H(+)-induced vasodilation of rat aorta is mediated by alterations in intracellular calcium sequestration.

Abstract

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 KCI or phorbol ester. Acidification in this range did not alter basal or norepinephrine-stimulated unidirectional 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. (Circulation Research 1990;67:426-439) Several lines of evidence suggest that a decrease in pH is associated with a decrease in vascular smooth muscle tone. Severe acidosis is often accompanied by a decreased pressor response to catecholamines."2 Furthermore, the external application of CO2 is known to produce local vasodilation,34 presumably by increasing tissue PCO2.' Similarly, in vitro studies indicate that the contractile response of blood vessels is reduced if the pH of the

Effect of changes in pH on wall tension in isolated rat pulmonary artery: role of the RhoA/Rho-kinase pathway

“…In the systemic circulation, the mechanisms responsible for the vasodilator effect of acidosis have been extensively explored. Ca 2ϩ influx (16,21), Ca 2ϩ release, and Ca 2ϩ sequestration from internal stores (6,28,43), the activity of both the sarcolemmal and sarcoplasmic reticulum Ca 2ϩ -ATPase (SERCA) pump (14), and the activity of the Na ϩ -Ca 2ϩ exchanger have been shown to be sensitive to pH in a manner that favors a decrease in the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ). Because similar Ca 2ϩ regulatory mechanisms are found in pulmonary vascular smooth muscle, it is likely that they are also sensitive to acidosis and, therefore, may not account for the resistance of pulmonary vascular smooth muscle to acidosis.…”

Effects of changes in pH and P CO2 on wall tension in isolated rat intrapulmonary arteries

“…Hypercapnic acidosis has a vasodilator effect in systemic vessels which is partly endothelium dependent (Fukuda et al 1993) while there is evidence that the vasodilator response to normocapnic acidosis is attenuated by endothelium derived mediators (Sweeney et al 1998a) which may be products of the cyclo-oxygenase pathway of arachidonic acid metabolism (Wagerle & Mishra, 1988;Loutzenhiser et al 1990;Wagerle & Degiullio, 1994). Thus, in systemic vessels the effects of hypercapnia and acidosis are importantly modified by the vascular endothelium.…”

Mechanism of butyrate‐induced vasorelaxation of rat mesenteric resistance artery

“…However, intracellular acidosis has been shown to have many effects, not all of which would be expected to cause vasorelaxation. Those which should promote vascular relaxation include reduction of the voltage-gated Ca2+ current associated with a reduction of Ca2+ channel availability (Kl6ckner & Isenberg, 1994), and stimulation of Ca2+ sequestration (Loutzenhiser et al, 1990). On the other hand, rapid acidification causes an increase in tension which is transient or decays with time, (Spurway & Wray, 1986;Aalkjaer & Mulvany, 1988;Matthews et al, 1992), possibly by releasing or displacing intracellular Ca2+ (Jensen et al, 1993;Batlle et al, 1993).…”