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HCO3(-)-dependent intracellular pH regulation in the premature myocardium
1Department of Pediatric Cardiology, Heart Institute of Japan, Tokyo Women's Medical College.
Insights
Newborn rabbit hearts show increased bicarbonate-chloride exchange activity compared to adults, crucial for maintaining heart function during acidosis when sodium-hydrogen exchange is inhibited. This highlights developmental differences in cardiac ion transport.
Area of Science:
- Cardiovascular Physiology
- Cellular Acid-Base Balance
- Developmental Biology
Background:
- Cardiac cells utilize ion exchangers to regulate intracellular pH (pHi).
- Developmental changes in these mechanisms may impact cardiac function under stress.
Purpose of the Study:
- To investigate developmental differences in sodium-hydrogen (Na(+)-H(+)) exchange and bicarbonate-chloride (HCO3(-)-Cl(-)) exchange in rabbit hearts.
- To assess the role of these exchangers in maintaining myocardial mechanical function during acidosis.
Main Methods:
- Intracellular pH (pHi) measurement in isolated myocytes using a fluorescent dye.
- Assessment of myocardial contractile function in isolated ventricular preparations.
- Induction of intracellular acidosis using an ammonium chloride prepulse technique.
- Pharmacological inhibition of Na(+)-H(+) exchange (using EIPA) and HCO3(-)-Cl(-) exchange (using SITS).
Main Results:
- Newborn rabbit hearts exhibited a higher rate of pHi recovery in bicarbonate-buffered solutions compared to adults.
- Bicarbonate-chloride exchange activity was significantly more active in newborn hearts, contributing to pHi recovery, especially when Na(+)-H(+) exchange was inhibited.
- The activity of bicarbonate-chloride exchange was essential for maintaining myocardial contractile function during acidosis in newborns, particularly when Na(+)-H(+) exchange was blocked.
Conclusions:
- There are no significant developmental changes in Na(+)-H(+) exchange activity between newborn and adult rabbit hearts.
- Bicarbonate-chloride exchange activity is developmentally upregulated in the newborn rabbit myocardium.
- The HCO3(-)-Cl(-) exchanger plays a critical role in preserving cardiac contractile function during acidosis, especially in the context of inhibited Na(+)-H(+) exchange, contributing to the greater acidosis tolerance in the immature heart.
Abstract:
This study investigated developmental changes in Na(+)-H+ exchange and HCO3(-)-Cl- exchange activities in newborn and adult rabbit hearts. pHi was measured using the fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein in isolated myocytes. Myocardial mechanical function was measured in the isolated ventricular preparation. Intracellular acidosis with normal pHo was induced by an NH4Cl (10 mM) prepulse technique. Upon removal of NH4Cl, pHi fell transiently and then recovered toward the control level. In the HCO3-/CO2-buffered solution, the rate of recovery of pHi in the newborn was greater than in the adult. In the HCO3-/CO2-buffered solution, 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of Na(+)-H+ exchange, inhibited the recovery of pHi completely in the adult. In the newborn, however, significant recovery of pHi was observed in the presence of EIPA. In the presence of both EIPA and 4-acetamido-4'-isothiocyanatostilbene-2',2'-disulfonic acid (SITS), an inhibitor of HCO3(-)-Cl- exchange, the recovery of pHi was not observed in the two age groups. In the HEPES-buffered solution that did not contain HCO3-/CO2, the rate of recovery of pHi after NH4Cl removal was similar in the two age groups. In the HEPES-buffered solution, the recovery of pHi was completely inhibited by EIPA in the two age groups. In the presence of EIPA in the HCO3-/CO2-buffered solution, contractile function decreased during acidosis after NH4Cl removal and did not recover in the adult. In the newborn, significant recovery of contractile function was observed after NH4Cl removal in the presence of EIPA. The recovery of mechanical function observed in the presence of EIPA in the newborn was inhibited by SITS. These data suggest that, although there is no developmental change in the Na(+)-H+ exchange activity, HCO3(-)-Cl- exchange is more active in the premature myocardium. The presence of the HCO3(-)-Cl- exchanger is important in maintaining myocardial contractile function during acidosis, especially when Na(+)-H+ exchange is inhibited and may partly explain the greater resistance of the premature myocardium to acidosis.