B E Dunning

University of California, Davis, Davis, CA, United States

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Publications (27)104.32 Total impact

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    ABSTRACT: Our laboratory has investigated the role of the neuropeptide galanin in the sympathetic neural control of both the canine endocrine pancreas and liver. Galanin mRNA and peptide were found in the neuronal cell bodies of the celiac ganglion, which projects fibers to both organs. Galanin fibers formed dense networks around the islets. Galanin was released from these nerves and the amount released appeared sufficient to markedly inhibit basal insulin secretion. We therefore propose that galanin is a sympathetic neurotransmitter in canine endocrine pancreas. Galanin was also found in hepatic nerves usually co-localized with tyrosine hydroxylase, a sympathetic marker. Further, intraportal administration of the sympathetic neurotoxin, 6-hydroxydopamine, abolished galanin staining in the hepatic parenchyma. We evaluated the role of galanin in mediating the actions of sympathetic nerves to increase hepatic glucose production and decrease hepatic arterial conductance. Local infusion of synthetic galanin had little effect by itself, but it did potentiate the action of norepinephrine to stimulate hepatic glucose production, demonstrating a neuromodulatory action. In contrast, galanin had no effect on hepatic arterial blood flow. We therefore propose that in the liver galanin functions as a neuromodulator of norepinephrine's metabolic action.
    Hormone and Metabolic Research 06/1999; 31(5):351-4. · 2.15 Impact Factor
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    ABSTRACT: Vasoactive intestinal polypeptide (VIP) has been found in pancreatic nerves in several species. Studies were conducted to determine if VIP could be a parasympathetic neurotransmitter in the canine endocrine pancreas. To verify that VIP is localized in pancreatic parasympathetic nerves, sections of canine pancreas were immunostained for VIP. VIP staining was identified in the majority of neuronal cell bodies in intrapancreatic parasympathetic ganglia. In addition. VIP was localized in nerve fibers innervating pancreatic islets in the proximity of alpha cells. Next, to determine if VIP is released during electrical stimulation of parasympathetic nerves, pancreatic spillover of VIP was measured during vagal nerve stimulation (VNS) in anesthetized dogs. VIP spillover increased from a baseline of 630+/-540 pg/min to 2580+/-540 pg/min (delta = +1950+/-490 pg/min, p <0.01). Pancreatic VIP release during VNS was not affected by atropine, whereas ganglionic blockade with hexamethonium nearly abolished the VIP response to VNS (p<0.005 vs control), suggesting that VIP is a postganglionic neurotransmitter in the dog pancreas. To examine the effects of VIP on pancreatic hormone secretion, synthetic VIP was infused locally into the pancreatic artery. VIP, at a low dose (5 pmol/min), increased glucagon secretion from 1750+/-599 to 3800+/-990 pg/min (delta = +2060+/-870 pg/min, p<0.05), but did not affect insulin secretion (delta = -1030+/-760 microU/min, NS). Thus, VIP is contained in and released from pancreatic parasympathetic nerves in proximity to islet alpha cells and exogenous VIP, at a dose which approximates the increase of VIP spillover during VNS, preferentially stimulates glucagon vs insulin secretion. Therefore, VIP is likely to function as a parasympathetic neurotransmitter in the endocrine pancreas in dogs. We hypothesize that VIP could mediate the glucagon response to parasympathetic activation which has been shown to resistant to cholinergic blockade with atropine in several species.
