Alpha-adrenergic receptors and 45Ca2+ efflux in arteries from deoxycorticosterone acetate hypertensive rats.

Abstract

Increased vascular sensitivity to catecholamines characterizes mineralocorticoid hypertension. The present study investigated three possible sites that may account for this abnormality: agonist affinity, Ca 2+ release from intracellular stores, and Ca 2+ sensitivity of the contractile proteins. Adult male Sprague-Dawley rats underwent uninephrectomy and were implanted subcutaneously with deoxycorticosterone acetate (DOCA; 200 mg/kg, 1% NaC10.2% KC1 drinking water, 4-6 weeks). Control rats were sham treated. Helical strips of mesenteric arteries were placed in muscle baths for measurement of isometric force development. Although the ED 50 for norepinephrine was significantly lower in arteries from DOCA rats (pD 2 , 8.21 ±0.15) than in those from sham controls (pD 2 , 7.24±0.11), agonist affinity, determined by partial blockade with phenoxybenzamine, did not differ between the two groups. In contrast, norepinephrine-stimulated 45 Ca2+ efflux in the absence of extracellular Ca 2+ was significantly greater in arteries from DOCA rats than in those from sham rats. In the presence of ryanodine to deplete intracellular Ca 2+ stores, force development to Ca 2+ was not different in saponin-permeabilized vessels from DOCA rats, indicating that the Ca 2+ sensitivity of the contractile proteins was not altered in DOCA hypertension. We conclude that increased vascular sensitivity to norepinephrine in mineralocorticoid hypertension is related to increased release of Ca 2+ from a subcellular store and not to changes in agonist affinity or to the contractile protein interaction. Based on previous reports, it is likely that this abnormality reflects a postreceptor change in signal transduction, but there is also evidence to suggest that an increase in the number of a-adrenergic receptors may be involved. (Hypertension 1992;19:734-738) KEY WORDS • adrenergic receptors • norepinephrine • calcium • vascular smooth muscle • deoxycorticosterone • mineralocorticoid hypertension • sarcoplasmic reticulum I ncreased vascular sensitivity to catecholamines has been well documented in various forms of hypertension and has been implicated in the development of increased peripheral vascular resistance. From a mechanistic standpoint, changes at a number of levels may contribute to observed differences in functional responses of vascular smooth muscle between hypertensive and normotensive control animals: alterations in receptor number or binding properties, 1 changes in postreceptor signal transduction, 2 and cellular changes that may directly affect a functional response, such as differences in the contractile proteins. The present study investigated three possible sites that may account for augmented contractile responsiveness to norepinephrine in mesenteric arteries from mineralocorticoid hypertensive rats. To evaluate agonist affinity, we determined the dissociation constant for norepinephrine using partial, irreversible a-adrenergic blockade with phenoxybenzamine. 3 We assessed agonist-induced mo- Ca2+ efflux. Finally, we examined t...

RhoA/Rho-kinase, vascular changes, and hypertension

“…The increased sensitivity in the hypertensive vasculature has been proposed to be due to increased phosphoinositide metabolism, increased number of receptors, and possibly increased efflux of sarcoplasmic reticulum calcium [35,39,40].…”

Aldosterone Regulates the Na-K-2Cl Cotransporter in Vascular Smooth Muscle

“…Both the Na ϩ content and passive flux of Na ϩ are increased in vascular smooth muscle from mineralocorticoid-treated animals, 5,7 and both the mRNA and activity of the Na ϩ pump are increased. [7][8][9][10] This upregulation of the Na ϩ pump is probably secondary to increased Na ϩ influx because intracellular [Na ϩ ] is increased rather than decreased. 5,11 Although increased intracellular [Na ϩ ] could stimulate Ca influx through the Na-Ca exchange, thereby increasing contractility, Ca stores do not appear to be increased in vascular smooth muscle from mineralocorticoid-treated rats.…”

Effects of Quercetin Treatment on Vascular Function in Deoxycorticosterone Acetate-Salt Hypertensive Rats. Comparative Study with Verapamil

“…We found that the vasoconstrictor response to KCl was significantly increased in endothelium-denuded aortic rings from DOCA-salt treated rats as compared to that from control group. No changes in calcium sensitivity have been shown in arteries [17] from mineralocorticoidsalt hypertensive rats. So, a greater increase in extracellular calcium influx evoked by KCl may account for its enhanced contractile response in DOCA-salt rats.…”