Aldosterone modulates neural vasomotor response in hypertension: role of calcitonin gene-related peptide Gloria Balfago ´n a, * , Iva ´n Ma ´rquez-Rodas a , Yolanda A ´ lvarez b , Marı ´a Jesu ´s Alonso b , Victoria Cachofeiro c , Mercedes Salaices b , Vicente Lahera c a Departamento de Fisiologı ´a, Facultad de Medicina, Universidad Auto ´noma de Madrid, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain b Departamento de Farmacologı ´a y Terape ´utica, Facultad de Medicina, Universidad Auto ´noma de Madrid, Spain c Departamento de Fisiologı ´a, Facultad de Medicina, Universidad Complutense, Spain Received 11 September 2003; received in revised form 16 March 2004; accepted 26 March 2004 Available online 6 May 2004 Abstract Objective: We analyse the effect of aldosterone on vasomotor response induced by electrical field stimulation (EFS) in mesenteric arteries from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Results: Aldosterone (0.001 – 1 AM) reduced vasoconstrictor response to EFS in a dose- and time-dependent manner only in SHR. Thus, the rest of experiments were performed only in SHR. Aldosterone did not affect either noradrenaline response or release. Effect of aldosterone (1 AM) on EFS response was not affected by N G -nitro-arginine- methyl esther (100 AM), and was abolished by capsaicin (0.5 AM) and the calcitonin gene-related peptide antagonist (CGRP 8 – 37, 0.5 AM). Calcitonin gene-related peptide (0.1 nM – 0.1 AM) induced a concentration-dependent relaxation, which was enhanced by aldosterone (1 AM). Incubation with either spironolactone (1 AM), glibenclamide (10 AM), RU 486 10 AM, ODQ (10 AM) or cycloheximide (10 AM) significantly reduced the enhancement of CGRP-relaxation produced by aldosterone, while remained unmodified by SQ 22,536. Conclusions: Aldosterone decreases the vasoconstrictor response to EFS in mesenteric arteries from SHR but not from WKY. This effect is mediated by an increased response to the sensory neurotransmitter CGRP, substantially, through glucocorticoid receptors activation. Furthermore, this effect is mediated by an increase of cGMP synthesis and ATP-dependent potassium channel activation. D 2004 Elsevier B.V. All rights reserved. Keywords: Sensory innervation; Vasomotor regulation; Mesenteric arteries; Glucocorticoid receptors 1. Introduction Vascular tone is determined by an equilibrium among several mechanisms in which innervation plays an important role. This regulation involves adrenergic, cholinergic, nitrer- gic, peptidergic and/or sensory innervations which are spe- cific of the vascular bed considered [1]. Electrical field stimulation (EFS) is widely used to study the influence of neurotransmitters released by nervous endings on vasomotor response, which depends on the balance between relaxing and contracting agents. EFS applied to rat mesenteric arteries produces a vasoconstrictor response which is the integrated result of the release of different neurotransmitters, mainly noradrenaline (NA) from adrenergic nerve terminals, neuro- nal nitric oxide (NO) from nitrergic innervation and calcito- nin gene-related peptide (CGRP) from sensory nerves [2–5]. Aldosterone is a mineralocorticoid which participates in electrolyte balance and plays an important physiological role in the long-term regulation of Na + and K + in the distal tubule and collecting duct [6–9]. In addition, aldosterone is now recognized to participate in a number of different pathophysiological effects in the cardiovascular system such as endothelial dysfunction, vascular smooth muscle cell hypertrophy and hyperplasia, fibrosis and inflammation, although the mechanisms underlying these effects are not well understood [10–15]. Aldosterone circulates at subna- nomolar levels; however, cardiovascular tissues elaborate steroids, including aldosterone, with the result that is more concentrate in the vascular tissue than in the circulation [16]. Although aldosterone has lower affinity for glucocor- 0167-0115/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2004.03.016 Abbreviations: CGRP, calcitonin gene-related peptide; CGRP (8– 37), calcitonin gene-related peptide antagonist; EFS, electrical field stimulation; L-NAME, N G -nitro-arginine-methyl-esther; NA, noradrenaline; NO, nitric oxide; SHR, spontaneously hypertensive rat; WKY, Wistar Kyoto rat. * Corresponding author. Tel.: +34-1-4975450; fax: +34-1-4975353. E-mail address: gloria.balfagon@uam.es (G. Balfago ´n). www.elsevier.com/locate/regpep Regulatory Peptides 120 (2004) 253 – 260