Altered biochemical and functional responses in aorta from hypertensive rats.

Abstract

SUMMARY Factors that lead to supersensitivity of vascular smooth muscle to norepinephrine during aldosterone-salt-induced hypertension in rats appear to reside beyond ligand-a-adrenergic receptor binding, which we have shown previously to be normal. The objective of this study was to determine whether significant shifts occur in the coupling between receptors and the production of putative second messengers. Measures of [ 3 H]mjo-inositol phosphates in aorta (endothelium removed) exhibited a concentration-dependent increase to norepinephrine, with the 50% response shifted significantly to the left in the hypertensive group (7.0 ± 0.9 x 10~7 M in 8 control rats vs 1.1 ± 0.2 x 10" 7 M in 8 hypertensive rats; p<0.001). The production of [ 32 P]phosphatidic acid was also shifted (6.5 ± 2.5 x 10" 7 M in 16 control vs 1.9 ± 0.8 x 10" 7 M in 12 hypertensive rats; p<0.05). The functional responses of 42 K efflux and contraction to norepinephrine were also significantly shifted threefold to 15-fold in the hypertensive group (p<0.001), but the 50% response typically occurred at a 10 to 100 times lower concentration than that for the production of mvo-inositol phosphates and phosphatidic acid. The amplification between receptor occupancy and functional responses apparently occurs beyond the production of phosphoinositide metabolites. The fivefold shift in the 50% response of biochemical end points for the hypertensive group accounted for most of the shift (sixfold) in the functional end points. It is concluded that the increased efficacy in the hypertensive group resulted more from shifts in the relation between receptor occupancy and production of phosphoinositide metabolites than from shifts in the action of these metabolites on functions that control to catecholamines has been associated with several models of hypertension. 1 * 3 Moreover, it precedes the elevation of blood pressure in the mineralocorticoid-salt hypertensive rat, thus implicating supersensitivity as a pathogenic factor. '• 4 -5 A systematic characterization of a-adrenergic receptors revealed no significant alteration in receptor type (a,), equilibrium dissociation constants, or maximum binding (receptor concentration) of aortic smooth muscle from the aldosterone-salt hypertensive rat (AHR).6 7 Analyses of the ligand binding and dose-response curves revealed that the agonist dissociation constant (A" A ) for norepinephrine (NE) was not changed in AHR, while the efficacy was 4.4 times higher. These findings support the conclusion that postreceptor events underlie the supersensitivity in AHR.There has been an explosion of information relating phosphoinositide metabolites to cellular regulation in many tissues, including smooth muscle.8 "' 2 The regulation of phospholipase C (PLC) by a-adrenergic receptor occupancy is a potential site for the development of supersensitivity. PLC acts on phosphatidylinositol 4,5-bisphosphate to form mjo-inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG), which are thought to be important regulators of calcium rele...

Role of the α 1D - Adrenegric Receptor in the Development of Salt-Induced Hypertension

“…7 Hyperreactivity of vascular smooth muscle to adrenergic stimulation has been suggested as a major cause for the increase and maintenance of BP in animal models such as spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 3,6,8,9 Catecholamines cause vascular smooth muscle contraction by activating ␣ 1 -adrenergic receptors (␣ 1 -ARs), and drugs that block ␣ 1 -ARs lead to a fall in peripheral vascular resistance and in venous return to the heart and in BP. Three subtypes of ␣ 1 -AR (␣ 1A , ␣ 1B , and ␣ 1D ) have been isolated and shown to share a high degree of structural similarity (50% to 60% amino acid identity).…”

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

“…In the present experiments, mean pD 2 and pK t values for arteries from sham rats were within the 95% confidence band for the theoretically expected relation, suggesting that the mean pD 2 value approximates the value for pK t . In contrast, pD 2 and pK, values in arteries from DOCA hypertensive rats fell outside the derived 95% confidence band, indicating that factors other than receptor affinity are involved in the determination of sensitivity in these vessels. However, this result is also consistent with an increase in the number of receptors.…”

“…2 It has been suggested that inositol 1,4,5-trisphosphate-mediated mobilization of intracellular calcium is an important step in the activation of contraction in vascular smooth muscle. 15 Based on measures of 45 Ca 2+ efflux, this study demonstrates that norepinephrine-induced release of intracellular calcium is increased in mesenteric arteries from DOCA hypertensive rats.…”

“…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.…”

Altered Aortic Production of 6-Keto-Prostaglandin F_1&alpha;from Aldosterone-Salt Hypertensive Rats

“…Aortae from aldosterone-Others have shown an ai-adrenoceptor activation of phospholipase C (PLC) in vascular smooth muscle in rat aorta [6][7][8]. In subsequent studies of phosphatidic acid production, we have demonstrated a leftward shift in the norepinephrine concentration-response curve in AHR compared with CSR [9], These data imply a possible alter ation in norepinephrine-stimulated PLC activation in AHR resulting in increases of diacylglycérol (DAG) and/or subsequent DAG kinase activity [9], Another product of the PLC pathway is arachidonic acid which is released from DAG by the enzyme DAG lipase [10]. Ara chidonic acid is also released from other phospholipids by phospholipase Ai (PLAi).…”