Increase in force of contraction by activation of the Na+/Ca(2+)-exchanger in human myocardium

Br J Clin Pharmacol. 1997 Apr;43(4):399-405. doi: 10.1046/j.1365-2125.1997.00581.x.

Abstract

Aims: The aim of the present study was to investigate whether agents which enhance force of contraction via increasing intracellular Na+, i.e. cAMP-independently, remain effective in failing human myocardium.

Methods: Cumulative concentration-response curves with (+/-)BDF 9148 (0.01-10 mumol l-1), a Na(+)-channel activator, and ouabain (0.01-0.1 mumol l-1), a Na+/K(+)-ATPase inhibitor, were performed on electrically driven left ventricular human papillary muscle strips (1 Hz, 37 degrees C; dilative cardiomyopathy, NYHA IV, heart transplantation, n = 16; nonfailing, donor hearts, n = 5). The beta-adrenoceptor agonist isoprenaline (0.001-1 mumol l-1) and Ca2+ (1.8-15 mmol l-1) were studied for control. In addition, Ca2+ response curves were obtained on skinned fibre preparations from left ventricular myocardium (NYHA IV, n = 7) in the presence of BDF 9148 (1 mumol l-1) or a high Na+ concentration (50 mmol l-1) to investigate a possible direct or indirect interaction of (+/-)BDF 9148 with the myofilaments.

Results: While isoprenaline was significantly less effective in increasing force of contraction in failing human myocardium than in nonfailing myocardium (P < 0.01), in NYHA IV, (+/-)BDF 9148 and ouabain were as effective as in nonfailing human tissue. In failing and nonfailing myocardium, (+/-)BDF 9148 and ouabain exerted positive inotropic effects similar to those of Ca2+. However, the potency for (+/-)BDF 9148 to increase force of contraction was higher in NYHA IV than in nonfailing human myocardium (P < 0.05). Neither (+/-)BDF 9148 (1 mumol l-1) nor an increased concentration of Na+ (50 mmol l-1) altered the Ca2+ sensitivity or maximal developed tension of the contractile apparatus in experiments on chemically skinned left ventricular fibres.

Conclusions: The enhanced sensitivity of the failing human myocardium towards Na(+)-channel modulation is not due to a direct or indirect interaction of (+/-)BDF 9148 with cardiac myofilaments but may be due to an altered Na(+)-homeostasis in human heart failure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Antiporters / drug effects
  • Antiporters / metabolism*
  • Azetidines / pharmacology*
  • Calcium / metabolism
  • Calcium / pharmacology
  • Cardiotonic Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Enzyme Inhibitors / pharmacology*
  • Heart Failure / surgery
  • Heart Transplantation
  • Humans
  • Isoproterenol / pharmacology
  • Muscle Contraction / drug effects
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Smooth, Vascular / drug effects
  • Myocardial Contraction / drug effects*
  • Ouabain / pharmacology*
  • Papillary Muscles / drug effects
  • Sodium / metabolism
  • Sodium-Calcium Exchanger
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*

Substances

  • Adrenergic beta-Agonists
  • Antiporters
  • Azetidines
  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Sodium-Calcium Exchanger
  • BDF 9148
  • Ouabain
  • Sodium
  • Sodium-Potassium-Exchanging ATPase
  • Isoproterenol
  • Calcium