Advertisement
Clinical Therapeutics
Advanced searchSave search
Research Article| Volume 19, SUPPLEMENT 1, 53-73, 1997

Download started.

Ok

The clinical significance of neurohormonal activation

  • Peter E. Pool
    Correspondence
    Address correspondence to: Peter E. Pool, MD, Reno Cardiology Research Laboratory, 15 Sawbuck Road, Reno, NV 89509.
    Affiliations
    Reno Cardiology Research Laboratory, Reno, Nevada U.S.A.
    Search for articles by this author
DOI:https://doi.org/10.1016/S0149-2918(97)80037-9
The clinical significance of neurohormonal activation
Previous ArticleReappraisal of the importance of heart rate as a risk factor for cardiovascular morbidity and mortality
Next ArticleRationale for the use of calcium antagonists in the treatment of silent myocardial ischemia
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Progressive heart disease after the onset of left ventricular dysfunction has typically been attributed to hemodynamic factors. As left ventricular function declines, decreased cardiac output and tissue hypoperfusion lead to compensatory increases in afterload, preload, and heart rate. The purpose of these compensatory responses is to increase cardiac output and maintain tissue perfusion; however, they may also create hemodynamic stress for the failing heart. However, this does not explain the progression of heart failure despite hemodynamic maintenance with pharmacologic therapy. Activation of neurohormonal systems that are essential for homeostasis in the normal heart plays a key role in the progression of heart failure. In acute heart failure, these systems have beneficial effects, but in chronic heart failure their activation produces deleterious effects by increasing the load on the left ventricle and promoting structural remodeling, which may further impair left ventricular function. The issue of neurohormonal activation is an important one in cardiovascular medicine, not only for patients with heart failure but also for patients with hypertension and ischemic heart disease when left ventricular dysfunction is present. As neurohormonal activation may play a pathogenic role in the long-term outcome of patients, interventions that have favorable hemodynamic but unfavorable neurohormonal effects can actually exacerbate cardiac disease and may increase cardiovascular morbidity and mortality. As neurohormonal activation appears to parallel the severity of heart failure, whether assessed according to symptoms or prognosis, an understanding of neurohormonal activation and its interaction with hemodynamic factors is essential for optimizing pharmacologic therapy for cardiovascular disease.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Register: Create an account
      Institutional Access: Sign in to ScienceDirect

