Abstract
We determined if the increased vascular responsiveness to endothelin-1 (ET-1) observed in male, but not in female, DOCA-salt rats is associated with differential vascular mRNA expression of ET-1 and/or ET A/ET B receptors or with functional differences in Ca2+ handling mechanisms by vascular myocytes. Uninephrectomized male and female Wistar rats received DOCA and drinking water containing NaCl/KCl. Control rats received vehicle and tap water. Blood pressure and contractile responses of endothelium-denuded aortic rings to agents which induce Ca2+ influx and/or its release from internal stores were measured using standard procedures. Expression of mRNA for ET-1 and ET A/ET B receptors was evaluated by RT-PCR after isolation of total cell RNA from both aorta and mesenteric arteries. Systolic blood pressure was higher in male than in female DOCA rats. Contractions induced by Bay K8644 (which activates Ca2+ influx through voltage-operated L-type channels), and by caffeine, serotonin or ET-1 in Ca2+-free buffer (which reflect Ca2+ release from internal stores) were significantly increased in aortas from male and female DOCA-salt compared to control aortas. DOCA-salt treatment of male, but not female, rats statistically increased vascular mRNA expression of ET-1 and ET B receptors, but decreased the expression of ET A receptors. Molecular up-regulation of vascular ET B receptors, rather than differential changes in smooth muscle Ca2+ handling mechanisms, seems to account for the increased vascular reactivity to ET-1/ET B receptor agonists and higher blood pressure levels observed in male DOCA-salt rats.
Highlights
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by endothelial and vascular smooth muscle cells and its effects are mediated by activation of ETA and ETB receptor subtypes
We have demonstrated that male DOCAsalt rats display increased vascular sensitivity to ET-1 and to IRL-1620, an ETB receptor agonist which induces contraction in aortas from male deoxycorticosterone acetate (DOCA)-salt rats, but not in preparations from control or female DOCA-salt animals [6]
These gender-related differences in ET-1/IRL-1620 vascular reactivity were observed in the mesenteric microcirculation in vivo, where IRL-1620 induces vasodilatation in control rats, vasoconstriction in male DOCA-salt rats, and minimal changes in vessel diameter in female hypertensive rats [6]
Summary
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by endothelial and vascular smooth muscle cells and its effects are mediated by activation of ETA and ETB receptor subtypes. ETA receptors are expressed in smooth muscle cells whereas ETB receptors are expressed predominantly in endothelial cells and, to a much lesser extent, in smooth muscle cells [1,2]. Both ETA and ETB receptor subtypes can activate various signaling mechanisms in vascular smooth muscle, including i) G protein-mediated activation of phospholipase C, leading to phosphatidylinositol hydrolysis and formation of inositol trisphosphate (IP3) and diacylglycerol, ii) increase in cytosolic free Ca2+ concentration ([Ca2+]i), iii) activation of protein kinase C, and iv) changes in intracellular pH via stimulation of the Na+-H+ exchanger [2,3]. The second [Ca2+]i phase, which appears to contribute to the sustained ET-1-induced vasoconstriction, depends on external Ca2+ and is the result of transmembrane Ca2+ influx, mainly through voltage-dependent L-type Ca2+ channels (VOC), which may be directly or indirectly activated by ET-1 [3,4,5]
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