A new type of Ca-channel modulation by a novel class of 1,4-dihydropyridines

  • Life Sci. 1997;60(2):107-18. doi: 10.1016/s0024-3205(96)00600-5.
M Bechem  1 ,  S Goldmann ,  R Gross ,  S Hallermann ,  S Hebisch ,  J Hütter ,  H P Rounding ,  M Schramm ,  J Stoltefuss ,  A Straub
Affiliations
  • 1. Institute of Cardiovascular Research, and Chemistry Research Laboratories, Bayer AG, Wuppertal, Germany.
PMID: 9000116 DOI: 10.1016/s0024-3205(96)00600-5
Abstract

Both Ca-antagonistic as well as Ca-agonistic 1,4-dihydropyridines (DHPs) have become extremely important tools to investigate the role of Ca-channels under various physiological and pathophysiological conditions. While Ca-antagonists stabilize the inactivated state of the Ca-channel without influencing the voltage dependent open and closed times, Ca-agonists prolong the mean open time of the channel. We here report for the first time the effects of a novel DHP, BAY Y 5959, which modulates Ca-channel gating in a unique manner: It increases both the mean open time and the mean closed time of the Ca-channel by binding to the DHP receptor. This results in a reduced rate of Ca-current activation, an increased peak current, and a strongly prolonged tail current decay. All these effects are strongly voltage dependent. Therefore it depends on resting membrane potential and shape of the action potential whether and how the Ca-influx into the cell is influenced. This novel mode of action of BAY Y 5959 results in an interesting pharmacological profile: It has a strong positive inotropic effect in the heart without influencing vessel tone. Therefore the term Ca-promoter is suggested; it could become a new approach for the drug treatment of congestive heart failure.

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