      References

        • Ho K
        • Pinsky J
        • Kannel W
        • Levy D
        The epidemiology of heart failure: The Framingham study.
        J Am Coll Cardiol. 1993; 22 (Suppl): 6A-13A
        • Massie B
        Is neurohormonal activation deleterious to the long-term outcome of patients with congestive heart failure? I. Introduction.
        J Am Coll Cardiol. 1988; 12: 547-548
        • Benedict C
        Neurohormonal aspects of heart failure.
        Cardiol Clin. 1994; 12: 9-23
        • Packer M
        The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure.
        J Am Coll Cardiol. 1992; 20: 248-254
        • Packer M
        Evolution of the neurohormonal hypothesis to explain the progression of chronic heart failure.
        Eur Heart J. 1995; 16 (Suppl F): 4-6
        • Elsner D
        Changes in neurohormonal systems during the development of congestive heart failure: Impact on cardiovascular and renal function.
        Eur Heart J. 1995; 16 (Suppl N): 52-58
        • Opie L
        Calcium channel antagonists in the treatment of coronary artery disease: Fundamental pharmacological properties relevant to clinical use.
        Prog Cardiovasc Dis. 1996; 38: 273-290
        • Parmley W
        Neuroendocrine changes in heart failure and their clinical relevance.
        Clin Cardiol. 1995; 18: 440-445
        • Laragh J
        Renin-angiotensin-aldosterone system for blood pressure and electrolyte homeostasis and its involvement in hypertension, in congestive heart failure and in associated cardiovascular damage (myocardial infarction and stroke).
        J Hum Hypertens. 1995; 9: 385-390
        • Brooks V
        • Osborn J
        Hormonal-sympathetic interactions in long-term regulation of arterial pressure: An hypothesis.
        Am J Physiol. 1995; 268: R1343-R1358
        • Goldberg L
        • Rajfer S
        Dopamine receptors: Applications in clinical cardiology.
        Circulation. 1985; 72: 245-248
        • Dzau V
        • Packer M
        • Lilly L
        • et al.
        Prostaglandins in severe congestive heart failure: Relation to activation of the renin-angiotensin system and hyponatremia.
        NEJM. 1984; 310: 347-352
        • Kubo S
        Neurohormonal activity in congestive heart failure.
        Crit Care Med. 1990; 18 (Suppl): S39-S44
        • Rundqvist B
        • Elam M
        • Bergmann-Sverrisdottir Y
        • et al.
        Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure.
        Circulation. 1997; 95: 169-175
        • Bristow M
        Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with beta-blocking agents.
        Am J Cardiol. 1993; 71 (Suppl): 12C-22C
        • Bristow M
        • Hershberger R
        • Port J
        • et al.
        β-adrenergic pathways in nonfailing and failing human ventricular myocardium.
        Circulation. 1990; 82 (Suppl I): I12-I25
        • Rona G
        Catecholamine cardiotoxicity.
        J Mol Cell Cardiol. 1985; 17: 291-306
        • Thomas J
        • Marks B
        Plasma norepinephrine in congestive heart failure.
        Am J Cardiol. 1978; 41: 233-243
        • Cohn J
        • Levine T
        • Olivari M
        • et al.
        Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.
        NEJM. 1984; 311: 819-823
        • Kaye D
        • Kelly R
        • Smith T
        Cytokines and cardiac hypertrophy: Roles of angiotensin II and basic fibroblast growth factor.
        Clin Exp Pharmacol Physiol. 1996; 3 (Suppl 3): S136-S141
        • Dzau V
        Implications of local angiotensin production in cardiovascular physiology and pharmacology.
        Am J Cardiol. 1987; 59 (Suppl): 59A-65A
        • Linz W
        • Schölkens B
        • Han Y-F
        Beneficial effects of the converting enzyme inhibitor, ramipril, in ischemic rat hearts.
        J Cardiovasc Pharmacol. 1986; 8 (Suppl 10): S91-S99
        • Abraham W
        New neurohormonal antagonists and atrial natriuretic peptide in the treatment of congestive heart failure.
        Coron Artery Dis. 1994; 5: 127-136
        • Sato F
        • Kamoi K
        • Wakiya Y
        • et al.
        Relationship between plasma atrial natriuretic peptide levels and atrial pressure in man.
        J Clin Endocrinol Metab. 1986; 63: 823-827
        • Raine A
        • Erne P
        • Bürgisser E
        • et al.
