CHF. In an early study, xamoterol, a β1-blocker with intrinsic sympathomimetic activity (ISA), was found to increase exercise time and improve quality of life in patients with mild CHF (4). In a subsequent study in patients with more advanced CHF, however, xamoterol was found to increase mortality (5), but the mechanism of this effect has remained unclear.

Epanolol is a cardioselective β1-antagonist and partial agonist (6). The degree of agonist activity of epanolol is 20% of the activity of the full agonist isoprenaline (7; xamoterol has a more pronounced ISA, 43%). In previous studies, epanolol was found to reduce cardiac ischemia (8) and had little effect, at rest, on heart rate, blood pressure, various measures of cardiac hemodynamic parameters, peripheral blood flow, and renal function (9,10).

There are no data so far with epanolol in patients with left ventricular (LV) dysfunction. In these patients, autonomic function is disturbed and not only tachyarrhythmias, but also bradyarrhythmias are common (11), which may be prevented by β-blockade in combination with ISA. We conducted a study in which the hemodynamic, neurohumoral, and antiischemic effects of this compound were examined in patients with ischemia-related LV dysfunction. Invasive systemic and coronary hemodynamic measurements were performed at rest and during myocardial ischemia, which was induced by atrial pacing. These measurements were repeated after intravenous administration of 4 mg epanolol.

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METHODS

Patient selection

Patients were included after approval of the protocol by the institutional Ethical Review Board and after written informed consent. The investigation conformed with the principles outlined in the Declaration of Helsinki. All patients had a medical indication for a coronary angiography. Patients of either sex with stable, exercise-induced angina pectoris and objective signs of ischemia (>0.1 mV ST-segment depression) during stress testing were evaluated. To be included, a coronary diameter stenosis of ≥70% in at least one epicardial artery (i.e., the left anterior descending artery, its diagonal branches, the left circumflex artery or its proximal marginal branches) had to be present, thus enhancing the possibility of pacing-induced myocardial ischemia.

Exclusion criteria were hypertension, defined as a supine systolic blood pressure ≥220 mm Hg or a supine diastolic blood pressure ≥100 mm Hg or both, heart failure (NYHA class III and IV), a recent myocardial infarction (<3 months), conduction disturbances, valvular heart disease, insulin-dependent diabetes mellitus, significant renal dysfunction (serum creatinine, ≥150 μM), bronchial asthma or chronic obstructive airway disease, and glaucoma treated with a β-adrenoceptor antagonist. Women of childbearing potential were not allowed in the study. Patients were not included if they received β-blockade, angiotensin-converting enzyme (ACE) inhibition, diuretics, or digitalis glycosides. All other cardiac medication was withdrawn 36-72 h before the study, depending on their respective half-lives, except for short-acting nitroglycerin, which was permitted until 5 h before the study.

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Study protocol

After positioning of the catheters, a stabilization period of 20 min was allowed to reach a minimum interval of 40 min preceding coronary angiography and the study. Thereupon, repetitive control measurements were made of hemodynamic and electrocardiographic variables to ensure stable baseline values. Blood sampling for myocardial oxygen utilization and neurohormones was carried out once. After control determinations, the first pacing test was performed with increments in heart rate of 10 beats/2 min until angina or atrioventricular block occurred or a maximal heart rate of 170 beats/min was reached. All hemodynamic and electrocardiographic measurements were repeated at maximal pacing rate. After a delay of 45 min, during which no procedures were carried out, epanolol was administered over a 5-min period in a dose of 4 mg in 10 ml normal saline. At 15 min after onset of epanolol administration, control measurements for the second pacing test were made, followed by the second pacing test, which was identical to the first pacing test.

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Catheterization procedures

All patients were catheterized in the morning after an overnight fast, without premedication. After local anesthesia with 1% lidocaine (Xylocaine), introducer systems (Desilet, Vÿgon, Veenendaal, The Netherlands) were introduced in a femoral artery and femoral vein. Hereafter, routine left and right coronary angiography was performed. If at least one ≥70% stenosis was present in the left coronary system, as indicated previously, patients were eligible for the study, and further study procedures were carried out. A 7F coronary sinus thermodilution flow and pacing catheter (model CCS-7U-9OB; Wilton Webster, Baldwin Park, CA, U.S.A.) was positioned into the midportion of the coronary sinus through a Desilet introducer system introduced in a brachial vein. Next, a 7F pigtail micromanometer catheter (Sentron, Amers Foort, The Netherlands) was introduced in the left ventricle through the arterial Desilet system, of which the side arm was used to monitor arterial pressures.

