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...