Carvedilol analog modulates both basal and stimulated sinoatrial node automaticity

Area of Science:

• Cardiovascular Physiology
• Cardiac Electrophysiology
• Pharmacology

Background:

• Sinoatrial node (SAN) automaticity is regulated by both membrane voltage and calcium (Ca2+) clocks.
• VK-II-36, a carvedilol analog, inhibits sarcoplasmic reticulum (SR) Ca2+ release but lacks beta-receptor blocking activity.
• The impact of VK-II-36 on SAN function and its potential to modulate the Ca2+ clock are not well understood.

Purpose of the Study:

• To investigate whether VK-II-36 influences SAN automaticity by inhibiting the Ca2+ clock.
• To evaluate the effects of VK-II-36 on intracellular Ca2+ dynamics and membrane potential in the SAN.

Main Methods:

• Simultaneous mapping of intracellular Ca2+ and membrane potential in isolated canine right atria.
• Detection of the Ca2+ clock using late diastolic intracellular Ca elevation (LDCAE) timing relative to action potential upstroke.
• Pharmacological interventions using isoproterenol (ISO), ryanodine, caffeine, and VK-II-36.

Main Results:

• VK-II-36 reduced sinus rate and LDCAE under basal conditions (P < 0.01).
• Isoproterenol (ISO) increased sinus rate, shifted the pacemaking site, and augmented LDCAE.
• VK-II-36 (30 μmol/l) abolished ISO-induced effects on pacemaking site and LDCAE (P < 0.01), and suppressed ISO-induced heart rate increase (P = 0.02).

Conclusions:

• The Ca2+ clock, through SR Ca2+ release, plays a significant role in controlling sinus rate, particularly during beta-adrenergic stimulation.
• VK-II-36 effectively inhibits the Ca2+ clock, demonstrating its potential as a tool to study SAN automaticity.
• These findings highlight the importance of SR Ca2+ release in regulating cardiac rhythm and suggest a novel mechanism for controlling heart rate.