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Hemodynamic measurements

The fluid-filled catheters were calibrated by using transducers (Baxter-Bentley, Utrecht, The Netherlands) with a zero level set at midchest. After calibration, all pressures, the first derivative of LV systolic pressure, coronary sinus blood flow, and electrocardiogram (ECG) were recorded on paper by using a Nihon Kohden cath-lab system (Tefa-Pórtanje, Woerden, The Netherlands). In addition, all hemodynamic parameters were determined on-line by a different cath-lab computer system (Mennen Medical, Tefa-Pórtanje, Woerden, The Netherlands). Calculations were made according to the formula Equation 1 where Tb is blood temperature before injection; Ti, temperature of injectate; Tcs, temperature of mixture of coronary sinus blood and injectate; and Vi, the rate of injection (ml/min). From the measured hemodynamic variables, coronary vascular resistance was derived by using standard formulas (12).

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Electrocardiographic parameters

The ECG was monitored continuously to measure heart rate. ST-segments were determined by hand, at a paper speed of 100 mm/s in 5 successive beats, 60 ms after the J point of the QRS complex, by using a calibrated magnifying lens. This was performed blinded to the study group.

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Oxygen and neurohumoral measurements

Simultaneous sampling of arterial and coronary sinus blood was carried out for the measurements of oxygen. Sampling of arterial blood was carried out for the measurement of norepinephrine (NE), epinephrine, and angiotensin II. Coronary sinus and arterial oxygen saturation was determined with an OSM-80 oximeter (Waters Associates, Tefa-Pórtanje, Woerden, The Netherlands). Myocardial oxygen consumption was calculated from the difference in arterial and coronary sinus oxygen content × coronary blood flow. NE, epinephrine, and angiotensin II were all measured by using high-pressure liquid chromatography (HPLC), as previously described in detail (13).

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Statistical analysis

Values are expressed as mean ± SEM in the tables. For differences between both groups, the 95% confidence intervals are provided. In the figures, individual data are presented. A two-way analysis of variance (ANOVA) multiple comparison with Bonferroni correction was performed. A two-tailed p value <0.05 was indicative of a significant difference.

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RESULTS

Fourteen patients, 11 men and three women, participated in this study. Patients were divided into a group with normal LV ejection fraction (≥0.45, n = 8) and a group with impaired LV ejection fraction (<0.45, n = 6). The mean LV ejection fraction in the LV-dysfunction group was 0.33 ± 0.08, and in the normal subjects, 0.52 ± 0.04. A summary of the patients' characteristics is given in Table 1. Baseline hemodynamic and neurohumoral parameters were not significantly different between the two groups. During the first pacing test, the reason not to increase the pacing rate in three patients was angina pectoris (two patients in the group with normal LV function and one patient in the group with LV dysfunction. In the rest of the patients, AV block was the reason not to increase pacing rate. As by design, maximal pacing rate was similar during the second pacing test.

TABLE 1

TABLE 1

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Systemic hemodynamic effects

After epanolol (Table 2) heart rate at rest decreased significantly in the LV-dysfunction group by 11%. Changes in systemic hemodynamics during the first pacing test were similar in both groups. During the second pacing test (after epanolol), the increases in rate-pressure product (RPP) and in myocardial contractility (dP/dt positive) were significantly less than during the first pacing test (no group differences). During the first pacing test, mean arterial pressure increased significantly in both groups, by 10% in the normal subjects and by 15% in the LV-dysfunction group. In contrast, during the second pacing test, mean arterial pressure increased only in the LV-dysfunction group. Changes in other systemic hemodynamic variables were comparable between both pacing tests in both groups.

TABLE 2

TABLE 2

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Coronary hemodynamic effects

During the first pacing test (Table 3), coronary sinus blood flow increased and coronary vascular resistance decreased in both groups. After epanolol, coronary vascular resistance decreased again by 22%, accompanied by a 37% improvement of coronary sinus blood flow in the normal group (both p values <0.05). In contrast, in the LV-dysfunction group no significant changes occurred. As a consequence, during the second pacing test, coronary blood flow was significantly less and coronary vascular resistance higher in the LV-dysfunction group, compared with the normal group (p < 0.05; Fig. 1). Myocardial oxygen consumption was decreased after epanolol in both groups.

