It has been demonstrated in reflex-intact animals that the sensitivity to calcitonin gene-related peptide (CGRP) is increased during pregnancy and that this action is mediated by sex steroids but not by nitric oxide (NO). We assessed the effects of CGRP in the following groups of anesthetized ganglion-blocked rats: 1) pregnant, 2) ovariectomized, and 3) ovariectomized and treated with estradiol and progesterone. Changes in mean arterial pressure (MAP) were assessed after the administration of varying doses of CGRP. Decreases in MAP after CGRP administration were significantly greater in pregnant rats and ovariectomized rats administered sex steroids than in ovariectomized controls. The CGRP antagonist CGRP8–37 produced a pressor response of similar magnitude in both pregnant and ovariectomized rats. We also assessed the effects of CGRP and the modulating role of NO in the isolated uterine vascular bed preparation. CGRP reduced perfusion pressure to a greater degree in ovariectomized animals treated with sex steroids than in ovariectomized animals. This response was attenuated by pretreatment with an NO synthesis inhibitor. CGRP8–37 produced a similar increase in perfusion pressure in both groups. We conclude that 1) the increased vascular sensitivity observed during pregnancy or after treatment with sex steroids is in part mediated by NO, and 2) CGRP8–37 has a vasoconstrictor action of its own.

1 The isolated stomach preparation of the immature rat has been used to study the stimulation and inhibition of pepsin secretion. 2 The isolated stomach secretes a basal level of pepsin. High concentrations (10-3M) of the H2-receptor antagonist, cimetidine, and the muscarinic receptor blocking drug, atropine, did not affect this secretion in a manner which was consistently of statistical significance.3 Concentrations of histamine of 10-5M, 10-4M and 10-3M stimulated maximum levels of pepsin output of 126%, 155 % and 299% respectively of control. There was no evidence that this secretion was secondary to the stimulation of acid secretion. 4 Cimetidine (10-4M and 10-3M) produced a dose-related inhibition of the pepsin output to 10-3M histamine, suggesting that histamine H2-receptors mediate this response. 5 Atropine (10-3M) had no effect on the pepsin response to 10-3M histamine, suggesting that muscarinic mechanisms play no part, even modulatory, in this secretion.

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Diabetes and obesity are associated with dysregulated liver lipid metabolism. Glucagon has an essential role in lipid metabolism, in addition to regulating glucose homeostasis. The brain is a key coordinator of whole-body metabolism. Glucagon signalling in the mediobasal hypothalamus (MBH), a forebrain region that senses hormones and nutrients to regulate metabolism, lowers hepatic glucose production and appetite. However, whether glucagon action in the MBH affects lipid homeostasis in healthy and high-fat diet (HFD)-fed animals remains unknown. We assessed glucagon signaling in the MBH in regulating hepatic TG secretion in chow-fed normolipidemic and HFD-induced hyperlipidemic rats. Stereotaxic MBH cannulation and vascular catheterizations in Sprague-Dawley rats allowed for direct MBH infusions, intravenous (IV) injections, and blood sampling. Plasma TGs were measured in 10h-fasted rats after IV poloxamer injection with concurrent MBH infusions. MBH glucagon decreased TG secretion compared to MBH vehicle control animals. This hypothalamic effect of glucagon was blocked by a simultaneous MBH co-infusion of an antagonist to the glucagon receptor (GCGR) and by protein kinase A (PKA) inhibition in the MBH in chow-fed rats. Direct MBH infusion of a PKA activator recapitulated the TG-lowering effects of MBH glucagon. Together, this suggests that MBH glucagon signals via a MBH GCGR-PKA pathway. Interestingly, both MBH glucagon and MBH PKA activation lowered TG secretion and plasma FFAs in HFD-induced hyperlipidemic animals. However, MBH glucagon did not affect hepatic TG content or liver lipogenic protein levels of MTP, FAS, or pACC:ACC of RC and HFD rats compared to their MBH vehicle controls. We demonstrate that hypothalamic glucagon modulates hepatic TG secretion via a MBH GCGR-PKA signalling pathway, and activating MBH glucagon signalling improves lipid metabolism in hyperlipidemic rats. These findings may provide therapeutic insight on lowering lipids in hyperlipidemia. Disclosure M. S. Grewal: None. B. Vasilev: None. C. M. Soltys: None. B. Lum: None. J. T. Yue: None. Funding Canadian Institutes of Health Research (PJT-378765); Canada Foundation for Innovation (37267); Canada Research Chairs Tier 2 in Brain Regulation of Metabolism