L-type Ca2+ channel blockers inhibit the window contraction of mouse aorta segments with high affinity

Area of Science:

• Pharmacology
• Cardiovascular Physiology
• Molecular Biology

Background:

• L-type calcium channel blockers (LCCBs) are more effective in hypertensive individuals and vascular smooth muscle (VSM) than normotensive subjects or cardiac muscle.
• This differential efficacy is attributed to the depolarized resting potential in VSM and hypertension, favoring the high-affinity inactivated state of L-type calcium channels (LCCs).
• However, depolarized potentials also increase Ca(2+) influx through window, non-inactivating LCCs.

Purpose of the Study:

• To investigate the efficacy of nifedipine, verapamil, and diltiazem in blocking window, non-inactivating LCCs.
• To elucidate the role of these channels in VSM contractions and their sensitivity to LCCBs.

Main Methods:

• C57Bl6 mouse aortic segments were depolarized using 50mM K(+) to induce inactivation.
• Biphasic contractions were analyzed, and the sensitivity of fast and slow force components to LCCBs was assessed.
• The effects of removing the fast force component and stimulating Ca(2+) influx with BAY K8644 on LCCB efficacy were examined.

Main Results:

• Depolarization evoked biphasic contractions, with the slow force component showing higher sensitivity to LCCBs.
• Removal of the fast force component enhanced LCCB efficacy, while BAY K8644 decreased it.
• LCCBs induced concentration-dependent relaxation, independent of the fast force component, but with reduced sensitivity when BAY K8644 was present.

Conclusions:

• Steady-state contractions induced by 50mM K(+) depolarization are primarily mediated by window Ca(2+) influx, which is effectively inhibited by LCCBs.
• Interactions between LCCB receptors, Ca(2+) ions, and BAY K8644 influence LCCB efficacy.
• The high affinity of LCCBs for open, non-inactivating LCCs likely plays a significant role in their anti-hypertensive actions.