TABLE 3

TABLE 3

FIG. 1

FIG. 1

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Antiischemic effects

During the first pacing test (Fig. 1), all patients in both groups had >0.1 mV ST-segment depression. Epanolol significantly reduced myocardial ischemia in the normal subjects. In this group, the ST depression was 36% less during the second pacing test as compared with the first pacing test (0.16 ± 0.04 vs. 0.25 ± 0.06 mV, respectively; p < 0.05). In contrast, no differences in ST depression were observed in the LV-dysfunction group.

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Neurohormonal effects

After epanolol (Fig. 2), in the normal LV-function group, arterial angiotensin II decreased by 30%. In the normal LV-function group, the pacing-induced changes in NE, epinephrine, and angiotensin II during the first pacing test were comparable after epanolol. However, in the LV-dysfunction group, NE increased significantly more during the second pacing test (801 vs. 1,130 pg/ml; p < 0.05). As a consequence, during the second pacing test, NE level was 60% higher in the LV-dysfunction group, compared with that of the normal subjects (p < 0.05). Epinephrine was not influenced by epanolol. In addition, angiotensin II was 43% higher in the LV-dysfunction group during the second pacing test compared with that of the normal subjects (p < 0.05).

FIG. 2

FIG. 2

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Adverse effects

Epanolol was well tolerated. Side effects were not reported. In none of the patients was a clinically significant decrease in blood pressure observed. Also, there were no signs of CHF, myocardial ischemia, or conduction disturbances as a direct result of epanolol administration before pacing.

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DISCUSSION

This study was designed to evaluate whether epanolol may be useful in patients with LV dysfunction and CHF, by comparing its effects in impaired subjects with those in patients with normal LV function. The results of this study indicate that whereas intravenous epanolol reduced myocardial oxygen demand to a similar extent in both groups, it reduced myocardial ischemia in normal subjects but failed to do so in the LV-dysfunction group. In patients with normal LV function, epanolol did not affect pacing-induced changes in coronary blood flow or coronary vascular resistance. In contrast, in the LV-dysfunction group, the improvement in coronary sinus blood flow and reduction in coronary vascular resistance during pacing was inhibited by epanolol. This inhibition of the normal coronary vasodilating effects during atrial pacing coincided with more systemic neurohormonal activation after administration of epanolol during pacing-induced ischemia in LV dysfunction.

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Hemodynamic effects

It has been found that β-blockade, in patients with normal LV function, reduces myocardial oxygen demand (14,15) and decreases myocardial ischemia in angina pectoris (9,16). Reduced total coronary blood flow (14,15) and increased subendocardial blood flow also were observed (17). In this study, we found no reduction in myocardial ischemia (ST-segment depression) in the group with LV dysfunction, which coincided with a lower total coronary sinus blood flow. Although by design in each group, the increase in pacing rates was comparable during both tests, epanolol nevertheless reduced myocardial oxygen demand, as LV systolic pressure was less during pacing after epanolol.

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Neurohormonal effects

In humans, sympathetic stimuli, such as cold pressor testing, lead to vasodilation in normal but to vasoconstriction in severely and in minimally stenosed coronary arteries (18). This study shows that in patients with LV dysfunction and coronary heart disease, the reduced total coronary sinus blood flow coincided with more pronounced neurohormonal activation during the second pacing test. Our results suggest that in patients with preexisting LV dysfunction, epanolol may adversely affect coronary vasomotor tone and flow as a result of enhanced neurohormonal activation, which subsequently limits its antiischemic potential. In contrast, in patients with a normal LV function, in whom changes in catecholamines were moderate, epanolol had no negative effect on coronary blood flow and coronary vascular resistance during ischemia. By which mechanism epanolol leads to more sympathetic activation during pacing-induced ischemia cannot be answered from the results of this study. First, it should be kept in mind that the level of arterial plasma NE as a parameter in the assessment of sympathetic activity has some limitations, because the level of NE in the plasma represents the net result of release, reuptake, and catabolism of NE from many regions. A possible mechanism is the more pronounced endothelial dysfunction in patients with LV dysfunction (19), which causes vasoconstriction when influenced by ISA. Moreover, studies with β-blockers without ISA showed beneficial effects on myocardial metabolism during pacing (20). Another possible mechanism is the well-known β-receptor downregulation (21), which makes the heart less sensitive to sympathetic influence. This mechanism also could explain why angiotensin II did not decrease after epanolol in the LV-dysfunction group.