    Regulatory Peptides 08/1997; 71(3):163-70. · 2.06 Impact Factor
  • B E Dunning, B Ahrén
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    ABSTRACT: Galanin inhibits insulin secretion and has been proposed to function as a sympathetic neurotransmitter in the endocrine pancreas in some species, for example in the dog. In this study, pancreatic and adrenal gland galanin content were measured following experimental diabetes induced by alloxan in mice. Three days after administration of alloxan (70 mg kg-1, i.p.) in normal mice, pancreatic content of galanin-like immunoreactivity (GLIR) was reduced to 65 +/- 11% of that in untreated controls (P < 0.01), whereas adrenal gland GLIR was unchanged. Similarly, 8 days after alloxan administration, pancreatic GLIR was reduced (P < 0.002), whereas adrenal gland GLIR was unaffected. Pancreatic GLIR also inversely correlated with plasma glucose levels (r = -0.5055, P < 0.005). To distinguish between the direct effects of alloxan vs. indirect metabolic effects induced by the drug, alloxan-diabetic mice were treated with insulin twice daily, which normalized the plasma glucose levels (7.6 +/- 0.3 mmol l-1). Pancreatic GLIR was then not significantly different from controls. Thus pancreatic but not adrenal gland GLIR content is reduced in alloxan-induced diabetes in mice. The data support a role for galanin as a pancreatic sympathetic neurotransmitter which may participate in the metabolic alterations seen in alloxan diabetes in mice.
    Acta Physiologica Scandinavica 10/1993; 149(2):215-9. · 2.55 Impact Factor
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    ABSTRACT: To determine whether norepinephrine (NE) and galanin are coreleased during reflex activation of the sympathetic nervous system by hypoglycemia, we administered insulin to halothane-anesthetized (0.8%) dogs and measured the spillover of NE and galanin-like immunoreactivity (GLIR) into pancreatic venous plasma. Insulin injection produced hypoglycemia [plasma glucose (PG) = 34 +/- 3 mg/dl] but did not activate pancreatic noradrenergic (delta pancreatic NE output = +20 +/- 130 pg/min) or galaninergic nerves (delta GLIR output = +40 +/- 50 fmol/min). To determine whether more severe hypoglycemia would activate these nerves, insulin was administered to dogs infused with somatostatin (SS; 2.5 micrograms/min) to block the counterregulatory increase of glucagon secretion. SS reduced the glucagon response to hypoglycemia by greater than 90%, which allowed PG to decrease to 14 +/- 1 mg/dl. Pancreatic NE output increased by 470 +/- 140 pg/min (P less than 0.005); however, pancreatic GLIR output did not increase significantly (delta = +70 +/- 50 fmol/min). When SS was discontinued, pancreatic NE output increased by 490 +/- 200 pg/min (P less than 0.025), and GLIR output increased by an additional +160 +/- 70 fmol/min (P less than 0.025; total delta from baseline = +230 +/- 90 fmol/min, P less than 0.025), suggesting that SS may restrain pancreatic NE and galanin release. Pancreatic NE and GLIR spillover were also increased during severe hypoglycemia when ganglionic neurotransmission was partially impaired with hexamethonium but not when the neural pathway was interrupted by spinal cord transection. We conclude that NE and galanin are coreleased from pancreatic sympathetic nerves when these nerves are centrally activated during severe hypoglycemia in halothane-anesthetized dogs.
    The American journal of physiology 08/1992; 263(1 Pt 1):E8-16. · 3.28 Impact Factor
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    ABSTRACT: We found previously that electrical stimulation of the mixed autonomic pancreatic nerves (MPNS) is anesthesized dogs elicits marked and rapid increases of pancreatic output of both norepinephrine (NE) and galanin, and on that basis hypothesized a role for galanin as a sympathetic cotransmitter in the endocrine pancreas. In the present study, direct evidence was sought for the co-release of galanin and NE from canine pancreas by determining whether pancreatic galanin output is subject to modulation by presynaptic alpha 2-adrenergic mechanisms as has been established for NE. During MPNS (8 Hz, 1 ms, 10 mA, 10 min) in anesthesized dogs, both pancreatic NE and galanin outflow were increased with similar temporal patterns during consecutive stimulations. Blockade of presynaptic alpha 2-adrenoceptors with yohimbine increased and stimulation of presynaptic alpha 2-adrenoceptors with clonidine reduced NE and galanin outflow. Over all experiments, pancreatic spillover of galanin was highly correlated with that of NE. It is concluded that presynaptic alpha 2-adrenergic mechanisms modulate not only NE but also pancreatic galanin release, suggesting that galanin is co-released with NE from noradrenergic nerves in the endocrine pancreas.