        Atrial natriuretic peptide and atrial pressure in patients with congestive heart failure.
        NEJM. 1986; 315: 533-537
        • Nakaoka H
        • Imataka K
        • Amano M
        • et al.
        Plasma levels of atrial natriuretic factor in patients with congestive heart failure.
        NEJM. 1985; 313: 892-893
        • Lee M
        • Miller W
        • Edwards B
        • Burnett Jr, J
        Role of endogenous atrial natriuretic factor in acute congestive heart failure.
        J Clin Invest. 1989; 84: 1962-1966
        • Brenner B
        • Ballerman B
        • Gunning M
        • Zeidel M
        Diverse biologic actions of atrial natriuretic peptide.
        Physiol Rev. 1990; 70: 665-699
        • McMurray J
        • Ray S
        • Abdullah I
        • et al.
        Plasma endothelin in chronic heart failure.
        Circulation. 1992; 85: 1374-1379
        • Masaki T
        • Kimura S
        • Yanagisawa M
        • Goto K
        Molecular and cellular mechanisms of endothelin regulation: Implications for vascular function.
        Circulation. 1991; 84: 1457-1468
        • Cavero P
        • Miller W
        • Heublein D
        • et al.
        Endothelin in experimental congestive heart failure in the anesthetized dog.
        Am J Physiol. 1990; 259: F312-F317
        • Stewart D
        • Cernacek P
        • Costello K
        • Rouleau J
        Elevated endothelin-1 in heart failure and loss of normal response to postural change.
        Circulation. 1992; 85: 510-517
        • Remme W
        Pathophysiology and therapy of heart failure, new insights and developments, part II: Cardiac and peripheral alterations during progressive heart failure.
        Neth J Med. 1993; 43: 125-146
        • Svanegaard J
        • Johansen J
        • Thayssen P
        • Haghfelt T
        Neurohormonal systems during progression of heart failure: A review.
        Cardiology. 1993; 83: 21-29
        • Benedict C
        • Weiner D
        • Johnstone D
        • et al.
        Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: Results of the Studies of Left Ventricular Dysfunction (SOLVD) registry.
        J Am Coll Cardiol. 1993; 22 (Suppl A): 146A-153A
        • Pfeffer M
        • Braunwald E
        • Moyé L
        • et al.
        Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction—results of the Survival and Ventricular Enlargement trial.
        NEJM. 1992; 327: 669-677
        • Cohn J
        Is neurohormonal activation deleterious to the long-term outcome of patients with congestive heart failure? III. Antagonist's viewpoint.
        J Am Coll Cardiol. 1988; 12: 554-558
        • Packer M
        • Carver J
        • Rodeheffer R
        • et al.
        Effect of oral milrinone on mortality in severe chronic heart failure.
        NEJM. 1991; 325: 1468-1475
        • Yusuf S
        • Teo K
        Inotropic agents increase mortality in patients with congestive heart failure.
        Circulation. 1990; 82 (Abstract): 673
        • Cohn J
        • Archibald D
        • Ziesche S
        Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative study.
        NEJM. 1986; 314: 1547-1552
        • The CONSENSUS Trial Study Group
        Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study.
        NEJM. 1987; 316: 1429-1435
        • The SOLVD Investigators
        Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
        NEJM. 1991; 325: 293-302
        • Cohn J
        • Johnson G
        • Ziesche S
        A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure: V-HeFT II.
        NEJM. 1991; 325: 303-310
        • Swedberg K
        • Held P
        • Kjekshus J
        • et al.
        Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction—results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II).
        NEJM. 1992; 327: 678-684
        • The Multicenter Diltiazem Postinfarction Trial Research Group
        The effect of diltiazem on mortality and reinfarction after myocardial infarction.
        NEJM. 1988; 319: 385-392
        • Goldstein R
        • Boccuzzi S
        • Cruess D
        • Nattel S
        Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction.
        Circulation. 1991; 83: 52-60
        • Elkayam U
        • Amin J
        • Mehra A
        • et al.
        A prospective, randomized, double-blind, crossover study to compare the efficacy of and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure.
