Néstor G. Pérez

Reverse Mode of the Na+-Ca2+ Exchange After Myocardial Stretch : Underlying Mechanism of the Slow Force Response

Abstract— This study was designed to gain additional insight into the mechanism of the slow force response (SFR) to stretch of cardiac muscle. SFR and changes in intracellular Na+ concentration ([Na+]i) were assessed in cat papillary muscles stretched from 92% to ≈98% of Lmax. The SFR was 120±0.6% (n=5) of the rapid initial phase and coincided with an increase in [Na+]i. The SFR was markedly depressed by Na+-H+ exchanger inhibition, AT1 receptor blockade, nonselective endothelin-receptor blockade and selective ETA-receptor blockade, extracellular Na+ removal, and inhibition of the reverse mode of the Na+-Ca2+ exchange by KB-R7943. KB-R7943 prevented the SFR but not the increase in [Na+]i. Inhibition of endothelin-converting enzyme activity by phosphoramidon suppressed both the SFR and the increase in [Na+]i. The SFR and the increase in [Na+]i after stretch were both present in muscles with their endothelium (vascular and endocardial) made functionally inactive by Triton X-100. In these muscles, phosphoramidon also suppressed the SFR and the increase in [Na+]i. The data provide evidence that the last step of the autocrine-paracrine mechanism leading to the SFR to stretch is Ca2+ entry through the reverse mode of Na+-Ca2+ exchange.

Altered cardiac excitation–contraction coupling in mutant mice with familial hypertrophic cardiomyopathy

Excitation-contraction coupling in cardiac muscle of familial hypertrophic cardiomyopathy (FHC) remains poorly understood, despite the fact that the genetic alterations are well defined. We characterized calcium cycling and contractile activation in trabeculae from a mutant mouse model of FHC (Arg403Gln knockin, alpha-myosin heavy chain). Wild-type mice of the same strain and age ( approximately 20 weeks old) served as controls. During twitch contractions, peak intracellular Ca2+ ([Ca2+]i) was higher in mutant muscles than in the wild-type (P < 0.05), but force development was equivalent in the two groups. Ca2+ transient amplitude increased dramatically in both groups as stimulation rate increased from 0.2 to 4 Hz. Nevertheless, developed force fell at the higher stimulation rates in the mutants but not in controls (P < 0.05). The steady-state force-[Ca2+]i relationship was less steep in mutants (Hill coefficient, 2.94 +/- 0.27 vs. 5.28 +/- 0.64; P > 0.003), with no changes in the [Ca2+]i required for 50% activation or maximal Ca2+-activated force. Thus, calcium cycling and myofilament properties are both altered in FHC mutant mice: more Ca2+ is mobilized to generate force, but this does not suffice to maintain contractility at high stimulation rates.

Lusitropic changes induced by acid base alterations in cat papillary muscles

The present work investigates the effects of acid-base alterations upon myocardial relaxation. Experiments were performed in cat papillary muscles contracting isometrically at constant frequency (0.2 Hz) and temperature (29 degrees C). To induce intracellular alkalosis at constant pH0, 20 mM NH4Cl were added to the perfusate. Alkalosis at variable pH0 was induced by switching from the control solution (5% CO2-95% O2, pH0 7.40) to a solution identical to the control one, equilibrated with 3% CO2-97% O2. Acidosis was induced by switching the control perfusate to a solution equilibrated with 12% CO2-88% O2 in which pH0 was either allowed to change or kept constant by manipulation of bicarbonate concentration. Alkalosis produced a negative lusitropic effect either when pH0 was kept constant or when it was allowed to increase. For an increase in myocardial contractility of 30%, half relaxation tme (T50) and time to peak tension (TTP) were prolonged 9.4 +/- 5% and 5.4 +/- 2% respectively at constant pH0 and 6.8 +/- 0.8 and 4.7 +/- 1% respectively at variable pHo. It is suggested that this negative lusitropic effect of alkalosis can be attributed to an increase in myofilament sensitivity to calcium. Either at constant or at variable pHo acidosis decreased myocardial contractility by approximately 50%. This decrease in contractility was accompanied by a positive lusitropic action only when pHo was allowed to decrease, or when acidosis at constant pHo was evoked in the presence of EIPA, a specific inhibitor of the Na+/H+ exchanger.(ABSTRACT TRUNCATED AT 250 WORDS)

Early Activation of Intracellular Signals after Myocardial Stretch: Anrep Effect, Myocardial Hypertrophy and Heart Failure

The link between the Anrep effect -the increase in cardiac contractility that develops 10–15 min following myocardial stretch- and myocardial hypertrophy and failure was not appreciated until we proposed it in the 2005 edition of the book “Mechanosensitivity in Cells and Tissues”. In this new version of the chapter we will present the updated experimental evidence that led us to propose the autocrine/paracrine mechanism underlying the Anrep effect, as well as its resemblance to signals that have been described for cardiac hypertrophy development and heart failure. Interesting novel data supporting a crucial role for stretch-induced mineralocorticoid receptor activation, EGFR transactivation and increased mitochondrial production of reactive oxygen species leading to NHE-1 stimulation will be thoroughly described. A clear understanding of the early triggering mechanisms that stretch imposes to the myocardium will allow us to design novel weapons to win the battle against cardiac hypertrophy and failure, a major disease spread worldwide.