Testosterone-augmented contractile responses to alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart

Am J Physiol Cell Physiol. 2009 Apr;296(4):C766-82. doi: 10.1152/ajpcell.00193.2008.


We hypothesized that testosterone at physiological levels enhances cardiac contractile responses to stimulation of both alpha(1)- and beta(1)-adrenoceptors by increasing Ca(2+) release from the sarcoplasmic reticulum (SR) and speedier removal of Ca(2+) from cytosol via Ca(2+)-regulatory proteins. We first determined the left ventricular developed pressure, velocity of contraction and relaxation, and heart rate in perfused hearts isolated from control rats, orchiectomized rats, and orchiectomized rats without and with testosterone replacement (200 microg/100 g body wt) in the presence of norepinephrine (10(-7) M), the alpha(1)-adrenoceptor agonist phenylephrine (10(-6) M), or the nonselective beta-adrenoceptor agonist isoprenaline (10(-7) M) in the presence of 5 x 10(-7) M ICI-118,551, a beta(2)-adrenoceptor antagonist. Next, we determined the amplitudes of intracellular Ca(2+) concentration transients induced by electrical stimulation or caffeine, which represent, respectively, Ca(2+) release via the ryanodine receptor (RyR) or releasable Ca(2+) in the SR, in ventricular myocytes isolated from the three groups of rats. We also measured (45)Ca(2+) release via the RyR. We then determined the time to 50% decay of both transients, which represents, respectively, Ca(2+) reuptake by sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) and removal via the sarcolemmal Na(+)/Ca(2+) exchanger (NCX). We correlated Ca(2+) removal from the cytosol with activities of SERCA and its regulator phospholamban as well as NCX. The results showed that testosterone at physiological levels enhanced positive inotropic and lusitropic responses to stimulation of alpha(1)- and beta(1)-adrenoceptors via the androgen receptor. The increased contractility and speedier relaxation were associated with increased Ca(2+) release via the RyR and faster Ca(2+) removal out of the cytosol via SERCA and NCX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agonists / pharmacology*
  • Adrenergic alpha-1 Receptor Agonists*
  • Adrenergic beta-1 Receptor Agonists*
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Caffeine / pharmacology
  • Calcium Radioisotopes
  • Calcium Signaling / drug effects
  • Calcium-Binding Proteins / metabolism
  • Cells, Cultured
  • Electric Stimulation
  • Isoproterenol / pharmacology
  • Male
  • Myocardial Contraction / drug effects*
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Norepinephrine / pharmacology
  • Orchiectomy
  • Phenylephrine / pharmacology
  • Propanolamines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Adrenergic, beta-1 / metabolism
  • Receptors, Androgen / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Sodium-Calcium Exchanger / metabolism*
  • Testosterone / administration & dosage
  • Testosterone / metabolism*
  • Time Factors
  • Ventricular Function, Left / drug effects*
  • Ventricular Pressure / drug effects


  • Adrenergic Agonists
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic beta-1 Receptor Agonists
  • Adrenergic beta-Antagonists
  • Calcium Radioisotopes
  • Calcium-Binding Proteins
  • Propanolamines
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, beta-1
  • Receptors, Androgen
  • Ryanodine Receptor Calcium Release Channel
  • Sodium-Calcium Exchanger
  • phospholamban
  • Phenylephrine
  • Caffeine
  • Testosterone
  • ICI 118551
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Isoproterenol
  • Norepinephrine