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.

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.

MeSH terms

  • Action Potentials
  • Animals
  • Aorta / drug effects
  • Aorta / physiology
  • Calcium Channel Agonists / chemistry
  • Calcium Channel Agonists / pharmacology*
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / pharmacology*
  • Dihydropyridines / chemistry
  • Dihydropyridines / pharmacology*
  • Guinea Pigs
  • Heart / drug effects
  • Heart / physiology
  • In Vitro Techniques
  • Muscle Contraction / drug effects
  • Rabbits

Substances

  • Calcium Channel Agonists
  • Calcium Channel Blockers
  • Dihydropyridines
  • 1,4-dihydropyridine