    The American journal of physiology 06/1992; 262(5 Pt 2):R819-25. · 3.28 Impact Factor
  • B E Dunning, B Ahrén
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    ABSTRACT: Because abnormalities of the autonomic nervous system have been described in several animal models of obesity, and because galanin has been proposed to be a sympathetic neurotransmitter in the endocrine pancreas, we hypothesized that the hyperinsulinemia observed in genetically obese (ob/ob) mice may result either from defective ability of galanin to inhibit insulin release or from a reduced degree of pancreatic galaninergic innervation. To address these possibilities, we examined the effect of exogenous galanin on immunoreactive insulin (IRI) levels in ob/ob mice and compared the pancreatic content of galaninlike immunoreactivity (GLIR) in ob/ob mice with that in lean littermates. Intravenous administration of synthetic porcine galanin significantly reduced basal IRI levels in ob/ob mice, suggesting that a defect in galanin action is unlikely to account for the hyperinsulinemia in this model. In contrast, reduced pancreatic galaninergic innervation was supported by findings that pancreatic content of GLIR in ob/ob mice was less than 10% of that in age- and sex-matched lean littermates. The reduction of pancreatic GLIR in ob/ob mice appeared organ specific; no such reduction was observed in adrenal GLIR content when comparing obese and lean mice. In addition, the relationship between pancreatic GLIR content and plasma IRI levels was examined in groups of obese and lean mice. It was found in young females, young males, and older mice of mixed sex that there was a significant negative correlation between pancreatic GLIR and plasma IRI in lean mice, whereas no such correlation was observed in obese mice.(ABSTRACT TRUNCATED AT 250 WORDS)
    Pancreas 02/1992; 7(2):233-9. · 2.95 Impact Factor
  • B E Dunning, S Karlsson, B Ahrén
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    ABSTRACT: This study examines the potential role of the neuropeptide, galanin, in stress-induced inhibition of insulin secretion in swimming mice. Firstly, the pancreatic and adrenal content of galanin-like immunoreactivity was determined in mice after swimming stress. It was found that pancreatic content was significantly lower in stressed mice than in resting controls, both after 2 (P less than 0.05) and 6 (P less than 0.025) minutes of swimming, suggesting partial release of pancreatic galanin during stress. In contrast, the adrenal content of galanin-like immunoreactivity did not change during the swimming stress. Gel filtration of tissue extracts indicated that (1) mouse pancreas contains two forms of galanin-like immunoreactivity; one co-eluting with synthetic porcine galanin (centered on Kav of 0.70) and another with a larger molecular weight (centered on Kav of 0.30), and (2) mouse adrenal contains a small void volume-peak and a larger peak of immunoreactivity, the latter co-eluting with synthetic galanin. Secondly, the effects of swimming stress on plasma glucose and insulin levels were compared in mice that received high titre rabbit anti-galanin serum with those in mice receiving normal rabbit serum. In normal rabbit serum-pretreated swimming mice, glucose-induced insulin levels were only 50% of resting controls (P less than 0.01). Immunoneutralization of galanin with specific antiserum abolished this swimming stress-induced inhibition of glucose-stimulated insulin levels. This was accompanied by a modestly enhanced rate of glucose disappearance. These findings suggest that pancreatic galanin is released during swimming stress in mice and that endogenous galanin makes a major contribution to stress-induced impairment of insulin secretion.
