A new type of Ca-channel modulation by a novel class of 1,4-dihydropyridines.
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.
Bechem
M
M
Institute of Cardiovascular Research, and Chemistry Research Laboratories, Bayer AG, Wuppertal, Germany.
Goldmann
S
S
Gross
R
R
Hallermann
S
S
Hebisch
S
S
Hütter
J
J
Rounding
H P
HP
Schramm
M
M
Stoltefuss
J
J
Straub
A
A
D000200:Action Potentials; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002120:Calcium Channel Agonists / Q000737:chemistry / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C038806:1,4-dihydropyridine