Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

Yamamoto, Hiroshi; Lee, Charlotte E.; Marcus, Jacob; Williams, Todd D.; Overton, J. M.; Lopez, Marisol E.; Hollenberg, Anthony N.; Baggio, Laurie L.; Saper, Clifford B.; Drucker, Daniel J.; Elmquist, Joel K.

doi:10.1172/jci0215595

Cited by 400 publications

(105 citation statements)

References 45 publications

(14 reference statements)

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“…GLP-1 (7–36) also had no effect on systolic, diastolic or mean blood pressure relative to identically handled time control animals in non-ischemic hearts. This lack of a pressor effect in otherwise healthy hearts is consistent with previous investigations in human subjects [7;24;32;33;35], but contrasts findings in rodent models which largely report hypertensive effects of GLP-1 [4–6;8;15;19;39]. However, we did observe significant reductions in blood pressure in GLP-1 (7–36) treated swine during regional myocardial ischemia (Figure 1).…”

Section: Discussionsupporting

confidence: 91%

Glucagon-like peptide-1 (7–36) but not (9–36) augments cardiac output during myocardial ischemia via a Frank–Starling mechanism

et al. 2014

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This study examined the cardiovascular effects of GLP-1 (7–36) or (9–36) on myocardial oxygen consumption, function and systemic hemodynamics in vivo during normal perfusion and during acute, regional myocardial ischemia. Lean Ossabaw swine received systemic infusions of saline vehicle or GLP-1 (7–36 or 9–36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose, followed by ligation of the left circumflex artery during continued infusion at 10.0 pmol/kg/min. Systemic GLP-1 (9–36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. Systemic GLP-1 (7–36) exerted no cardiometabolic or hemodynamic effects prior to ischemia. During ischemia, GLP-1 (7–36) increased cardiac output by approximately 2 L/min relative to vehicle-controls (p=0.003). This response was not diminished by treatment with the non-depolarizing ganglionic blocker hexamethonium. Left ventricular pressure-volume loops measured during steady state conditions with graded occlusion of the inferior vena cava to assess load-independent contractility revealed that GLP-1 (7–36) produced marked increases in end diastolic volume (74 ± 1 to 92 ± 5 mL; p=0.03) and volume axis intercept (8 ± 2 to 26 ± 8; p=0.05), without any change in the slope of the end systolic pressure volume relationship vs. vehicle during regional ischemia. GLP-1 (9–36) produced no changes in any of these parameters compared to vehicle. These findings indicate that short-term systemic treatment with GLP-1 (7–36) but not GLP-1 (9–36) significantly augments cardiac output during regional myocardial ischemia, via increases in ventricular preload without changes in cardiac inotropy.

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Section: Discussionsupporting

confidence: 91%

Glucagon-like peptide-1 (7–36) but not (9–36) augments cardiac output during myocardial ischemia via a Frank–Starling mechanism

et al. 2014

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“…GLP-1 has been shown to increase blood pressure and heart rate in rats [35,36] although others failed to demonstrate any hemodynamic changes in the porcine models [37,38] and human studies [39–42]. In addition, Bose et al .…”

Section: Discussionmentioning

confidence: 99%

Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3

Tsutsumi

Hamaguchi

et al. 2014

Cardiovasc Diabetol

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BackgroundExendin-4, an exogenous glucagon-like peptide-1 receptor (GLP-1R) agonist, protects the heart from ischemia/reperfusion injury. However, the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for exendin-4 induced cardiac protection using in vitro and in vivo studies in control and caveolin-3 (Cav-3) knockout mice (Cav-3 KO).MethodsMyocytes were treated with exendin-4 and then incubated with methyl-β-cyclodextrin (MβCD) to disrupt caveolae formation. This was then followed by simulated ischemia/reperfusion (SI/R). In addition, cardiac protection in vivo was assessed by measuring infarct size and cardiac troponin levels.ResultsExendin-4 protected cardiac myocytes (CM) from SI/R [35.6 ± 12.6% vs. 64.4 ± 18.0% cell death, P = 0.034] and apoptosis but this protection was abolished by MβCD (71.8 ± 10.8% cell death, P = 0.004). Furthermore, Cav-3/GLP-1R co-localization was observed and membrane fractionation by sucrose density gradient centrifugation of CM treated with MβCD + exendin-4 revealed that buoyant (caveolae enriched) fractions decreased Cav-3 compared to CM treated with exendin-4 exclusively. Furthermore, exendin-4 induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 25.1 ± 8.2% vs. 41.4 ± 4.1%, P < 0.001; troponin: 36.9 ± 14.2 vs. 101.1 ± 22.3 ng/ml, P < 0.001). However, exendin-4 induced cardiac protection was abolished in Cav-3 KO mice (infarct size: 43.0 ± 6.4%, P < 0.001; troponin: 96.8 ± 26.6 ng/ml, P = 0.001).ConclusionsWe conclude that caveolae and caveolin-3 are critical for exendin-4 induced protection of the heart from ischemia/reperfusion injury.

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“…The protocol used for combined immunohistochemistry and in situ hybridization is a modification of previously described protocols (Chan et al, 1995; Chan and Sawchenko, 1995; Kelly and Watts, 1996; Elias et al, 1998; Yamamoto et al, 2002, 2003; Liu et al, 2003). Free-floating tissue was rinsed with DEPC-treated PBS, pH 7.0, for 1 hour before pretreatment with 0.1% sodium borohydride (Sigma) in DEPC-PBS for 15 minutes.…”

Section: Methodsmentioning

confidence: 99%

Expression of the diabetes‐associated gene TCF7L2 in adult mouse brain

Lee

Elias

et al. 2009

J of Comparative Neurology

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Polymorphisms of the gene TCF7L2 (transcription factor 7-like 2) are strongly associated with the development and progression of type 2 diabetes. TCF7L2 is important in the development of peripheral organs such as adipocytes, pancreas, and the intestine. However, very little is known about its expression elsewhere. In this study we used in situ hybridization histochemistry to show that TCF7L2 has a unique expression pattern in the mouse brain. TCF7L2 is expressed in two distinct populations. First, it is highly ex pressed in thalamic and tectal structures. Additionally, TCF7L2 mRNA is expressed at moderate to low levels in specific cells of the hypothalamus, preoptic nucleus, and circumventricular organs. Collectively, these patterns of expression suggest that TCF7L2 has distinct functions within the brain, with a general role in the development and maintenance of thalamic and midbrain neurons, and then a distinct role in autonomic homeostasis.

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Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

Cited by 400 publications

References 45 publications

Glucagon-like peptide-1 (7–36) but not (9–36) augments cardiac output during myocardial ischemia via a Frank–Starling mechanism

Glucagon-like peptide-1 (7–36) but not (9–36) augments cardiac output during myocardial ischemia via a Frank–Starling mechanism

Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3

Expression of the diabetes‐associated gene TCF7L2 in adult mouse brain

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