H(+)-induced vasodilation of rat aorta is mediated by alterations in intracellular calcium sequestration.
Acidosis induces vasodilation both in vivo and in vitro. Although it is commonly surmised that acidosis alters contractility by affecting contractile proteins and calcium entry, the exact role of these mechanisms in acidosis-induced vasodilation has not been determined. In the present study, we demonstrated that a novel mechanism, involving increased calcium sequestration into intracellular sites sensitive to norepinephrine, mediates the vasodilation associated with relatively modest decreases in pH. The effects of changing pH from 7.4 to 7.0 on tension development, 45Ca fluxes, and the norepinephrine-releasable intracellular calcium stores were studied in isolated rat aorta. Acute acidification produced marked endothelium-independent dilations of aortic rings that had been precontracted with norepinephrine. In contrast, this maneuver had only modest effects on contractions elicited by 80 mM KCl or phorbol ester. Acidification in this range did not alter basal or norepinephrine-stimulated undirectional 45Ca influx, nor did it reduce the norepinephrine-induced net gain in 45Ca content. Furthermore, neither norepinephrine-stimulated 45Ca efflux nor the peak contractile response to norepinephrine in calcium-free buffer was affected, although in this setting, the duration of the phasic contractile response was shortened. When calcium was restored to tissues exposed to norepinephrine in calcium-free buffer, acidification slowed the rate of tension development without altering 45Ca uptake, thus changing the relation between tension development and calcium entry. These effects of acidification were shown to be associated with an increase in the amount of calcium sequestered into the norepinephrine-sensitive intracellular calcium store. These findings clearly indicate that acidification, within a range that has no effect on other aspects of smooth muscle activation, elicits vasodilation by stimulating intracellular calcium sequestration. This action may represent a predominant mechanism whereby acidosis alters vascular smooth muscle contractility.
Loutzenhiser
R
R
Nephrology Section, Veterans Administration Medical Center, Miami, FL 33125.
Matsumoto
Y
Y
Okawa
W
W
Epstein
M
M
D000109:Acetylcholine / Q000494:pharmacology; D000138:Acidosis / Q000503:physiopathology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D004533:Egtazic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014664:Vasodilation
D000001:Calcimycin; D004533:Egtazic Acid; D011189:Potassium Chloride; D000109:Acetylcholine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D009638:Norepinephrine