Calcium, phosphoinositide, and 1,2-diacylglycerol responses of blood vessels of deoxycorticosterone acetate-salt hypertensive rats to endothelin-1.

Abstract

In previous studies a decreased responsiveness to endothelin-1 (ET-1) of conduit arteries and resistance vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats was found in comparison with uninephrectomized controls. Decreased isometric force, number of receptors, and inositol phosphate accumulation were reported in the DOCA-salt animals. In the present study effects of ET-1 on cytosolic free calcium, inositol phosphates, and 1,2-diacylglycerol were investigated in blood vessels of DOCA-salt hypertensive rats. Basal cytosolic free calcium, measured with the fluorescent dye fura-2, was 201 ±41 nmol/l in mesenteric arteries of DOCA-salt rats and 45±9 nmol/l in uninephrectomized controls (p<0.01). The maximal response of cytosolic free calcium (to 30 nmol/l ET-1) was 176±22% of the basal value for DOCA-salt and 242±6% for uninephrectomized rats (p<0.05). The concentration giving 50% of the maximum response was 9.0 and 6.5 nmol/l for DOCA-salt rats and controls, respectively. Inositol phosphate production after stimulation with 100 nmol/l ET-1 in the presence of LiCl was lower by at least 30% (p<0.01) in both aorta and mesenteric arteries of DOCA-salt hypertensive versus control rats. Basal levels of diacylglycerol in aorta were similar in DOCA-salt rats and in controls and did not respond to a 100 nmol/l ET-1 stimulation in the DOCA-salt rats, in contrast to the increase found in the control uninephrectomized rats (p<0.05). Thus, the diminished response to ET-1 of DOCA-salt rat arteries may be due to a lower density of ET-1 receptors, resulting in a blunted signal transduction, as reflected by decreased responses of inositol phosphate, cytosolic free calcium, and diacylglycerol. 6 Although endothelin infusion may raise blood pressure, its role in hypertension is unproven. 7 The vascular effects of this peptide have been extensively investigated: endothelins most likely act as paracrine hormones and exert their cellular effects through the phosphoinositide pathway, In a previous study we reported that the density of mesenteric artery ET-1 receptors and vascular responses to ET-1 are decreased in DOCA-salt hypertensive rats.3 Moreover, we demonstrated that vascular accumulation of inositol phosphates (InsPs) in response to ET-1 was significantly lower in DOCA-salt hypertensive rats when compared with uninephrectomized controls. These observations led to the question of whether diacylglycerol (DG) production and intracellular calcium metabolism are also altered in DOCA-salt hypertensive rats. It is indeed well established that DG can be produced by phosphatidylcholine breakdown as well as through the phosphatidyl inositol pathway.10 Therefore, DG levels might not change in parallel with endothelinstimulated InsP production in vascular smooth muscle cells. ET-1 has also been shown to exert a wide range of effects on calcium metabolism: low ET-1 concentrations (<1 nmol/l) provoke calcium influx through calcium channels, 81112 whereas higher concentrations stimulate inositol 1,4,5-trisphosphate-dependent ca...

Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats.

“…7 - 22 This suggests that, indeed as a consequence of increased production of ET-1 in blood vessels of DOCA-salt hypertensive rats, endothelin receptors are downregulated, resulting in depressed responses to exogenous and probably endogenous endothelin. Because the walls of blood vessels in DOCA-salt rats are significantly hypertrophied and their lumen reduced, vasoconstrictor responses are magnified in resistance vessels, 21 and thus increased production of ET-1 may play a role in the maintenance of hypertension in this model despite depressed responsiveness to ET-1. Because ET-1 is also a potent mitogen, increased vascular production of ET-1 in DOCA-salt hypertensive rats could be in part responsible for the very important vascular hypertrophy present in this hypertensive model.…”

“…20 We have previously shown that in DOCA-salt hypertensive rats, responses of aorta and large and small mesenteric arteries to exogenous ET-1 are blunted. 7 - 21 Furthermore, binding of ET-1 to mesenteric arteries is decreased, and signal transduction is also blunted in both mesenteric arteries and aorta. 7 - 22 This suggests that, indeed as a consequence of increased production of ET-1 in blood vessels of DOCA-salt hypertensive rats, endothelin receptors are downregulated, resulting in depressed responses to exogenous and probably endogenous endothelin.…”

Hyperparathyroidism and the Calcium Paradox of Aldosteronism

“…Here, the early, persistent reduction in plasma ␣ 1 -AP activity seen is likely in keeping with Ca 2ϩ overload of PBMCs and ventricular tissue and may include other cells and tissues (eg, platelets, erythrocytes, fibroblasts, endothelial cells, and vascular tissue). 51,[53][54][55] A direct effect of ALDOST on cultured lymphocyte [Ca 2ϩ ] i could not be demonstrated. 20 Widespread Ca 2ϩ loading, which may be a response to elevated plasma PTH levels, could explain the systemic induction of oxi/ nitrosative stress.…”

Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats.

“…6 -10 This was in part explained by downregulation of vascular endothelin receptors, accompanied by a reduction of phospholipase C activity. 6 - 11 We have speculated that downregulation of endothelin receptors could be secondary to exaggerated production of ET-1 in blood vessels of DOCA-salt hypertensive rats. Here, we show that aorta and mesenteric arteries of DOCA-salt hypertensive rats contain greater amounts of immunoreactive ET-1 (ir-ET-1), suggesting that vascular ET-1 may be involved in some forms of hypertension.…”