Dual interactions between alpha 2-adrenoceptor agonists and the proximal Na(+)-H+ exchanger.
In the kidney, the proximal nephron is a major site for Na+ reabsorption and H+ secretion. An electroneutral exchanger mediates the uptake of luminal Na+ with the secretion of cellular H+. In these studies, alpha-adrenoceptor-stimulated influx of 22Na+ into rat proximal tubules through the Na(+)-H+ exchanger was examined. The activity of this exchanger was defined as the component of 22Na+ uptake sensitive to inhibition by ethylisopropyl amiloride (EIPA) and was observed to be increased by both alpha 1- and alpha 2-adrenoceptor agonists as well as by phorbol 12-myristate 13-acetate (PMA). Selective alpha 2-adrenoceptor agonists produced a range of stimulation of EIPA-suppressible 22Na+ uptake: from a 72% increase above control with guanabenz to a 253% increase with B-HT 933. Because heterogeneity of alpha 2-adrenoceptor structure and function has been postulated, we examined whether the effects of alpha 2-adrenoceptors were sensitive to pertussis toxin. the responses to alpha 1-adrenoceptor agonists and PMA were unaffected, but the stimulation of Na(+)-H+ exchange by each of the selective alpha 2-adrenoceptor agonists tested was blocked. When Na(+)-H+ exchange was increased directly by PMA acting on protein kinase C, guanabenz but not B-HT 933 inhibited the response. The results indicated that the alpha 2-adrenoceptor agonists stimulated 22Na+ influx by activating a pertussis toxin-sensitive pathway but that certain alpha 2-adrenergic agonists such as guanabenz could additionally inhibit the exchanger through a pertussis toxin-resistant mechanism. This inhibition by guanabenz could be reversed by selective alpha 2-adrenoceptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Gesek
F A
FA
Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University Medical Center, Winston-Salem, North Carolina 27103.
Strandhoy
J W
JW
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006143:Guanabenz / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000037:antagonists & inhibitors / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers; D014357:Trypsin / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D001381:Azepines; D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; D010566:Virulence Factors, Bordetella; D000584:Amiloride; D012964:Sodium; C015603:azepexole; D037342:Pertussis Toxin; D014357:Trypsin; D006143:Guanabenz; C039614:ethylisopropylamiloride