Impact of caveolin-1 knockout on NANC relaxation in circular muscles of the mouse small intestine compared with longitudinal muscles

Abstract

. Impact of caveolin-1 knockout on NANC relaxation in circular muscles of the mouse small intestine compared with longitudinal muscles. Am J Physiol Gastrointest Liver Physiol 290: G394 -G403, 2006. First published September 15, 2005 doi:10.1152/ajpgi.00321.2005.-Recently, we showed that caveolin-1 (cav1) knockout mice (Cav1 Ϫ/Ϫ mice) have impaired nitric oxide (NO) function in the longitudinal muscle (LM) layer of the small intestine. The defect was a reduced responsiveness of the muscles to NO compensated by an increase in the function of apamin-sensitive, nonadrenergic, noncholinergic (NANC) mediators. In the present study, we examined similarly the effects of cav1 knockout on the relaxation in circular muscle (CM) of the mouse small intestine. CM of Cav1Ϫ/Ϫ mice also showed defective NO function, but less than in LM, as well as more activation of apamin-sensitive NANC mediators. CM of Cav1Ϫ/Ϫ mice, like LM, lacked cav1 but retained small amounts of cav3 and caveolae in the outer CM layer. In addition, we also examined the effects of a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-␣]quinazolin-1-one (ODQ), on electric field stimulation (EFS)-mediated relaxation in both LM and CM. ODQ had an effect similar to the block of NO synthesis. Moreover, we compared the actions of two NO donors in the LM and CM of control and Cav1 Ϫ/Ϫ mice. Similar to LM, CM of Cav1 Ϫ/Ϫ mice showed a reduced responsiveness to the NO donors sodium nitroprusside and S-nitroso-N-acetyl penicillamine. However, both ODQ and apamin blocked the inhibitory effects of the NO donors in LM, whereas apamin had no effect in CM. In conclusion, cav1 knockout affects NO function in both LM and CM, but its effects in CM differ significantly.

Caveolin-1 knockout alters β-adrenoceptors function in mouse small intestine

“…In addition, cAMP was postulated to produce relaxation in the intestinal smooth muscles by PKA-independent mechanisms such as the activation of uncoupling protein 1 (45) or cross activation of PKG (28). In previous studies, we showed that smooth muscle relaxation downstream of nitric oxide is reduced in cav1 Ϫ/Ϫ as a result of a defective soluble guanylate cyclase function (11,12), but the function of PKG was not tested.…”

“…We also found that caveolin-1 knockout (cav1 Ϫ/Ϫ ) mice, which lack caveolin-1 and most caveolae, have an altered response to nitric oxide and other nonadrenergic, noncholinergic mediators in the small intestine (11,12). In the present study, we investigated alterations of GIT motility in the cav1 Ϫ/Ϫ mice small intestine associated with ␤-adrenoceptor function.…”

Caveolins: targeting pro-survival signaling in the heart and brain

“…Mice deficient in Cav-1 display increased nitric oxide (NO) production from increased eNOS activity (Razani et al, 2001) with resultant increased vascular permeability in mouse lung endothelium (El-Yazbi et al, 2006), both of which are reversed by injection of a truncated Cav-1 peptide containing the CSD. Inhibition of eNOS by caveolin occurs within the systemic vascular endothelium, whereby eNOS activity does not respond to regulatory signals, NO levels remain increased, and basal cGMP levels remain elevated in rings of aorta from Cav-1 deficient mice (Drab et al, 2001; Razani et al, 2001).…”

Caveolae and calcium handling, a review and a hypothesis

“…In caveolin1 knockout animals, there is both a loss of the myogenic nNOS isoform and also a reduced NO mediated relaxation to nerve stimulation, compensated in part by an increased response of apamin sensitive inhibitory mediators [52,53]. The site of failure appears to be downstream from mediator release and associated with decreased responses to NO donors, sodium nitroprusside and S-nitroso-Nacetyl penicillamine.…”