Phentolamine, a deceptive tool to investigate sympathetic nervous control of insulin release

Schulz, Axel; Hasselblatt, A.

doi:10.1007/bf00175789

Cited by 62 publications

(30 citation statements)

References 43 publications

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“…However, this idea was soon left behind when the insulinotropic and glucoselowering activity of individual imidazolines seemed to deviate from their α 2 -antagonistic properties [11][12][13][14]. Accordingly, non-adrenergic mechanisms of imidazoline action were discovered, which included promotion of insulin release via interaction with the pore-forming subunit of the ATP-dependent K + (K ATP ) channel [15][16][17][18] as well as via modulation of downstream events relevant to the exocytosis of insulin [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

Lehner

Stadlbauer

Adorjan³

et al. 2012

Diabetologia

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Aims/hypothesis Inspired by recent speculation about the potential utility of α 2A -antagonism in the treatment of type 2 diabetes, the study examined the contribution of α 2 -antagonism vs other mechanisms to the antihyperglycaemic activity of the imidazoline (±)-efaroxan. Methods Effects of the racemate and its pure enantiomers on isolated pancreatic islets and beta cells in vitro, as well as on hyperglycaemia in vivo, were investigated in a comparative manner in mice. Results In isolated perifused islets, the two enantiomers of efaroxan were equally potent in counteracting inhibition of insulin release by the ATP-dependent K + (K ATP ) channelopener diazoxide but (+)-efaroxan, the presumptive carrier of α 2 -antagonistic activity, was by far superior in counteracting inhibition of insulin release by the α 2 -agonist UK14,304. In vivo, (+)-efaroxan improved oral glucose tolerance at 100-fold lower doses than (−)-efaroxan and, in parallel with observations made in vitro, was more effective in counteracting UK14,304-induced than diazoxide-induced hyperglycaemia. The antihyperglycaemic activity of much higher doses of (−)-efaroxan was associated with an opposing pattern (i.e. with stronger counteraction of diazoxide-induced than UK14,304-induced hyperglycaemia), which implicates a different mechanism of action. Conclusions/interpretation The antihyperglycaemic potency of (±)-efaroxan in mice is almost entirely due to α 2 -antagonism, but high doses can also lower blood glucose via another mechanism. Our findings call for reappraisal of the possible clinical utility of α 2A -antagonistic compounds in recently identified subpopulations of patients in which a congenitally higher level of α 2A -adrenergic activation contributes to the development and pathophysiology of type 2 diabetes.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

Lehner

Stadlbauer

Adorjan³

et al. 2012

Diabetologia

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“…Recent studies have shown that certain compounds which possess an imidazoline moeity within their structure, are able to enhance the rate of insulin secretion, both in vivo and in vitro (Ahren & Lundquist, 1985;Schulz & Hasselblatt, 1988;1989a;Chan et al, 1988;1991a). 86Rb+ efflux experiments and electrophysiological studies have provided evidence that this response is due to a reduction in potassium efflux through ATP-sensitive K+ channels in the islet P-cell plasma membrane, resulting in membrane depolarization (Chan & Morgan, 1990;Chan et al, 1991a,b;Dunne, 1991;Jonas et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I₁‐ and I₂‐sites

Chan

Brown

Scarpello

et al. 1994

British J Pharmacology

103

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“…Some studies, but not others, have reported that ␣ 2 AR antagonists can increase insulin secretion (Struthers et al, 1985;Hsu et al, 1987;Schulz and Hasselblatt, 1988). Efaroxan is an insulin secretagogue in vitro, allegedly via an agonist action at putative I 3 -imidazoline receptors (Chan et al, 2001), but very high concentrations (10 -100 M) are required to elicit insulin secretion.…”

mentioning

confidence: 99%

The Role of I₁-Imidazoline and α₂-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Velliquette

Ernsberger

2003

J Pharmacol Exp Ther

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We examined glucose metabolism after I 1 -imidazoline (I 1 R) and ␣ 2 -adrenergic receptor (␣ 2 AR) activation in an animal model of metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I 1 R/␣ 2 AR agonists moxonidine and rilmenidine or the ␣ 2 AR agonist guanabenz. Because of the dual specificity of moxonidine, its actions were split into adrenergic and nonadrenergic components by using selective antagonists: rauwolscine (␣ 2 AR) efaroxan (I 1 R/␣ 2 AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane (AGN 192403) (I 1 R). Hyperglycemia induced by moxonidine, rilmenidine, and guanabenz resulted from inhibition of insulin secretion. Similar responses were observed after oral dosing and in lean littermates. Glucagon was reduced by the I 1 R agonists (moxonidine, 32 Ϯ 5%; rilmenidine, 24 Ϯ 7%) but elevated by guanabenz (71 Ϯ 32%). The hyperglycemic and hypoinsulinemic responses to moxonidine were blocked by rauwolscine. In contrast, rauwolscine potentiated the reduction in glucagon (39 Ϯ 6%). AGN 193402 blocked the glucagon response without affecting hyperglycemia and hypoinsulinemia. Efaroxan blocked all responses to moxonidine. When SHROB rats were treated with moxonidine 15 min before an oral glucose tolerance test, the glucose area under the curve (AUC) was increased. Antagonizing the ␣ 2 AR component of moxonidine's action with rauwolscine improved glucose AUC 3-fold and facilitated the insulin secretory response and reduced glucagon secretion. Testing fasting glucose and insulin during 3 weeks of oral moxonidine revealed early hyperglycemia that later faded, and a progressive drop in fasting insulin. The acute hyperglycemia and hypoinsulinemia elicited by moxonidine and rilmenidine was mediated by ␣ 2 AR, whereas I 1 R may reduce glucagon and increase insulin, particularly after a glucose load.

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Phentolamine, a deceptive tool to investigate sympathetic nervous control of insulin release

Cited by 62 publications

References 43 publications

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I₁‐ and I₂‐sites

The Role of I₁-Imidazoline and α₂-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

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Phentolamine, a deceptive tool to investigate sympathetic nervous control of insulin release

Cited by 62 publications

References 43 publications

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

Mechanisms of antihyperglycaemic action of efaroxan in mice: time for reappraisal of α2A-adrenergic antagonism in the treatment of type 2 diabetes?

The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I1‐ and I2‐sites

The Role of I1-Imidazoline and α2-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

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The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I₁‐ and I₂‐sites

The Role of I₁-Imidazoline and α₂-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X