Adjunctive sympathoplegic therapy to ACE inhibition in Blacks with congestive heart failure: a comparison of alpha-1 with beta-1 blockade on exercise tolerance and cardiac sympathovagal reflex activity.
OBJECTIVE
Congestive heart failure (CHF) is characterized by an initial compensatory, but subsequently deleterious, activation of both the renin-angiotensin (RAS) and the sympathetic nervous system (SNS). Incomplete suppression of the SNS may contribute to the residual mortality during optimal ACE inhibitor therapy in CHF. Carvedilol, a mixed alpha and beta-blocker with antioxidant properties, and other pure beta-adrenoceptor blockers reduce morbidity and mortality in Caucasians with CHF. However, beta-blocker monotherapy is of poor efficacy in Blacks with essential hypertension or in the treatment of glaucoma. The efficacy of beta-blockers in the treatment of African Americans with congestive heart failure is a controversial issue with conflicting findings. The aims of the present study were to examine and compare the cardiovascular, autonomic, and clinical effects of additional alpha-1, or beta-1 blockade in ACE-inhibitor treated Black patients with moderate to severe CHF.


METHODS
Twenty-eight Nigerian patients with chronic CHF stabilized on digoxin and diuretics, were randomized to 3 groups of similar demographics according to a single blind, parallel group design. The patients were aged 53 +/- 6 years, and comprised 14 men and 14 women, with a mean cardiothoracic ratio of 0.66 +/- 0.03, and ejection fraction of 0.38 +/- 0.10, 60% hypertensive etiology. Group 1 patients received 5 mg enalapril alone, group 2 received 5 mg enalapril + 1 mg prazosin, and group 3 received 5 mg enalapril + 50 mg atenolol. All medication was taken daily for 4 weeks. Blood pressure, heart rate, pressure rate product, 6-minute walk test, NYHA class, and cardiac autonomic reflexes were measured at baseline and again at 2 and 4 weeks of treatment. Two-way repeated measures ANOVA, and a one-way ANOVA were used in data analysis.


RESULTS
The 3 treatments caused significant (P<.001 ANOVA) and similar improvements for the NYHA class (-1.0 to -1.6), and increased the 6-minute distance covered (+130 m to +205 m). Although no treatment differences were observed, a trend suggesting a greater improvement with enalapril + atenolol became apparent. By the fourth week, the sympathoplegic treatments, enalapril + atenolol, and enalapril + prazosin, caused significant reductions in the pressure rate product (-3726 +/- 1885 mm Hg x beats/min; -3498 +/- 396 mm Hg beats/min, respectively), (compared to enalapril alone (-1349 +/- 894 mm Hg x beats/min) (P<.001 ANOVA). During the Valsalva maneuver, the phase IV bradycardia were significantly greater after treatment with enalapril + atenolol (944 +/- 66 msec) or with enalapril + prazosin (825 +/- 48 msec), compared to enalapril alone (760 +/- 45 msec) (P<.001 ANOVA). The phase II Valsalva tachycardia were similar between treatments. The respiratory sinus arrhythmia ratio increased significantly (P<.005 ANOVA) and equally on all treatments. However, the pressor and chronotropic responses to forearm isometric handgrip increased significantly on the enalapril + prazosin combination (P<.02), compared to the other treatments.


CONCLUSIONS
Our findings demonstrated not only the safety of providing additional therapy with alpha-1 or beta-1 receptor blockade concurrent with ACE inhibition in Blacks with CHF, but also the resultant improvement in exercise tolerance and NYHA class. Compared to using ACE inhibition alone, the combined therapies caused a marked reduction in the pressure rate product, an index of myocardial oxygen consumption, and a greater enhancement of cardiac parasympathetic activity. Selective beta-1 blockade caused a greater enhancement of central baroreceptor vagal activity compared to alpha-1 blockade. Conversely, the pressor and chronotropic abnormalities during forearm isometric handgrip in CHF, were normalized by alpha-1, but not beta-1, blockade. Thus, the combined reflex cardiac vagal augmentation following selective beta-1 blockade, and the hemodynamic effects of alpha-1 antagonism with concurrent ACE inhibition, may be of major therapeutic and prognostic benefit in Blacks with non-ischemic (hypertensive) CHF stabilized on digoxin and diuretics.
Department of Medicine, Division of Clinical Pharmacology, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria. adeajayi@aol.com
Adesuyi A Leslie
AA
Ajayi
Gbenga G
GG
Sofowora
Adegboyega Q
AQ
Adigun
Bola
B
Asiyanbola
D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001262:Atenolol / Q000627:therapeutic use; D044383:Black People; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use; D017079:Exercise Tolerance / Q000187:drug effects*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000208:ethnology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D009549:Nigeria / Q000208:ethnology; D011224:Prazosin / Q000627:therapeutic use; D011446:Prospective Studies; D012119:Respiration / Q000187:drug effects; D016037:Single-Blind Method; D001741:Black or African American
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001262:Atenolol; D004656:Enalapril; D011224:Prazosin