The effects of interleukin-6 on the contraction and relaxation responses of the cavernous smooth muscle from rats

https://doi.org/10.1016/j.ejphar.2008.04.053Get rights and content

Abstract

The purpose of this study is to elucidate the effect of IL-6 on the vasomotor reactivity of the corpus cavernosum of the rats. The strips were either left untreated or treated with 1 ng/ml of IL-6 for 60 min. By increasing concentrations of phenylephrine, acetylcholine, or sodium nitroprusside, we assessed concentration–contraction or relaxation responses. The IL-6-treated strips were incubated for 30 min with or without l-NAME (NW-nitro-l-arginine methyl ester), l-arginine, indomethacin, BQ-123 (an endothelin receptor A inhibitor), or SQ 29,548 (a thromboxane A2 [TXA2] receptor blocker), and the effects on phenylephrine-induced contraction or acetylcholine-induced relaxation of phenylephrine-induced contraction were measured. The contractile responses to phenylephrine were significantly enhanced in the IL-6-treated strips, compared with the IL-6-nontreated strips, and the relaxation responses to acetylcholine were significantly inhibited in the IL-6-treated group compared with the IL-6-nontreated group. But after endothelial denudation, there was no difference between the IL-6-treated strips and the IL-6-nontreated strips on the contraction–relaxation responses to phenylephrine or acetylcholine. The relaxation responses to sodium nitroprusside were not inhibited in both groups. l-NAME completely inhibited the relaxation response to acetylcholine in the IL-6-treated strips, as well as the IL-6-nontreated strips. Indomethacin and SQ 29,548 significantly inhibited the increased contractile responses to phenylephrine in the IL-6-treated strips. But BQ 123 rarely affected the same responses. l-arginine reversed the inhibited relaxation responses to acetylcholine in the IL-6-treated strips. Therefore, IL-6 inhibits endothelium-dependent, NO-mediated relaxation and also enhances α1-adrenergic receptor-mediated contraction via an endothelium-dependent TXA2-mediated mechanism in the corpus cavernosum of the rat.

Introduction

The severity of erectile dysfunction has been correlated with the number and intensity of risk factors for atherosclerosis (Bortolotti et al., 1997, Feldman et al., 1994, Roumeguere et al., 2003). The mean rate of erectile dysfunction was 57% in patients with coronary artery disease (Feldman et al., 1994, Morley et al., 1988). Erectile dysfunction has similar pathogenic progression with other vascular diseases. Early impairment of endothelium-dependent vasodilation (endothelial dysfunction) appears first, followed by late obstruction of the vascular lumen (Azadzoi and Goldstein, 1992, Sullivan et al., 1999). Endothelial cells contribute to the regulation of vascular tone by releasing vasoactive factors such as vasodilators; nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin and vasoconstrictors; endothelin-1, thromboxane A2 (TXA2), prostaglandin H2, radical superoxide anion, components of the renin–angiotensin system. Endothelial dysfunction refers to an imbalance in the production or bioavailability of endothelial vasodilating factors. These vasoactive factors are released under the influence of cytokines (Vila and Salaices, 2005).

Interleukin (IL)-6, a pro-inflammatory cytokine, has been shown to have endocrine roles as well as autocrine and paracrine (Papanicolaou and Vgontzas, 2000), and is a major mediator in the induction of the acute phase response (Nomura et al., 2000). IL-6 modulate arterial vascular tone via endothelium-dependent mechanisms. Therefore, IL-6 may significantly modify blood supply to inflamed or ischemic tissues with elevated local concentrations of IL-6 (Iversen et al., 1999). Subchronic in vivo treatment with IL-1 and IL-6 impaired the reduction of perfusion pressure induced by acetylcholine (De Salvatore et al., 2003).

In a clinical trial, low grade systemic inflammation was shown to play a role in hypertension. Incremental changes of systolic and diastolic blood pressures, pulse pressure, and mean arterial pressure were significantly associated with IL-6 level (Chae et al., 2001). Giugliano et al. (2004) reported that circulating concentrations of pro-inflammatory cytokines such as IL-6, IL-8, and IL-18 did not differ in obese men with erectile dysfunction compared with obese men without erectile dysfunction but circulating C-reactive protein levels were significantly higher in obese men with erectile dysfunction than in potent obese men (Giugliano et al., 2004). However, we thought that this study was not well controlled for other risk factors and other inflammatory markers. In a recent relatively well controlled study, the prevalence of high blood pressure increased significantly with elevated levels of IL-6. The increasing rate was higher in the lower end of the distribution of IL-6 than in the upper end. IL-6 may result in elevated blood pressure by inducing endothelial dysfunction and increasing peripheral vascular resistance (Bautista et al., 2005). These results support the notion that IL-6 can modulate vascular tone. Hence, we set up the postulation that IL-6 may impair relaxation of the corpus cavernosum through endocrine or paracrine action in high circulating IL-6-inducing situation.

The purpose of this study is to elucidate the effect of IL-6 on the vasomotor reactivity of the corpus cavernosum of the rats.

Section snippets

Preparation of rat corpus cavernosum strips and tension recording

A total of 25 male Sprague–Dawley rats weighing 200–250 g were used throughout the study. Experiments were performed in accordance with the recommendations of the Committee for the Protection of Persons and Animals at the Institute of Medical Science, Chung-Ang University, Seoul, and Republic of Korea. The rats were blacked out by infusion into a tight container with 100% CO2 gas for 1 min, and were then killed instantly by a cut to the carotid artery. Penises were surgically removed at the

Contraction–relaxation responses by phenylephrine or acetylcholine on rat corpus cavernosum strips either nontreated or treated with IL-6

IL-6-treated strips were significantly different from IL-6-nontreated strips on the contraction–relaxation responses by phenylephrine or acetylcholine. The contractile responses to phenylephrine concentrations, 10 7, 10 6, 10 5, and 10 4 M, respectively, were significantly enhanced in the IL-6-treated strips than the IL-6-nontreated strips (P < 0.05). EC50 and maximal contraction value in the IL-6-nontreated strips was 5.48 × 10 6 ± 1.06 × 10 7 M and 1.19 ± 0.09 mN respectively, and EC50 and maximal

Discussion

The effects of cytokines on vascular reactivity seem to rely on the exposure time, and are dependent on mediator release. Cytokines can induce synthesis of endothelin-1, a vasoconstrictor, and also induces the expression of several enzymes that release mediators that act to relax (PGI2, PGE2, NO) or contract (PGH2, TXA2) arteries. Cytokines can also increase the production of oxygen radicals, which reduce the bioavailability of endothelial NO (Vila and Salaices, 2005). IL-6 can inhibit eNOS

Conclusions

IL-6 inhibits endothelium-dependent, NO-mediated relaxation, and also enhances α1-adrenergic receptor-mediated contraction via an endothelium-dependent TXA2-mediated mechanism in the corpus cavernosum of the rat.

Although further studies are necessary to reveal the role of IL-6, as well as other cytokines, in erectile dysfunction during vascular inflammatory or other stressful conditions, an IL-6 receptor antagonist that has been developed recently may be a possible adjuvant therapeutic modality

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