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First published online February 15, 2006
Journal of Experimental Biology 209, 916-926 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02087

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Contractile recovery from acidosis in toad ventricle is independent of intracellular pH and relies upon Ca²⁺ influx

Margarita A. Salas, Martín G. Vila-Petroff, Roque A. Venosa and Alicia Mattiazzi^*

Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 60 y 120, 1900 La Plata, Argentina

View larger version (57K): [in a new window]   Fig. 1. Biphasic inotropic effect of hypercapnic acidosis on toad ventricle. (A) Continuous recording of developed tension (DT) and maximal rate of rise of tension (+dT/dt) during isometric contraction. Hypercapnia produced an abrupt decrease in contractility followed by recovery that exceeded control values. (B) Overall results of the effect of acidosis on DT. Data are means ± s.e.m. (N=49). *P<0.05 with respect to values before hypercapnia.

View larger version (17K): [in a new window]   Fig. 2. Changes in pHi in isolated toad myocytes subjected to hypercapnic acidosis in the absence or presence of Na+/H+ exchanger (NHE) inhibition. (A) In the the absence of cariporide, the initial fall in pHi was followed by restitution towards the 5% CO2 values, in spite of the persistent extracellular acidosis. No pHi recovery was observed in the presence of cariporide (5 µmol l–1). (B) Overall results of five experiments of this type. *P<0.05 with respect to values with cariporide.

View larger version (26K): [in a new window]   Fig. 3. Effect of persistent hypercapnic acidosis on contractile recovery in the presence and absence of the Na+/H+ exchanger (NHE) inhibition. (A) Isolated myocytes. During hypercapnic acidosis, contractility followed a pattern similar to that of ventricular strips, reaching control values after an initial fall. In spite of abolishing pHi restitution with the NHE inhibitor cariporide (5 µmol l–1), the inotropic recovery was not cancelled. (B) Ventricular strips. The presence of cariporide (5 µmol l–1) did not modify the inotropic response of the toad ventricle to acidosis. There were no statistically significant differences between control and cariporide-treated preparations. Data are means ± s.e.m. of five experiments.

View larger version (26K): [in a new window]   Fig. 4. Effect of hypercapnic acidosis on calcium transient (CaiT). (A) Top, a typical continuous recording of myocyte cell length during hypercapnic acidosis. Below, actual tracings of the individual twitch contractions and the Fura-2 fluorescence transients at the times indicated by letters a–c on the continuous chart. (B) Overall results of the effect of acidosis on CaiT, shortening and relaxation time of both parameters. The results indicate that during the recovery there is an increase in diastolic and peak systolic [Ca2+]i with a prolongation of the CaiT (results from five different myocytes). *P<0.05 vs values before hypercapnia.

View larger version (19K): [in a new window]   Fig. 5. Effect of Na+/Ca+ exchanger (NCX) inhibition on toad ventricular contractility during hypercapnic acidosis. (A) Preincubation of isolated myocytes with 1 µmol l–1 KB-R did not modify basal contractility but completely abolished the contractile recovery from acidosis (results from four different myocytes). (B) Similar results were obtained when ventricular strips were preincubated with 20 µmol l–1 (2-[2-[4-(4-nitro-benzyloxy)phenyl]ethyl] isothiourea methanesulphonate (KB-R) (N=5). (C) A continuous record of tension showing that KB-R reverses the contractile recovery: the addition of the Na+/Ca+ exchanger (NCX) inhibitor (20 µmol l–1) to ventricular strips, once the recovery reached stabilization produced a fall of developed tension (DT) to the values before the recovery. (D) Overall results of these experiments (N=4). *P<0.05 vs values before hypercapnia.

View larger version (15K): [in a new window]   Fig. 6. Effect of hypercapnic acidosis and Na+/K+ ATPase-pump inhibition on intracellular Na+ levels. (A) Typical recording of [Na+]i in the continued presence of 5 µmol l–1 cariporide. Switching from a 5% to a 12% CO2 buffered solution had no effect on Na+i levels, whereas addition of the Na+/K+ ATPase pump inhibitor, ouabain at 10 µmol l–1 during hypercapnic acidosis, substantially increased [Na+]i. (B) Overall results showing mean sodium-binding benzofuran isophthalate (SBFI) fluorescence values, indicating the lack of effect of hypercapnic acidosis on Na+i levels and the significant increase produced by ouabain. Values are means ± s.e.m., N=5 cells. *P<0.05 with respect to values before hypercapnia.

View larger version (15K): [in a new window]   Fig. 7. Effect of blocking Ca2+ channels on contractile recovery. The treatment of ventricular strips with 0.5 µmol l–1 nifedipine abolished the contractile recovery from acidosis (N=5). *P<0.05 vs values with nifedipine. DT, developed tension.

View larger version (20K): [in a new window]   Fig. 8. Action potential duration of ventricular strips at control pH and during acidosis. (A) A representative tracing of AP under both conditions indicates a lengthening of repolarization. (B) Overall results showing hypercapnic acidosis-induced prolongation of the action potential (AP) duration at the time of the 20%, 50% and 90% of repolarization (N=6). *P<0.05 vs value before acidosis.