        Circulation. 1990; 82: 1954-1961
        • The SOLVD Investigators
        Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.
        NEJM. 1992; 327: 685-691
        • van Veldhuisen D
        • Man in't Veld A
        • Dunselman P
        • et al.
        Double-blind placebo-controlled study of ibopamine and digoxin in patients with mild to moderate heart failure: Results of the Dutch Ibopamine Multicenter Trial (DIMT).
        J Am Coll Cardiol. 1993; 22: 1564-1573
        • Engelmeier R
        • O'Connell J
        • Walsh R
        • et al.
        Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: A double-blind, randomized, placebo-controlled trial.
        Circulation. 1985; 72: 536-546
        • Gilbert E
        • Anderson J
        • Deitchman D
        • et al.
        Long-term β-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: A double-blind, randomized study of bucindolol versus placebo.
        Am J Med. 1990; 88: 223-229
        • Wisenbaugh T
        • Katz I
        • Davis J
        • et al.
        Long-term (3-month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy.
        J Am Coll Cardiol. 1993; 21: 1094-1100
        • Bristow M
        • O'Connell J
        • Gilbert E
        • et al.
        Dose-response of chronic β-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy.
        Circulation. 1994; 89: 1632-1642
        • Metra M
        • Nardi M
        • Giubbini R
        • Dei Cas L
        Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy.
        J Am Coll Cardiol. 1994; 24: 1678-1687
        • Waagstein F
        • Bristow M
        • Swedberg K
        • et al.
        Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy.
        Lancet. 1993; 342: 1441-1446
        • CIBIS Investigators and Committees
        A randomized trial of β-blockade in heart failure: The Cardiac Insufficiency Bisoprolol Study (CIBIS).
        Circulation. 1994; 90: 1765-1773
        • Packer M
        • Bristow M
        • Cohn J
        • et al.
        • US Carvedilol Heart Failure Study Group
        The effect of carvedilol on morbidity and mortality in patients with chronic heart failure..
        NEJM. 1996; 334: 1349-1355
        • Young J
        • Weiner D
        • Yusuf S
        • et al.
        Patterns of medication use in patients with heart failure: A report from the Registry of Studies of Left Ventricular Dysfunction (SOLVD).
        South Med J. 1995; 88: 514-523
        • Paolisso G
        • Gambardella A
        • Marrazzo G
        Metabolic and cardiovascular benefits deriving from beta-adrenergic blockade in chronic congestive heart failure.
        Am Heart J. 1992; 123: 103-110
        • DiBianco R
        ACE inhibitors in the treatment of heart failure.
        Clin Cardiol. 1990; 13 (Suppl VII): 32-38
        • Sigurdsson A
        • Swedberg K
        Neurohormonal activation and congestive heart failure: Today's experience with ACE inhibitors and rationale for their use.
        Eur Heart J. 1995; 16 (Suppl N): 65-72
        • Swedberg K
        Is neurohormonal activation deleterious to the long-term outcome of patients with congestive heart failure? II. Protagonist's viewpoint.
        J Am Coll Cardiol. 1988; 12: 550-554
        • van Veldhuisen D
        • Brouwer J
        • Man in't Veld A
        • et al.
        Progression of mild untreated heart failure during six months follow-up and clinical and neurohumoral effects of ibopamine and digoxin as monotherapy.
        Am J Cardiol. 1995; 75: 796-800
        • Hampton J
        • van Veldhuisen D
        • Kleber F
        • et al.
        Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure.
        Lancet. 1997; 349: 971-977
        • Garg R
        • Gorlin R
        • Smith T
        • Yusuf S
        • Digitalis Investigation Group
        The effect of digoxin on mortality and morbidity in patients with heart failure.
        NEJM. 1997; 336: 525-533
        • Fitzpatrick M
        • Rademaker M
        • Charles C
        • et al.
        Angiotensin II receptor antagonism in ovine heart failure: Acute hemodynamic, hormonal, and renal effects.
        Am J Physiol. 1992; 263: H250-H256
        • Qing G
        • Garcia R
        Chronic captopril and losartan (DuP 753) administration in rats with high-output heart failure.
