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Reduced contraction strength with increased intracellular [Ca2+] in left ventricular trabeculae from failing rat
Marie-Louise Ward1, Adèle J Pope, Denis S Loiselle
1Department of Physiology, Faculty of Medicine and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. m.ward@auckland.ac.nz
Insights
Reduced contractile function in failing hypertensive rat hearts is linked to increased collagen, not altered intracellular calcium levels. This study investigates the mechanisms behind heart failure in spontaneously hypertensive rats (SHR).
Area of Science:
- Cardiology
- Physiology
- Biochemistry
Background:
- Spontaneously hypertensive rats (SHR) exhibit heart failure with reduced contractile function.
- Altered intracellular calcium handling is a common hypothesis for contractile dysfunction in heart failure.
Purpose of the Study:
- To investigate the role of intracellular calcium ([Ca2+](i)) and collagen content in the reduced cardiac contractility of SHR with failing hearts compared to normotensive Wistar-Kyoto (WKY) controls.
Main Methods:
- Isometric force and intracellular calcium transients were measured in isolated left ventricular (LV) trabeculae from SHR and WKY rats.
- Fura-2 was used to quantify intracellular calcium concentrations.
- Histological examination assessed perimysial collagen content.
Main Results:
- SHR trabeculae exhibited significantly reduced peak stress compared to WKY controls.
- Intracellular calcium transients in SHR showed increased peak and resting levels, with prolonged decay, but these did not correlate with reduced contractility.
- Increased perimysial collagen content was observed in SHR compared to WKY rats.
Conclusions:
- Altered intracellular calcium dynamics do not fully explain the reduced contractile performance in this model of heart failure.
- Increased collagen content and its organization likely compromise contractile function in SHR failing hearts.
Abstract:
Intracellular calcium ([Ca2+](i)) and isometric force were measured in left ventricular (LV) trabeculae from spontaneously hypertensive rats (SHR) with failing hearts and normotensive Wistar-Kyoto (WKY) controls. At a physiological stimulation frequency (5 Hz), and at 37 degrees C, the peak stress of SHR trabeculae was significantly (P < or = 0.05) reduced compared to WKY (8 +/- 1 mN mm(-2) (n = 8) vs. 21 +/- 5 mN mm(-2) (n = 8), respectively). No differences between strains in either the time-to-peak stress, or the time from peak to 50 % relaxation were detected. Measurements using fura-2 showed that in the SHR both the peak of the Ca2+ transient and the resting [Ca2+](i) were increased compared to WKY (peak: 0.69 +/- 0.08 vs. 0.51 +/- 0.08 microM(P < or = 0.1) and resting: 0.19 +/- 0.02 vs. 0.09 +/- 0.02 microM(P < or = 0.05), SHR vs. WKY, respectively). The decay of the Ca2+ transient was prolonged in SHR, with time constants of: 0.063 +/- 0.002 vs. 0.052 +/- 0.003 s (SHR vs. WKY, respectively). Similar results were obtained at 1 Hz stimulation, and for [Ca2+ ](o) between 0.5 and 5 mM. The decay of the caffeine-evoked Ca2+ transient was slower in SHR (9.8 +/- 0.7 s (n = 8) vs. 7.7 +/- 0.2 s (n = 8) in WKY), but this difference was removed by use of the SL Ca2+ -ATPase inhibitor carboxyeosin. Histological examination of transverse sections showed that the fractional content of perimysial collagen was increased in SHR compared to WKY (18.0 +/- 4.6 % (n = 10) vs. 2.9 +/- 0.9 % (n = 11) SHR vs. WKY, respectively). Our results show that differences in the amplitude and the time course of the Ca2+ transient between SHR and WKY do not explain the reduced contractile performance of SHR myocardium per se. Rather, we suggest that, in this animal model of heart failure, contractile function is compromised by increased collagen, and its three-dimensional organisation, and not by reduced availability of intracellular Ca2+.