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  • br In vivo actions of GLP GLP R agonists

    2022-01-17


    In vivo actions of GLP-1/GLP-1R agonists on the vascular endothelium Using contrast-enhanced ultrasound, male Sprague Dawley rats receiving an intravenous infusion of native GLP-1 (30 pmol/kg/min) for 2 h demonstrated significant improvements in both microvascular blood volume and microvascular blood flow [12]. This improvement resulted in increased muscle tetraethylammonium receptor utilization, insulin uptake, and interstitial oxygenation, as well as increases in circulating NO levels. Similar findings have been reported in male Sprague Dawley rats fed a high fat diet for 4 weeks to induce insulin resistance [13]. Of interest, these vascular/endothelial actions of GLP-1 were dependent on both PKA and NOS activity, as they could be prevented by either co-infusion with H89 (160 pmol/kg/min) or L-NAME (50 μg/kg/min) [12,16]. Conversely, femoral artery infusion of GLP-1 (1 pmol/kg/min) significantly augmented microvascular recruitment in vastus lateralis muscles from overnight-fasted healthy young men, but failed to stimulate muscle glucose uptake [52]. Reasons for these discrepancies remain enigmatic, but could stem from species differences (rats versus humans), dose differences (30 pmol/kg/min versus 1 pmol/kg/min), or the fact that the rat studies did not control for GLP-1 mediated insulin secretion. The above-described human studies included a group of volunteers co-infused with octreotide to suppress the insulinotropic effect of GLP-1, which did not prevent the GLP-1 effect on microvascular recruitment in vastus lateralis muscle. As the above-described rat studies did not include a group of GLP-1 rats co-infused with octreotide, the GLP-1-induced increase in muscle glucose utilization the authors observed could be a combination of both GLP-1 mediated increases in microvascular recruitment and insulin secretion. The vascular/endothelial actions of GLP-1/GLP-1R agonists also demonstrate protection against hypertension and/or atherosclerosis. For example, treatment with exendin-4 (20 nmoL/kg twice daily) for 12 weeks significantly reduced systolic blood pressure (SBP) in hypertensive db/db mice provided with 2% salt in their drinking water [24]. Moreover, osmotic pump-mediated subcutaneous infusion of exendin-4 (1 μg/kg/day) for 1 week reversed corticosterone-induced increases in SBP and diastolic BP (DBP) in rats, findings which were independent of changes in body weight and caloric intake [33]. These beneficial actions of GLP-1/GLP-1R agonists also translate to the angiotensin II-infusion model of hypertension, as twice tetraethylammonium receptor daily treatment with liraglutide (30 μg/kg) markedly reduced both SBP and DBP in angiotensin II-infused male C57BL/6J mice. Of interest, these findings were dependent on liraglutide-induced atrial natriuretic peptide (ANP) secretion, since liraglutide treatment increased circulating ANP levels and failed to lower SBP/DBP in ANP deficient mice [31]. With regards to experimental atherosclerosis, a continuous infusion of exendin-4 (300 pmoL/kg/day or 24 nmol/kg/day) for 28 days reduced atherosclerotic lesion size in non-diabetic C57BL/6 and ApoE-/- mice [2]. The authors attributed these salutary effects to direct actions on macrophages, as exendin-4 treatment reduced inflammatory marker gene expression (Mcp1 and Tnfa) in peritoneal macrophages harvested from mice following treatment with 3% thioglycolate. However, it remains equivocal whether macrophages express the GLP-1R [17], and the authors never considered whether direct vascular actions of GLP-1R agonism could explain the attenuation of atherosclerosis. Indeed, Jojima et al. infused high-cholesterol fed ApoE-/- mice with liraglutide (150 μg/kg/day or 400 μg/kg/day) for 4 weeks and also saw a reduction in atherosclerotic lesion size, which they attributed to liraglutide-induced activation of AMPK in VSMCs, thereby reducing VSMC proliferation [29]. Lixisenatide has also been demonstrated to confer protection against atherosclerosis, as a 2-month subcutaneous infusion with lixisenatide (10 μg/kg/day) decreased aortic arch lesion size in high-cholesterol fed ApoE-/- mice that were also heterozygous for insulin receptor substrate 2 protein [60]. Moreover, lixisenatide treatment also improved plaque stability as determined by decreased plaque collagen content and increased plaque fibrous cap thickness. The authors also observed reduced macrophage content in the atherosclerotic plaque, but it remains uncertain whether these results were due to the overall systemic metabolic improvements elicited by lixisenatide, or whether direct actions on macrophages were involved. Interestingly, these authors also included a liraglutide treatment arm (400 μg/kg/day) in their studies, which produced similar actions on aortic arch lesion size, but had negligible actions on plaque stability.