        Am J Physiol. 1992; 263: H833-H840
        • Crozier I
        • Ikram H
        • Awan N
        • et al.
        Losartan in heart failure. Hemodynamic effects and tolerability.
        Circulation. 1995; 91: 691-697
        • Pitt B
        • Segal R
        • Martinez F
        • et al.
        Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE).
        Lancet. 1997; 349: 747-752
        • Nicod P
        • Waeber B
        • Bussien J-P
        • et al.
        Acute hemodynamic effect of a vascular antagonist of vasopressin in patients with congestive heart failure.
        Am J Cardiol. 1985; 55: 1043-1047
        • Creager M
        • Faxon D
        • Cutler S
        • et al.
        Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: Comparison with the renin-angiotensin system and the sympathetic nervous system.
        J Am Coll Cardiol. 1986; 7: 758-765
        • Elsner D
        • Müntze A
        • Kromer E
        • Riegger G
        Effectiveness of endopeptidase inhibition (candoxatril) in congestive heart failure.
        Am J Cardiol. 1992; 70: 494-498
        • Katz A
        Calcium channel diversity in the cardiovascular system.
        J Am Coll Cardiol. 1996; 28: 522-529
        • Mehrke G
        • Zong X
        • Flockerzi V
        • Hofmann F
        The Ca++-channel blocker Ro 40-5967 blocks differently T-type and L-type Ca++ channels.
        J Pharmacol Exp Ther. 1994; 271: 1483-1488
        • Mishra S
        • Hermsmeyer K
        Selective inhibition of T-type Ca2+ channels by Ro 40-5967.
        Circ Res. 1994; 75: 144-148
        • Elkayam U
        • Shotan A
        • Mehra A
        • Ostrzega E
        Calcium channel blockers in heart failure.
        J Am Coll Cardiol. 1993; 22 (Suppl): 139A-144A
        • The Danish Study Group on Verapamil in Myocardial Infarction
        Secondary prevention with verapamil after myocardial infarction.
        Am J Cardiol. 1990; 66 (Suppl): 33I-40I
        • Packer M
        • O'Connor C
        • Ghali J
        • et al.
        Effect of amlodipine on morbidity and mortality in severe chronic heart failure.
        NEJM. 1996; 335: 1107-1114
        • Ryman K
        • Kubo S
        • Lystash J
        • et al.
        Effect of nicardipine on rest and exercise hemodynamics in chronic congestive heart failure.
        Am J Cardiol. 1986; 58: 583-588
        • Olivari M
        • Levine T
        • Cohn J
        Acute hemodynamic effects of nitrendipine in congestive heart failure.
        J Cardiovasc Pharmacol. 1984; 6 (Suppl): S1002-S1004
        • Lewis B
        • Shefer A
        • Merdler A
        • et al.
        Effect of the second-generation calcium channel blocker nisoldipine on left ventricular contractility in cardiac failure.
        Am Heart J. 1988; 115: 1238-1244
        • Timmis A
        • Campbell S
        • Monaghan M
        • et al.
        Acute haemodynamic and metabolic effects of felodipine in congestive heart failure.
        Br Heart J. 1984; 51: 445-451
        • Greenberg B
        • Siemienczuk D
        • Broudy D
        Hemodynamic effects of PN 200-110 (isradipine) in congestive heart failure.
        Am J Cardiol. 1987; 59 (Suppl): 70B-74B
        • Barjon J
        • Rouleau J-L
        • Bichet D
        • et al.
        Chronic renal and neurohormonal effects of the calcium entry blocker nisoldipine in patients with severe left ventricular dysfunction.
        J Am Coll Cardiol. 1987; 9: 622-630
        • Aroney C
        • Semigran M
        • Dec G
        • et al.
        Inotropic effect of nicardipine in patients with heart failure: Assessment by left ventricular end-systolic pressure-volume analysis.
        J Am Coll Cardiol. 1989; 14: 1331-1338
        • Tan L
        • Murray R
        • Littler W
        Felodipine in patients with chronic heart failure: Discrepant haemodynamic and clinical effects.
        Br Heart J. 1987; 58: 122-128
        • Ikram H
        • Chan W
        • Bennett S
        • Bones P
        Hemodynamic effects of acute beta-adrenergic receptor blockade in congestive cardiomyopathy.
        Br Heart J. 1979; 42: 311-315
        • Foult J-M
        • Tavolaro O
        • Anthony I
        • Nitenberg A
        Direct myocardial and coronary effects of enalaprilat in patients with dilated cardiomyopathy: Assessment by a bilateral intracoronary infusion technique.
