SummarySince glucagon-like peptide-1 (7-36) amide (7-37) (GLP-1) has been found to be a potent insulinotropic hormone, it has been postulated that glucagon stimulates insulin secretion from islet beta cells through the GLP-1 receptor. We therefore examined the effects of a GLP-1 receptor antagonist, exendin (9-39) amide, on glucagon-or GLP-l-stimulated insulin release from isolated perfused rat pancreas. When infusion of 100 nmol/1 exendin (9-39) amide was started 5 min before that of 1 nmol/1 glucagon, the stimulation of insulin release by glucagon was similar to that found in the control situation (preinfusion with vehicle alone). By contrast, when 0.3 nmol/1 GLP-1 was used in the same experimental setting, exendin (9-39) amide clearly inhibited insulin release. These results indicate that glucagon stimulates insulin release mainly through glucagon receptors but not GLP-1 receptors on islet beta cells. [Diabetologia (1995) 38: 274-276] Key words Glucagon, insulin secretion, exendin (9-39), GLP-1, pancreas perfusion.Glucagon stimulates insulin secretion from islet beta cells although its physiologic significance is not yet clear [1]. As a mechanism of this action, it had been generally accepted that insulin secretion is stimulated by glucagon directly through its own receptor on the beta cell, because specific binding sites of ~25I-glucagon have been demonstrated in hamster beta-cell tumours [2] and purified beta cells [3]. Since then however, a proglucagon gene product, glucagon-like peptide-1 (7-36) amide/(7-37) (GLP-1), was shown to stimulate insulin secretion more potently [4,5], and has been accepted as a physiologic insulin secretagogue; a candidate for incretin [6]. Specific receptors for GLP-1 have been detected on rat, mouse, and hamster insulinoma cell lines [7][8][9], and it is bound by glucagon with an affinity 100 to 1000 times lower than GLP-1 [7,8]. The insulinotropic activity of glucagon is less potent than that of GLP-1 in the same order [10], leading to the hypothesis that glucagon exhibits its insulinotropic activity through GLP-1 receptors but not glucagon receptors on islet beta cells [11]. Recently, it has been shown that exendin (9-39) amide is a potent receptor antagonist of GLP-1 [12,13]. In this study, we examined the effects of exendin (9-39) amide on GLP-1 or glucagonstimulated insulin release from isolated perfused rat pancreas in order to clarify whether or not glucagon stimulates the insulin release through its own receptor. Materials and methodsChemicals. Glucagon, GLP-1 (7-36) amide (GLP-1) and exendin (9-39) amide (exendin (9-39)) were synthesized by the stepwise solid-phase method using an automatic synthesizer (model 430A, Applied Biosystem, Foster City, Calif., USA), and then purified by high-performance liquid chromatography (HPLC). The purity of peptides was monitored by analytical reverse-phase HPLC on a column of Nucleosil 5C-18 (4.6 x 150 mm; GL Sciences, Tokyo, Japan) under the isocratic conditions of 0.1% trifluoroacetic acid and 39 % acetonitril, and proved to be ...

Nishiyasu T, Tsukamoto R, Kawai K, Hayashi K, Koga S, Ichinose M. Relationships between the extent of apnea-induced bradycardia and the vascular response in the arm and leg during dynamic two-legged knee extension exercise. Am J Physiol Heart Circ Physiol 302: H864 -H871, 2012. First published December 9, 2011; doi:10.1152/ajpheart.00413.2011.-Our aim was to test the hypothesis that apnea-induced hemodynamic responses during dynamic exercise in humans differ between those who show strong bradycardia and those who show only mild bradycardia. After apneainduced changes in heart rate (HR) were evaluated during dynamic exercise, 23 healthy subjects were selected and divided into a large response group (L group; n ϭ 11) and a small response group (S group; n ϭ 12). While subjects performed a two-legged dynamic knee extension exercise at a work load that increased HR by 30 beats/min, apnea-induced changes in HR, cardiac output (CO), mean arterial pressure (MAP), arterial O2 saturation (SaO 2 ), forearm blood flow (FBF), and leg blood flow (LBF) were measured. During apnea, HR in the L group (54 Ϯ 2 beats/min) was lower than in the S group (92 Ϯ 3 beats/min, P Ͻ 0.05). CO, SaO 2 , FBF, LBF, forearm vascular conductance (FVC), leg vascular conductance (LVC), and total vascular conductance (TVC) were all reduced, and MAP was increased in both groups, although the changes in CO, TVC, LBF, LVC, and MAP were larger in the L group than in the S group (P Ͻ 0.05). Moreover, there were significant positive linear relationships between the reduction in HR and the reductions in TVC, LVC, and FVC. We conclude that individuals who show greater apnea-induced bradycardia during exercise also show greater vasoconstriction in both active and inactive muscle regions. mean arterial pressure; femoral blood flow; breath hold LARGE CARDIOVASCULAR RESPONSES occur during breath-hold diving in both animals and humans (10,12,14,19,28,36). The response is characterized by bradycardia and vasoconstriction related to the so-called "diving reflex" (1,8,10,20,24,36), and it has been proposed that the function of these changes is primarily to preserve an adequate O 2 supply to vital organs (1,4,15,18,19,24). Some diving animals, such as seals, show remarkable bradycardia during voluntary diving (36). In humans, the bradycardic response seen during apnea or diving is smaller than in diving animals and varies a great deal from individual to individual (5,21,24,31,32).Acute apnea-induced bradycardia is observed in humans during exercise on land (3,4,6,7,22,25,26,27,30,33). Bjertnaes et al. (7) reported that during exercise, the decrease in cardiac output (CO) induced by apnea was nearly paralleled by a reduction in heart rate (HR). In addition, Lindholm et al. (27) reported that the extent of the bradycardia induced by apnea during exercise had a significant negative relationship with the reduction in arterial blood O 2 saturation (Sa O 2 ) and suggested that the reduction in CO during apnea could conserve O 2 in arterial blood during apnea in exercisin...

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