Synergistic alpha-1 and alpha-2 adrenergic stimulation of rat proximal nephron Na+/H+ exchange
Both alpha-1 and alpha-2 adrenoceptors have been localized to the renal cortex, with the majority of binding sites on the proximal tubule. Because the major regulator of Na+ uptake into the proximal tubule is the Na+/H+ exchanger, and because alpha-1 and alpha-2 adrenoceptors stimulate it in other tissues, we tested the hypothesis that both alpha adrenoceptor subtypes can increase Na+ uptake into the proximal nephron by stimulating the Na+/H+ antiporter. Enhancement of Na+ transport by agonists was studied in isolated rat proximal tubules by determining the uptake of 22Na that was suppressible by the Na+/H+ inhibitor, 5-(N-ethyl-N-isopropyl)amiloride (EIPA). The phorbol ester, phorbol-12-myristate-13-acetate, (0.1 microM), directly stimulated the antiporter through protein kinase C and increased EIPA-suppressible 22Na uptake 250% above control. The alpha-1 adrenoceptor agonists, cirazoline and phenylephrine, in addition to the mixed agonist, norepinephrine, maximally stimulated uptake by 226 to 232% at 1 microM concentrations. alpha-2 agonists produced a range of maximal stimulations at 1 microM from 65% with guanabenz to 251% with B-HT 933. Increases in 22Na uptake by agonists were inhibited by selective adrenergic antagonists and by EIPA. The drugs did not change the EIPA-resistant component of 22Na uptake. Inasmuch as the adrenoceptor subtypes likely stimulated Na+/H+ exchange by differing intracellular pathways impinging upon common transport steps, we examined whether simultaneous stimulation of both pathways was additive. Submaximal concentrations (5 nM each) of alpha-1 and alpha-2 adrenoceptor agonists in combination synergistically enhanced 22Na uptake to a level similar to 1 microM concentrations of adrenoceptor agonists alone or in combination.
- Research Organization:
- Wake Forest Univ. Medical Center, Winston-Salem, NC (USA)
- OSTI ID:
- 5879112
- Journal Information:
- J. Pharmacol. Exp. Ther.; (United States), Vol. 249:3
- Country of Publication:
- United States
- Language:
- English
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PHORBOL ESTERS
BIOLOGICAL EFFECTS
SODIUM COMPOUNDS
MEMBRANE TRANSPORT
SYMPATHOMIMETICS
RECEPTORS
BIOLOGICAL PATHWAYS
HYDROGEN IONS
IN VITRO
INHIBITION
ION EXCHANGE
MICROTUBULES
NORADRENALINE
PHOSPHOTRANSFERASES
PROTEINS
RATS
SODIUM 22
SYMPATHOLYTICS
SYNERGISM
TRACER TECHNIQUES
ADRENAL HORMONES
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ALKALI METAL ISOTOPES
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BETA DECAY RADIOISOTOPES
BETA-PLUS DECAY RADIOISOTOPES
CARCINOGENS
CARDIOTONICS
CARDIOVASCULAR AGENTS
CELL CONSTITUENTS
CHARGED PARTICLES
DRUGS
ENZYMES
ESTERS
IONS
ISOMERIC TRANSITION ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
LIGHT NUCLEI
MAMMALS
MEMBRANE PROTEINS
NEUROREGULATORS
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
PHOSPHORUS-GROUP TRANSFERASES
RADIOISOTOPES
RODENTS
SODIUM ISOTOPES
TRANSFERASES
VERTEBRATES
YEARS LIVING RADIOISOTOPES
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