Cross-bridge-dependent change in Ca2+ sensitivity is involved in the negative inotropic effect of nifedipine in aequorin-injected ferret ventricular muscles.
BACKGROUND
We hypothesized that the negative inotropic effect of nifedipine (Nif) on cardiac ventricular muscle is partly due to the cross-bridge-dependent decrease of Ca2+ sensitivity of the myofilaments as well as the decrease in Ca2+ influx.


RESULTS
We used aequorin-injected ferret papillary muscles and measured the slope of the extra-Ca(2+)-tension relation which expresses the change in the Ca2+ sensitivity through the feedback from the cross-bridges. Twitch tension was decreased significantly by 0.5 micromol/L Nif accompanying a significant reduction of the Ca2+ transient peak. When Nif (0.2-0.5 micromol/L) was added to the solution with 8 mmol/L Ca2+, the slope of the extra-Ca2+-tension relation became steeper in a concentration-dependent manner, which was similar to the change in the slope when the concentration of Ca2+ was decreased from 8 to 1 mmol/L in the absence of Nif. BAY-K 8644 (0.3 micromol/L), a dihydropyridine receptor agonist, showed the opposite effect on the slope of the extra-Ca2+-tension relation to that observed in Nif. However, 2,3-butanedione monoxime (3 mmol/L), an inhibitor of the active cross-bridges, antagonized the effect of BAY-K 8644.


CONCLUSIONS
Nif exerts its negative inotropic effect on cardiac muscle by suppressing Ca2+ binding to troponin C via the inhibition of the L-type Ca2+ channel, and by the cross-bridge-dependent decrease in the Ca2+ sensitivity, as in low extracellular Ca2+ concentration.
Ishikawa
Tetsuya
T
Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan. ishikawa@jikei.ac.jp
Mochizuki
Seibu
S
Kurihara
Satoshi
S
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000331:Aequorin / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003864:Depression, Chemical; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological; D005289:Ferrets; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D049408:Luminescent Agents / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology*; D011485:Protein Binding; D019209:Troponin C / Q000378:metabolism
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D049408:Luminescent Agents; D019209:Troponin C; C004717:diacetylmonoxime; D000331:Aequorin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D003931:Diacetyl; D002118:Calcium