Modulation of cardiac contractility through endothelin-1 release and myocardial mast cell degranulation

Area of Science:

• Cardiovascular Physiology
• Pharmacology

Background:

• Hypertonic saline-dextran-40 (HSD) infusion can induce peripheral flow changes affecting ventricular function.
• Endothelin-1 (ET-1) and nitric oxide (NO) are implicated in cardiovascular regulation.
• Cardiac mast cells (MC) may influence myocardial responses.

Purpose of the Study:

• To investigate the impact of HSD-induced peripheral flow stimulus on ventricular function in dogs.
• To determine the roles of ET-1, NO, and MC degranulation in HSD-mediated cardiac responses.
• To evaluate the effects of MC stabilization and endothelin receptor antagonism on these responses.

Main Methods:

• Utilized a closed-chest, pentobarbital-anesthetized dog model.
• Administered HSD infusion and measured hemodynamic parameters (cardiac index, peripheral resistance).
• Assessed plasma and myocardial levels of ET-1 and NO, NO synthase activity, and MC degranulation. Evaluated effects of disodium cromoglycate and ETR-p1/fl peptide.

Main Results:

• HSD infusion increased cardiac index and myocardial contractility, decreasing peripheral resistance.
• Elevated plasma NO and ET-1, decreased myocardial ET-1 content, reduced NO synthase activity, and enhanced MC degranulation were observed post-infusion.
• Disodium cromoglycate and ETR-p1/fl peptide treatments attenuated these changes, normalizing myocardial ET-1 and NO synthesis.

Conclusions:

• Peripheral NO and ET-1 release modulate cardiac contractility following HSD infusion.
• Myocardial ET-A receptor activation and cardiac MC degranulation are critical pathways involved.
• HSD influences ventricular function through complex interactions between vasoactive mediators and cardiac mast cells.