Effect of capsaicin on plasma and tissue levels of insulin-like growth factor-I in spontaneously hypertensive rats

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Abstract

Objective

Plasma levels of insulin-like growth factor-I (IGF-I), an important substance for maintaining cardiovascular homeostasis, are lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar Kyoto rats (WKY). Calcitonin gene-related peptide (CGRP) increases IGF-I production in vitro and in vivo, suggesting that stimulation of sensory neurons might increase the production of IGF-I in SHR.

Design

Levels of CGRP and IGF-I in plasma, kidneys and heart in WKY and SHR and cellular cyclic AMP levels in dorsal root ganglion neurons (DRGs) isolated from WKY and SHR were measured by an ELISA-based method.

Results

Levels of CGRP and IGF-I in plasma, kidneys and heart of SHR were about half of those of WKY. Administration of capsaicin significantly increased levels of CGRP and IGF-I in plasma and tissues of SHR to the levels in WKY and these increases were completely reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation. CGRP release and cellular levels of cAMP in DRGs isolated from SHR were significantly lower than those in DRGs isolated from WKY. Capsaicin increased both CGRP release and cellular cAMP levels in DRGs isolated from SHR to the levels in DRGs isolated from WKY.

Conclusions

Sensory neuron activation might be lower in SHR than in WKY probably due to decreased production of cAMP in sensory neurons, explaining why IGF-I levels in plasma and tissues are lower in SHR than in WKY.

Introduction

Insulin-like growth factor-I (IGF-I) is a basic peptide comprised of 70 amino acids with rather ubiquitous distribution in various tissues and cells, mediating growth-promoting actions of growth hormone (GH) and playing an important role in postnatal and adolescent growth [1]. IGF-I has been shown to have important biological activities such as promotion of differentiation of various cell types, potent anti-apoptotic activity, and an anabolic effect [2]. Cardiac abnormalities associated with GH deficiency are corrected by GH therapy, and IGF-I protects against endothelial dysfunction, atherosclerotic plaque development, insulin resistance, and ischemic myocardial damage [3], [4], suggesting that IGF-I might play critical roles in maintaining cardiovascular homeostasis.

Capsaicin-sensitive sensory neurons are nociceptive neurons that can be found in many tissues within the lining epithelia, around blood vessels, and associated with nonvascular smooth muscle and the atrial myocardium [5]. These sensory neurons release calcitonin-gene related peptide (CGRP) on activation of vanilloid receptor-1 (VR-1) by a wide variety of noxious physical and chemical stimuli [6], thereby exerting sensory-efferent functions. CGRP, a 37-amino acid neuropeptide, is produced in dorsal root ganglion neurons (DRGs) by tissue-specific alternative processing of the calcitonin gene [7] and it has potent vasodilatory activity [8]. Vignery et al. [9] reported that CGRP increases IGF-I production by increasing cAMP levels in primary fetal rat osteoblasts in vitro. We recently demonstrated that topical application of capsaicin increases dermal IGF-I levels in mice [10]. These observations strongly suggested that sensory neuron activation might increase IGF-I production.

Spontaneously hypertensive rats (SHR) show various cardiovascular abnormalities including hypertension, heart failure [11], endothelial dysfunction and insulin resistance [12]. Since neuronal synthesis and release of CGRP are decreased in SHR [13], [14] and serum IGF-I levels are significantly lower in SHR than in control normotensive rats [15], it is possible that decreased release of CGRP results in reduction of IGF-I production, thereby contributing to the development of cardiovascular abnormalities in SHR. Consistent with this hypothesis is our previous report demonstrating that administration of capsaicin normalizes blood pressure in SHR by increasing CGRP release from sensory neurons [16].

In the present study, we examined whether activation of sensory neurons by capsaicin increases IGF-I production in SHR. Based on these observations, we propose that capsaicin administration might contribute to the maintenance of cardiovascular homeostasis by increasing IGF-I production in hypertensive patients.

Section snippets

Reagents

Capsaicin and capsazepine (CPZ), a VR-1 antagonist, were purchased from Sigma Chemical Co. (St. Louis, MO). All other reagents were of analytical grade.

Administration of capsaicin and CPZ

Capsaicin and CPZ were dissolved in 10% Tween 20/10% ethanol (10%) with normal saline. Capsaicin (1 mg/kg) and CPZ (15 mg/kg) were administered subcutaneously to male WKY and SHR (BW 280–320 g) aged 14 weeks as described previously [16], [17].

Determination of renal, cardiac, and plasma levels of CGRP

Renal and cardiac tissue levels and plasma levels of CGRP were determined in rats as described previously

Plasma, renal and cardiac tissue levels of CGRP and IGF-I in WKY and SHR

Plasma, renal and cardiac tissue levels of CGRP and IGF-I were determined in WKY and SHR (Fig. 1). Plasma levels of CGRP in SHR were about 60% of those in WKY (Fig. 1a). Renal and cardiac tissue levels of CGRP in SHR were about half of those in WKY (Fig. 1b and c). Plasma levels of IGF-I in SHR were also about half of those in WKY (Fig. 1d), while renal and cardiac tissue levels of IGF-I in SHR were about one-third of those in WKY (Fig. 1e and f).

Effect of capsaicin and/or CPZ, an inhibitor of VR-1, on plasma, renal and cardiac tissue levels of IGF-I in SHR

When administered subcutaneously to SHR,

Discussion

In the present study, we demonstrated that plasma and tissue levels of CGRP and IGF-I were significantly lower in SHR than in WKY. These observations are consistent with a previous report by Supowit et al. [13] demonstrating that CGRP gene expression is significantly lower in SHR than in WKY. Komiyama et al. [15] also demonstrated that serum levels of IGF-I in SHR are significantly lower than those in WKY. CGRP increases IGF-I production in primary fetal rat osteoblasts [9] and capsaicin

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