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

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 mucosal via the activation of the CRF2 receptor.

Corticotropin-Releasing Hormone Receptor 2 Gene Variants in Irritable Bowel Syndrome

“…Loss of CRHR2 leads to increased inflammation, delayed healing, and exacerbates the inflammatory insult [ 47 – 49 ]. Akiba et al reported that peripheral CRHR2 activation induces colonic hyperemia through nitric oxide synthesis without involving prostaglandin synthesis or sensory nerve activation and may protect the colonic mucosa [ 50 ]. In a recent study, low grade inflammation was observed in the colonic mucosa of IBS patients [ 51 ].…”

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“…This is believed to involve the peripheral neurons and the spinal cord as increased activity of inferior splanchnic nerve and phosphorylation of Erk in laminae II and I were recorded. Another mechanism that may contribute to the inhibitory role of CRF 2 is by inducing colonic hyperemia through nitric oxide pathway upon activation5 [129]. However, other studies indicate that both CRF receptors contribute to the visceral pain by increasing the epithelial permeability, as mentioned above.…”

Cardiovascular Effects of Urocortin-2: Pathophysiological Mechanisms and Therapeutic Potential

“…In vivo, the effects tend to vary according to the species and vascular bed. In rats, several studies have shown consistent dose-dependent decreases in blood pressure (BP) after Ucn-2 infusion [51,[42][43][44]52]. In this specie, Ucn-2 appears to induce marked mesenteric vasodilatation, while it produces an inconsistent renal vasodilation, indicating less powerful coupling of CRF-R2 receptors in the renal vascular bed.…”