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Limitations of the study

This study of CHF is limited to CHF of ischemic origin, and these results should not be extrapolated to patients with idiopathic dilated cardiomyopathy. Further, the study was not placebo controlled, and patients served as their own controls, because in this model, changes during the first pacing test are reproducible during the second pacing test (13). The number of patients studied in this exploratory and mechanistic study was rather small.

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Clinical implications

No definitive inference on the potential clinical benefit that may be associated with epanolol in patients with ischemic LV dysfunction can be made because of the small size of the study. Epanolol may cause a pronounced increase in ischemia-induced neurohormonal activation in patients with ischemic LV dysfunction. Subsequently coronary vasoconstriction and diminished coronary blood flow may follow. Theoretically, this may counteract the beneficial effects of this β-blocking drug. Indeed, ISA might play a role in the mechanism of the limited/adverse effects of β-blockade in ischemic CHF (2,5). Because of the small number of patients, these results should be interpreted cautiously.

Acknowledgment: We thank ICI Pharmaceuticals, Rotterdam, The Netherlands, for providing the study medication and financial support.

We thank P.J. de Kam, from the statistical department from Trial Coordination Centre, University Hospital, Groningen, The Netherlands, for his statistical advice.

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REFERENCES

1. Waagstein F, Bristow MR, Swedberg, et al., for the Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342:1441-6.
2. CIBIS investigators and committees. A randomized trial of β-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994;90:1765-73.
3. Packer M, Bristow MR, Cohn JN, et al., for the U.S. Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55.
4. The German and Austrian Xamoterol Study Group. Double-blind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. Lancet 1988;1:489-93.
5. The Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990;336:1-6.
6. Harry JD. Clinical pharmacology of epanolol. Drugs 1989;38(suppl 2):18-27.
7. Bonde J, Svendsen TL, Lyngborg K, Mehlsen J, Trap-Jensen J. Immediate haemodynamic effects of a novel partial agonist β1-adrenoceptor blocking drug ICI 141,292 after intravenous administration to healthy young volunteers and patients with ischaemic heart disease. Br J Clin Pharmacol 1987;23:35-40.
8. Vandenbosch H, Piessens J, De Geest H. Effects of a single oral administration of epanolol on exercise tolerance in patients with stable effort angina. Acta Cardiol 1991;66:11-25.
9. Nuttell A, Snow HM. The cardiovascular effects of ICI 118.587: A beta 1-adrenoceptor partial agonist. Br J Pharmacol 1982;77:381-8.
10. Akhras F, Jackson G. Epanolol: a new once-daily antianginal agent: dose finding and long term efficacy. Drugs 1989;38(suppl 2):28-34.
11. Luu M, Stevenson WG, Stevenson LW, Baron K, Walden J. Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation 1989;80:1675-80.
12. Grossman W, Baim DS. Cardiac catheterization, angiography and intervention. 4th ed. Philadelphia: Lea & Febiger, 1991.
13. Remme WJ, Kruijssen HACM, Look MP, Bootsma M, De Leeuw PW. Systemic and cardiac neuroendocrine activation and severity of myocardial ischemia in humans. J Am Coll Cardiol 1994;23:82-91.
14. Simonsen S, Ihlen H, Kjekshus JK. Hemodynamic and metabolic effects of timolol on ischaemic myocardium. Acta Med Scand 1983;213:393-8.
15. Wolfson S, Gorlin R. Cardiovascular pharmacology of propranolol in man. Circulation 1969;40:501-11.
16. Jackson G, Atkinson L, Oram S. Improvement of myocardial metabolism in coronary arterial disease by beta-blockade. Br Heart J 1977;39:829-33.
17. Gross GJ, Lamping KG, Warltier DC, Hardman HF. Effects of three bradycardiac drugs on regional myocardial blood flow and function in areas distal to a total or partial coronary occlusion in dogs. Circulation 1984;69:391-9.
18. Nabel EG, Ganz P, Gordon JB, Alexander RW, Selwyn AP. Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test. Circulation 1988;77:43-52.
19. Drexler H, Hayoz D, Münzel T. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992;69:1596-601.
20. Andersson B, Lomsky M, Waagstein F. The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure: a study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol. Eur Heart J 1993;14:1375-85.
21. Bristow MR, Ginsburg R, Fowler M, et al. Beta 1- and beta 2-adrenergic receptor subpopulations in normal and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor downregulation in heart failure. Circ Res 1986;59:297-309.
Keywords:

Epanolol; β-Blockade; Heart failure; Neurohormones; Coronary flow

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