Response to Letter to the Editor: “Hemodynamic Effects of Glucagon: A Literature Review” Free

We appreciate the clarification provided by Hernández-Cascales (1) regarding glucagon receptor expression in the Sprague-Dawley rat heart and hemodynamic effects of glucagon. We agree that differences in glucagon receptor expression in rat cardiac tissues may explain the observed differences in the studies by Hernández-Cascales (1) and we consider alterations in sampling (i.e., using different tissues) as part of a change in experimental design. We also agree that looking solely at the studies performed by Hernández-Cascales (1) does not illustrate differences between species, but we still believe that these differences are very important and worth mentioning in relation to preclinical data. Interspecies differences in heart expression of important class B G protein-coupled receptors [i.e., receptors for glucagon, glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2)] are becoming increasingly apparent, and evidenced by studies showing the presence of functional glucagon receptors (GCGR), but not GLP-1 receptors in left ventricles of mice (2), and ventricular GCGR in rats [as mentioned by Gonzalez-Muñoz et al. (3)], but no GCGR and abundant GLP-1 receptor expression in human left ventricular tissue (4). The sporadic cardiac GCGR expression primarily in atrial tissue and lack of glucagon receptors in the left ventricle (4) do not readily align (as alluded to by Hernández-Cascales) with some of the clinical studies reporting that high-dose glucagon led to increases in cardiac output/index, stroke volume, and left ventricular contractility, with and without concomitant heart rate increase (5, 6). The effect on stroke volume and left ventricular contractility observed in the human studies may therefore be artifacts or possibly owing to off-target effects of rather high (mg) doses of glucagon [e.g., engaging other receptors such as the GLP-1 receptor (which is also expressed with large interspecies differences and not evaluated by Hernández-Cascales)] or other targets (e.g., increased plasma epinephrine and norepinephrine levels) (7).

Although we agree with Hernández-Cascales (1) that chronotropic effects are generally observed in humans as well as rodents after glucagon administration, the extrapolation from findings in rats to clinical beta-blocker overdose in humans should be undertaken with caution. The clinical studies with glucagon in heart failure as well as the anecdotal reports of reversal of drug-induced bradycardia were without relevant control groups and glucagon was often used together with other chronotropic therapies. In addition, the response to glucagon when used as an antidote is variable, and lack of effect of glucagon has also been reported (8). A randomized human clinical trial evaluating the hemodynamic effects of the glucagon doses recommended for the treatment of beta-blocker poisonings is clearly warranted.

Acknowledgments

Disclosure Summary: The authors have nothing to disclose.

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