INVESTIGADORES
ENNIS Irene Lucia
artículos
Título:
Upregulation of myocardial Na+/H+ exchanger induced by chronic treatment with a selective inhibitor
Autor/es:
CAMILIÓN DE HURTADO MC; ENNIS IL; PÉREZ NG; CHIAPPE DE CINGOLANI GE; MORGAN PE; CINGOLANI HE
Revista:
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Editorial:
ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Manchester; Año: 2002 p. 1539 - 1547
ISSN:
0022-2828
Resumen:
Rats exposed to prolonged administration of the NHE-1 inhibitor
cariporide showed enhanced activity of the exchanger in cardiac tissue,
as assessed by the rise in the steady-state pHi value in the absence of
bicarbonate (7.15+/-0.01 in control vs 7.49+/-0.06 and 7.41+/-0.05 in
cariporide-treated for 1 or 2 months, respectively, P<0.05). In the
presence of bicarbonate, the change in pHi was blunted due to a
compensatory activation of acid loading pHi regulatory mechanisms. The
enhancement of NHE activity disappeared after 1 week of the inhibitor
withdrawal. The kinetic analysis of H+ fluxes after an acid load
revealed an increased net H+ efflux (JH+) at any given pHi value and an
alkaline shift of the apparent "set-point" of the exchanger (from
7.11+/-0.02 to 7.38+/-0.04,P <0.05) in treated rats. In the presence
of the PKC inhibitor chelerythrine, the "set-point" of the exchanger was
normalized in the cariporide-treated rats while JH+ at acidic pHi
values persisted elevated. Cardiac NHE-1 mRNA levels and protein
expression were increased in cariporide-treated rats. In addition to the
increased protein expression after the treatment, the normalization of
the augmented "set-point" by chelerythrine suggests an increased
turnover rate of the units through a PKC dependent pathway. These data
demonstrate that long-term treatment with the NHE-1 inhibitor cariporide
enhances the antiporter activity in cardiac tissue through an increase
of the number and turnover of functional units. This finding deserves
further experimental and clinical evaluations to consider whether it
would be advisable a gradual withdrawal of prolonged NHE inhibition to
avoid an enhanced response when the exchanger is stimulated.