Stretch-induced increase in cardiac contractility is independent of myocyte Ca2+ while block of stretch channels by streptomycin improves contractility after ischemic stunning.

Samhita S Rhodes,Mohammed Aldakkak,James S Heisner,David F Stowe,Amadou K S Camara

doi:10.14814/phy2.12486

Samhita S Rhodes, Mohammed Aldakkak + Show 3 more

Open Access

https://doi.org/10.14814/phy2.12486

Copy DOI

Abstract

Stretching the cardiac left ventricle (LV) enhances contractility but its effect on myoplasmic [Ca2+] is controversial. We measured LV pressure (LVP) and [Ca2+] as a function of intra-LV stretch in guinea pig intact hearts before and after 15 min global stunning ± perfusion with streptomycin (STM), a stretch-activated channel blocker. LV wall [Ca2+] was measured by indo-1 fluorescence and LVP by a saline-filled latex balloon inflated in 50 μL steps to stretch the LV. We implemented a mathematical model to interpret cross-bridge dynamics and myofilament Ca2+ responsiveness from the instantaneous relationship between [Ca2+] and LVP ± stretching. We found that: (1) stretch enhanced LVP but not [Ca2+] before and after stunning in either control (CON) and STM groups, (2) after stunning [Ca2+] increased in both groups although higher in STM versus CON (56% vs. 39%), (3) STM-enhanced LVP after stunning compared to CON (98% vs. 76% of prestunning values), and (4) stretch-induced effects on LVP were independent of [Ca2+] before or after stunning in both groups. Mathematical modeling suggested: (1) cooperativity in cross-bridge kinetics and myofilament Ca2+ handling is reduced after stunning in the unstretched heart, (2) stunning results in depressed myofilament Ca2+ sensitivity in the presence of attached cross-bridges regardless of stretch, and (3) the initial mechanism responsible for increased contractility during stretch may be enhanced formation of cross-bridges. Thus stretch-induced enhancement of contractility is not due to increased [Ca2+], whereas enhanced contractility after stunning in STM versus CON hearts results from improved Ca2+ handling and/or enhanced actinomyosin cross-bridge cycling.

Highlights

Myoplasmic calcium ([Ca2+]) is the preeminent regulator of myocardial contractility via three major mechanisms. These are (1) the upstream mechanism that is related to the gross concentration of [Ca2+], (2) the central mechanism that is related to the sensitivity of the regulatory protein troponin C (TnC) to the available [Ca2+], and lastly, (3) the downstream mechanism that is related to the interaction between contractile proteins actin and myosin, and actinomyosin cross-bridge cycling
Representative tracings of simultaneously obtained LV pressure (LVP) and [Ca2+] from hearts in the CON and STM groups before and after stunning (Fig. 2) showed that stretching the heart before or after stunning by increasing the volume of the balloon caused diastolic LVP to increase in steps
Systematic stretch caused an increase in phasic LVP in CON and STM hearts both before and after stunning

Summary

Introduction

Myoplasmic calcium ([Ca2+]) is the preeminent regulator of myocardial contractility via three major mechanisms. We hypothesized that myocardial stretch would result in an acute increase in [Ca2+] via stretch-activated cation channels to improve contractility via the upstream mechanism. To do so we examined several interrelationships of beat-to-beat phasic LVP and [Ca2+] in the absence and presence of streptomycin (STM), a known blocker of sarcolemmal stretch-activated cation channels (Yeung et al 2005). We examined these interrelationships after a brief period of ischemia (stunning) to assess if stunning might be mediated in part by stretch activated-cation channels as assessed by blocking stretch channels with STM before stunning

Objectives

Methods

Results

Conclusion