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Peripheral Corticotropin-Releasing Factor Receptor Type 2 Activation Increases Colonic Blood Flow Through Nitric Oxide Pathway in Rats

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Abstract

Background

Corticotropin-releasing factor (CRF) peptides exert profound effects on the secretomotor function of the gastrointestinal tract. Nevertheless, despite the presence of CRF peptides and receptors in colonic tissue, their influence on colonic blood flow (CBF) is unknown.

Aim

To determine the effect and mechanism of members of the CRF peptide family on CBF in isoflurane-anesthetized rats.

Methods

Proximal CBF was measured with laser-Doppler flowmetry simultaneously with mean arterial blood pressure (MABP) measurement. Rats were injected with intravenous human/rat CRF (CRF1 > CRF2 affinity), mouse urocortin 2 (mUcn2, selective CRF2 agonist), or sauvagine (SVG, CRF2 > CRF1 affinity) at 1–30 µg/kg. The nitric oxide (NO) synthase inhibitor, L-NAME (3 mg/kg, iv), the cyclooxygenase inhibitor, indomethacin (Indo, 5 mg/kg, ip), or selective CRF2 antagonist, astressin2-B (Ast2B, 50 µg/kg, iv) was given before SVG injection (10 µg/kg, iv).

Results

SVG and mUcn2 dose-dependently increased CBF while decreasing MABP and colonic vascular resistance (CVR). CRF had no effect on CBF, but increased CVR. The hyperemic effect of SVG was inhibited by L-NAME but not by Indo, whereas hypotension was partially reduced by L-NAME. Sensory denervation had no effect on SVG-induced changes. Ast2B inhibited SVG-induced hyperemia and decreased CVR, and partially reduced the hypotension.

Conclusions

Peripheral CRF2 activation induces colonic hyperemia through NO synthesis, without involving prostaglandin synthesis or sensory nerve activation, suggesting a direct action on the endothelium and myenteric neurons. Members of the CRF peptide family may protect the colonic mucosa via the activation of the CRF2 receptor.

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Acknowledgments

We would like to thank Dr. Yvette Taché (UCLA) and Dr. Jean Rivier (Salk Institute, Peptide Laboratories) for their suggestions and peptide supply. Authors received study support from NIHDDK-41303 Animal Model Core (MM, JDK), NIHDDK DK 57238-01A1S1 & DK078676 (MM), Department of Veterans Affairs Merit Review Award, and NIH-NIDDK RO1 DK54221 (JDK).

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Authors and Affiliations

  1. CURE: Digestive Diseases Research Center; Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Yasutada Akiba, Jonathan D. Kaunitz & Mulugeta Million

  2. VA Greater Los Angles Healthcare System, 11301 Wilshire Boulevard, Building 114, Room 217, Los Angeles, CA, 90073, USA

    Yasutada Akiba & Jonathan D. Kaunitz

  3. Brentwood Biomedical Research Institute, Los Angeles, CA, 90073, USA

    Yasutada Akiba & Jonathan D. Kaunitz

  4. VA Greater Los Angles Healthcare System, 11301 Wilshire Boulevard, Building 115, Room 118B, CURE Box 951792, Los Angeles, CA, 90073, USA

    Mulugeta Million

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  1. Yasutada Akiba
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Correspondence to Mulugeta Million.

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Akiba, Y., Kaunitz, J.D. & Million, M. Peripheral Corticotropin-Releasing Factor Receptor Type 2 Activation Increases Colonic Blood Flow Through Nitric Oxide Pathway in Rats. Dig Dis Sci 60, 858–867 (2015). https://doi.org/10.1007/s10620-015-3579-y

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