Endothelin isoforms and the response to myocardial stretch

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Cell Signaling

Background:

• Myocardial stretch induces a biphasic force response, including a slow force response (SFR).
• The SFR is attributed to increased intracellular calcium transients, but its underlying signaling pathway remains unclear.
• Endothelin (ET) isoforms and the Na+/H+ exchanger (NHE-1) are implicated in cardiac contractility.

Purpose of the Study:

• To elucidate the signaling pathway responsible for the slow force response (SFR) to myocardial stretch.
• To investigate the roles of endothelin isoforms and the Na+/H+ exchanger (NHE-1) in mediating the SFR.
• To determine the involvement of AT1 receptors in stretch-induced signaling.

Main Methods:

• Experiments were conducted on cat papillary muscles subjected to mechanical stretch.
• Pharmacological agents including BQ-123 (ET receptor antagonist), HOE-642 (NHE-1 inhibitor), and losartan (AT1 receptor antagonist) were used.
• Real-time RT-PCR was employed to measure mRNA expression of ET isoforms.

Main Results:

• BQ-123 selectively inhibited the contractile effects of ET-2 and ET-3, but not ET-1, suggesting ET-2/ET-3 involvement in SFR.
• All ET isoforms activated NHE-1, increasing intracellular sodium concentration, an effect blocked by HOE-642.
• Stretch induced a significant upregulation of ET-3 mRNA, which was suppressed by losartan, indicating AT1 receptor mediation.

Conclusions:

• The slow force response (SFR) to myocardial stretch involves endothelin-3 (ET-3) signaling.
• AT1 receptor-mediated release of ET-3 contributes to the early activation of the Na+/H+ exchanger (NHE-1) following myocardial stretch.
• This pathway plays a role in modulating cardiac contractility in response to mechanical stress.