Summary
Xamoterol acts as aβ 1-adrenoceptor agonist at low sympathetic activity and as an antagonist at high activity. Although its long-term efficacy has been proven in patients with mild to moderate heart failure, it remains unclear which effect, agonism or antagonism, accounts for its long-term activity.
To clarify the effect of xamoterol on cardiac sympathetic activity in daily life, 24-h R-R interval histograms were obtained during administration of xamoterol 100 mg b. d. for 1 week to 10 patients with mild to moderate heart failure. Eight normal subjects were also studied as controls. To examine the relation between the effect of xamoterol and sympathetic activity, plasma noradrenaline (NA) levels were measured under 5 graded conditions simulating daily living.
Xamoterol administration significantly decreased the standard deviation of the R-R interval, both in patients with heart failure and in normal subjects. The mean R-R interval, however, was increased in patients with heart failure, relative to normal subjects.
In both groups, the R-R interval histograms had two peaks, i. e. a short daytime peak and a long night-time peak. Xamoterol decreased the median of the night-time peak without changing the daytime peak in normal subjects. In contrast, it increased the median of the daytime peak without producing a significant change in the nighttime peak in patients with heart failure. Levels of plasma NA were significantly higher in patients than in normal subjects under all conditions.
Thus, in normal subjects xamoterol predominantly increased the slower heart rate at night with only a minor effect on the higher heart rate in the daytime, whereas it predominantly attenuated the daytime tachycardia induced by sympathetic stimulation in patients with heart failure.
It is concluded that xamoterol tends overall to act as aβ-adrenoceptor antagonist during the day, especially in the daytime in patients with mild to moderate heart failure. Its antagonist rather than its agonist effect may account for the long-term efficacy of xamoterol in patients with mild to moderate heart failure.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Nuttal A, Snow HM (1982) The cardiovascular effects of ICI 118, 587: aβ 1-adrenoceptor partial agonist. Br J Pharmacol 77: 381–388
Detry JMR, Decoster PM, Brasseur LA (1983) Hemodynamic effects of Corwin (ICI 118, 587), a new cardioselective betaadrenoceptor partial agonist. Eur Heart J 4: 584–591
Ohyagi A, Sasayama S, Nakamura Y, Lee JD, Kihara Y, Kawai C (1984) Effect of ICI 118, 587 on left ventricular function during graded treadmill exercise in conscious dogs. Am J Cardiol 54: 1108–1113
Sato H, Inoue M, Matsuyama T, Ozaki H, Shimazu T Takeda H, Ishida Y, Kamada T (1987) Hemodynamic effects of theβ 1-adrenoceptor partial agonist xamoterol in relation to plasma norepinephrine levels during exercise in patients with left ventricular dysfunction. Circulation 75: 213–220
Waller DG, Webster J, Sykes CA, Bhalla KK, Wray R (1989) Clinical efficacy of xamoterol, aβ 1-adrenoceptor partial agonist, in mild to moderate heart failure. Eur Heart J 10: 1003–1010
Sorensen EV, Faergeman O, Day MAE, Snow HM (1989) Longterm efficacy of xamoterol (aβ 1-adrenoceptor partial agonist) in patients with mild to moderate heart failure. Br J Clin Pharmacol 28:86S-88S
Pouleur H, van Eyll C, Hanet C, Cheron P, Charlier AA, Rousseau MF (1988) Long-term effects of xamoterol on left ventricular diastolic function and late remodeling: a study in patients with anterior myocardial infarction and single-vessel disease. Circulation 77:1081–1089
The German and Austrian Xamoterol Study Group (1988) Double-blind placebo controlled comparison of digoxin and xamoterol in chronic heart failure. Lancet I: 489–193
Malajo AO, Bennett DH (1985) Effect of xamoterol (ICI 118587), a new beta, adrenoceptor partial agonist, on resting haemodynamic variables and exercise tolerance in patients with left ventricular dysfunction. Br Heart J 54: 17–21
The Xamoterol in Severe Heart Failure Study Group (1990) Xamoterol in severe heart failure. Lancet 336:1–6
Thomas JA, Marks BH (1978) plasma norepinephrine in congestive heart failure. Am J Cardiol 41: 233–243
Minami M, Yasuda H, Yamazaki N, Kojima S, Nishijima H, Matsumura N, Togashi H, Koike Y, Saito H (1983) Plasma norepine-phrine concentration and plasma dopamine-β-hydroxylase activity in patients with congestive heart failure. Circulation 67:1324–1329
Swedberg K, Hjalmarson A, Waagstein F, Wallentin I (1980) Beneficial effects of long-term beta-blockade in congestive cardiomyopathy. Br Heart 144:117–133
Engelmeier RS, O'Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM (1985) Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation 72:536–546
Waagstein F, Caidhal K, Wallentin I, Bergh C, Hjalmarson A (1989) Long-term beta-blockade in dilated cardiomyopathy: effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol. Circulation 80: 551–563
Tochikubo O, Miyazaki N, Ochiai H, Kaneko Y (1986) Non-Gaussian distribution of arterial pressure and heart rate during sleep and waking in hypertensive and normotensive subjects. Jpn Circ J 50: 808–817
Ninomiya I, Nishiura N, Shimonura K (1983) Twenty-four-hour pattern of ventricular excitation rhythm in resting normal human subjects. Jpn J Physiol 33: 875–886
Hallman H, Farnebo LO, Hamberger B, Jonsson G (1978) A sensitive method for the determination of plasma catecholamines using liquid chromatography with electrochemical detection. Life Sci 23:1049–1052
Malajo AO, Coupe MO, Bennett DH (1984) Effect of Corwin (ICI 118587) on resting and exercise heart rate and exercise tolerance in digitalised patients with chronic atrial fibrillation. Br Heart J 52: 392–395
Tseu FL, Morley CA, Mackintosh AF (1986) Oral xamoterol in patients with sinoatrial disease. Br Heart J 56:469–472
Eckberg DL, Drabinsky M, Braunwald E (1971) Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 285: 877–883
Saul JP, Arai Y, Berger RD, Lilly LS, Wilson S, Colucci WS, Cohen RJ (1988) Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis. Am J Cardiol 61:1292–1299
Casolo G, Balli E, Taddei T, Amuhasi J, Gori C (1989) Decreased spontaneous heart rate variability in congestive heart failure. Am J Cardiol 64:1162–1167
Zucker IH, Peterson TV, Gilmore JP (1980) Ouabain increases left atrial stretch receptor discharge in the dog. J Pharmacol Exp Ther 212: 320–324
Osterziel KJ, Dietz R, Schmid W, Mikulaschek K, Manthey J, Kubler W (1990) ACE inhibition improves vagal reactivity in patients with heart failure. Am Heart J 120:1120–1129
Cai N, Dohnal M, Olsson SB (1987) Methodological aspects of the use of heart rate stratified RR interval histograms in the analysis of atrioventricular conduction during atrial fibrillation. Cardiovasc Res 21: 455–462
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ozaki, H., Sato, H., Hori, M. et al. Predominantβ-adrenoceptor blocking effect of xamoterol averaged over the day in patients with mild to moderate heart failure: insight into the mechanism of its long-term clinical efficacy. Eur J Clin Pharmacol 43, 455–461 (1992). https://doi.org/10.1007/BF02285085
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02285085