Effect of Na+/H+ exchange inhibitors on agonist-induced contraction of rat aorta.
A number of vasoconstrictor agonists activate the Na+/H+ antiport system in vascular smooth muscle, leading to alkalinization of the cytosol and influx of Na+. It is believed that agonist-induced Na+/H+ exchange may play an important role in contraction. We have evaluated this hypothesis by determining the effect of inhibition of Na+/H+ exchange on phenylephrine (PE)-induced contraction of rat aorta. Preincubation of rat aorta with the Na+/H+ exchange inhibitor amiloride (0.5 mM) inhibited subsequent PE-induced contraction. However, the more potent and specific Na+/H+ exchange inhibitor hexamethylene amiloride (10 microM) did not inhibit PE-induced contraction. Inhibition of Na+/H+ exchange by removal of extracellular Na+ and substitution with N-methyl-D-glucamine only moderately reduced PE-induced contraction. Hexamethylene amiloride (10 microM) and methyl-isobutyl amiloride (30 microM), another potent and specific inhibitor of Na+/H+ exchange, caused a slow, sustained and reversible contraction of rat aorta which was 114.7 and 86.6%, respectively, of maximal PE-induced contraction. Hexamethylene amiloride-induced contraction was dose-dependent, dependent on extracellular calcium and inhibited by nifedipine. We conclude that the vasorelaxant effects of amiloride are unrelated to inhibition of Na+/H+ exchange, and may be mediated by inhibition of kinases involved in contraction. These results demonstrate that inhibition of Na+/H+ exchange has no major effect on agonist-induced contraction of rat aorta, and suggest that vasoconstrictor activation of Na+/H+ exchange does not play a major role in agonist-induced contraction of rat aorta.
Reynolds
E E
EE
Department of Heart and Hypertension Research, Cleveland Clinic Foundation, Ohio.
Brum
J M
JM
Cragoe
E J
EJ
Ferrario
C M
CM
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017923:Sodium-Hydrogen Exchangers; D014661:Vasoconstriction / Q000187:drug effects*
D002352:Carrier Proteins; D017923:Sodium-Hydrogen Exchangers; C057360:5-(N,N-hexamethylene)amiloride; D010656:Phenylephrine; D011189:Potassium Chloride; D000584:Amiloride; D002118:Calcium