Elsevier

Neuroscience

Volume 150, Issue 3, 12 December 2007, Pages 730-741
Neuroscience

Systems neuroscience
Angiotensin II type 2 receptors facilitate reinnervation of phenol-lesioned vascular calcitonin gene-related peptide–containing nerves in rat mesenteric arteries

https://doi.org/10.1016/j.neuroscience.2007.09.026Get rights and content

Abstract

The present study was designed to investigate involvement of angiotensin II (Ang II) type 2 receptors (AT2 receptors) in restoration of perivascular nerve innervation injured by topical phenol treatment. Male Wistar rats underwent in vivo topical application of 10% phenol around the superior mesenteric artery. After phenol treatment, animals were subjected to immunohistochemistry of the third branch of small arteries, Western blot analysis of AT2 receptor protein expression in dorsal root ganglia (DRG) and studies of mesenteric neurogenic vasoresponsiveness. Ang II (750 ng/kg/day), nerve growth factor (NGF; 20 μg/kg/day) and PD123,319 (AT2 receptor antagonist; 10 mg/kg/day) were intraperitoneally administered for 7 days using osmotic mini-pumps immediately after topical phenol treatment. Losartan (AT1 receptor antagonist) was administered in drinking water (0.025%). Phenol treatment markedly reduced densities of both calcitonin gene-related peptide (CGRP)–like immunoreactivity (LI) and neuropeptide Y (NPY)–LI-containing fibers. NGF restored densities of both nerve fibers to the sham control level. Coadministration of Ang II and losartan significantly increased the density of CGRP-LI-fibers but not NPY-LI-fibers compared with saline control. The increase of the density of CGRP-LI-fibers by coadministration of Ang II and losartan was suppressed by adding PD123,319. Coadministration of Ang II and losartan ameliorated reduction of CGRP nerve-mediated vasodilation of perfused mesenteric arteries caused by phenol treatment. The AT2 receptor protein expression detected in DRG was markedly increased by NGF. These results suggest that selective stimulation of AT2 receptors by Ang II facilitates reinnervation of mesenteric perivascular CGRP-containing nerves injured by topical phenol application in the rat.

Section snippets

Experimental animals

Eight-week-old Wistar rats (purchased from Shimizu Experimental Animals, Shizuoka, Japan) were used in this study. The animals were given food and water ad libitum. They were housed in the Animal Research Center of Okayama University at a controlled ambient temperature of 22 °C with 50±10% relative humidity and with a 12-h light/dark cycle (lights on at 8:00 AM). This study was carried out in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research

Changes in SBP after phenol treatment

Fig. 1 shows the tail-cuff SBP in the six groups for 7 days after topical phenol or vehicle (sham) treatment. The Ang II group (Ph+Ang II) showed significantly increased blood pressure from 4 days after Ang II administration compared with the saline control group (Ph+Saline). Losartan administration (Ang II+Los and Ang II+Los+PD) completely inhibited the increase of blood pressure induced by Ang II.

Changes in innervation of CGRP-LI nerve fibers in mesenteric arteries following topical phenol treatment with or without administration of each drug

Fig. 2 and Fig. 3 show typical images of innervation of CGRP-LI nerves and changes in the density

Discussion

The present study is the first to demonstrate that activation of AT2 receptors facilitates reinnervation of perivascular CGRP-LI nerves, but not NPY-LI nerves, in the rat mesenteric artery, that was lesioned by topical application of phenol. Our recent report showed evidence that topical treatment with phenol around the rat superior mesenteric artery induced a marked reduction of innervation of perivascular NPY- and CGRP-containing nerves in the distal small artery (Hobara et al., 2006).

Conclusion

In conclusion, the present study suggests that AT2 receptors play an important role in the process of regeneration of CGRPergic nerves, which innervate mesenteric resistance arteries of the rat. We have reported that CGRPergic nerve innervation in SHR decreases with age and that long-term administration of AT1 receptor antagonist in SHR prevents the age-related decreases in function and distribution of CGRPergic nerves (Kawasaki et al 1990b, Hobara et al 2005). Therefore, we hypothesize that

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