        Circulation. 1988; 77: 337-344
        • Packer M
        • Lee W
        • Kessler P
        • et al.
        Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure.
        Circulation. 1987; 75 (Suppl IV): 80-92
        • Naftilan A
        • Oparil S
        The role of calcium in the control of renin release.
        Hypertension. 1982; 4: 670-675
        • Reicher-Reiss H
        • Barasch E
        Calcium antagonists in patients with heart failure: A review.
        Drugs. 1991; 42: 343-364
        • de Vries R
        • Queré M
        • Lok D
        • et al.
        Comparison of effects on peak oxygen consumption, quality of life, and neurohormones of felodipine and enalapril in patients with congestive heart failure.
        Am J Cardiol. 1995; 76: 1253-1258
        • Furberg C
        • Psaty B
        • Meyer J
        Nifedipine: Dose-related increase in mortality in patients with coronary heart disease.
        Circulation. 1995; 92: 1326-1331
        • Packer M
        Pathophysiological mechanisms underlying the adverse effects of calcium channel-blocking drugs in patients with chronic heart failure.
        Circulation. 1989; 80 (Suppl IV): 59-67
        • Bernink P
        • Prager G
        • Schelling A
        • Kobrin I
        Antihypertensive properties of the novel calcium antagonist mibefradil (Ro 40-5967): A new generation of calcium antagonists?.
        Hypertension. 1996; 27: 426-432
        • Braun S
        • van der Wall E
        • Emanuelsson H
        • Kobrin I
        Effects of a new calcium antagonist, mibefradil (Ro 40-5967), on silent ischemia in patients with stable chronic angina pectoris: A multicenter placebo-controlled study.
        J Am Coll Cardiol. 1996; 27: 317-322
        • Bakx A
        • van der Wall E
        • Braun S
        • et al.
        Effects of the new calcium antagonist mibefradil (Ro 40-5967) on exercise duration in patients with chronic stable angina pectoris: A multicenter, placebo-controlled study.
        Am Heart J. 1995; 130: 748-757
        • Orito K
        • Satoh K
        • Taira N
        Cardiovascular profile of Ro 40-5967, a new nondihydropyridine calcium antagonist, delineated in isolated, blood-perfused dog hearts.
        J Cardiovasc Pharmacol. 1993; 22: 293-299
        • Clozel J-P
        • Véniant M
        • Osterrieder W
        The structurally novel Ca2+ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts.
        Cardiovasc Drugs Ther. 1990; 4: 731-736
        • Véniant M
        • Clozel J-P
        • Hess P
        • Wolfgang R
        Hemodynamic profile of Ro 40-5967 in conscious rats: Comparison with diltiazem, verapamil, and amlodipine.
        J Cardiovasc Pharmacol. 1991; 18 (Suppl 10): S55-S58
        • Clozel J-P
        • Banken L
        • Osterrieder W
        Effects of Ro 40-5967, a novel calcium antagonist, on myocardial function during ischemia induced by lowering coronary perfusion pressure in dogs: Comparison with verapamil.
        J Cardiovasc Pharmacol. 1989; 14: 713-721
        • Véniant M
        • Clozel J-P
        • Hess P
        • Wolfgang R
        Ro 40-5967, in contrast to diltiazem, does not reduce left ventricular contractility in rats with chronic myocardial infarction.
        J Cardiovasc Pharmacol. 1991; 17: 277-284
        • Boulanger C
        • Nakashima M
        • Olmos L
        • et al.
        Effects of the Ca2+ antagonist Ro 40-5967 on endothelium-dependent responses of isolated arteries.
        J Cardiovasc Pharmacol. 1994; 23: 869-876
        • Schmitt R
        • Kleinbloesem C
        • Belz G
        • et al.
        Hemodynamic and humoral effects of the novel calcium antagonist Ro 40-5967 in patients with hypertension.
        Clin Pharmacol Ther. 1992; 52: 314-323
        • Levine TB
        The design of the Mortality Assessment in Congestive Heart Failure Trial (MACH-1, mibefradil).
        Clin Cardiol. 1997; 20: 320-326

      Article info

      Identification

      DOI: https://doi.org/10.1016/S0149-2918(97)80037-9

      Copyright

      © 1997 Published by Elsevier Inc.

      ScienceDirect

      Access this article on ScienceDirect

      The content on this site is intended for healthcare professionals.


      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie Preference Center for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties.


      RELX