    Acta Physiologica Scandinavica 11/1991; 143(2):145-52. · 2.55 Impact Factor
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    ABSTRACT: To determine the role of the autonomic nervous system (ANS) in mediating the glucagon response to marked insulin-induced hypoglycemia in dogs, we measured arterial and pancreatic venous glucagon responses to insulin-induced hypoglycemia during acute, terminal experiments in halothane-anesthetized dogs in which the ANS was intact (control; n = 9), pharmacologically blocked by the nicotinic ganglionic antagonist hexamethonium (n = 6), or surgically ablated by cervical vagotomy and cervical spinal cord section (n = 6). In control dogs, insulin injection caused plasma glucose to fall by 4.4 +/- 0.2 mM to a nadir of 1.7 +/- 0.2 mM. Arterial epinephrine (EPI) levels increased by 13,980 +/- 1860 pM (P less than 0.005), confirming marked activation of the ANS. Pancreatic output of glucagon increased from 0.53 +/- 0.12 to 2.04 +/- 0.38 ng/min during hypoglycemia (change [delta] +1.51 +/- 0.33 ng/min, P less than 0.005). This increased arterial plasma glucagon from 27 +/- 3 to 80 +/- 15 ng/L (delta +52 +/- 14 ng/L, P less than 0.025). Hexamethonium markedly reduced the ANS response to insulin injection (delta EPI +2130 +/- 600 pM, P less than 0.025 vs. control) despite a similar fall of plasma glucose (delta -4.1 +/- 0.2 mM) and a lower nadir (0.6 +/- 0.1 mM). Both the pancreatic glucagon response (delta glucagon output +0.45 +/- 0.2 ng/min) and the arterial immunoreactive glucagon response (delta +5 +/- 4 ng/L) were substantially reduced by hexamethonium (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)
    Diabetes 10/1991; 40(9):1107-14. · 7.90 Impact Factor
  • B. E. DUNNING, S. KARLS SON, B. AHRÉN
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    ABSTRACT: This study examines the potential role of the neuropeptide, galanin, in stress-induced inhibition of insulin secretion in swimming mice. Firstly, the pancreatic and adrenal content of galanin-like immunoreactivity was determined in mice after swimming stress. It was found that pancreatic content was significantly lower in stressed mice than in resting controls, both after 2 (P < 0.05) and 6 (P < 0.025) minutes of swimming, suggesting partial release of pancreatic galanin during stress. In contrast, the adrenal content of galanin-like immunoreactivity did not change during the swimming stress. Gel filtration of tissue extracts indicated that (1) mouse pancreas contains two forms of galanin-like immunoreactivity; one co-eluting with synthetic porcine galanin (centred on Kav of 0.70) and another with a larger molecular weight (centred on Kav, of 0.30), and (2) mouse adrenal contains a small void volume-peak and a larger peak of immunoreactivity, the latter co-eluting with synthetic galanin. Secondly, the effects of swimming stress on plasma glucose and insulin levels were compared in mice that received high titre rabbit anti-galanin serum with those in mice receiving normal rabbit serum. In normal rabbit serum-pretreated swimming mice, glucose-induced insulin levels were only 50% of resting controls (P < 0.01). Immunoneutralization of galanin with specific antiserum abolished this swimming stress-induced inhibition of glucose-stimulated insulin levels. This was accompanied by a modestly enhanced rate of glucose disappearance. These findings suggest that pancreatic galanin is released during swimming stress in mice and that endogenous galanin makes a major contribution to stress-induced impairment of insulin secretion.
    Acta Physiologica Scandinavica 09/1991; 143(2):145 - 152. · 2.55 Impact Factor
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    ABSTRACT: In several animal species, galanin occurs in pancreatic nerves and inhibits insulin secretion. However, the presence and action of galanin in the human pancreas have not been established. Therefore, we examined the presence and nature of human pancreatic galanin-like immunoreactive material (GLIR) and the effects of galanin on glucose-stimulated insulin secretion from isolated human islets. Immunofluorescent staining of human pancreas revealed GLIR in fine varicose fibers in both islets and exocrine parenchyma. Furthermore, acid extracts of pancreas (n = 3) and isolated islets (n = 3) contained 0.17 +/- 0.06 and 0.23 +/- 0.11 pmol GLIR/mg protein. Human pancreatic GLIR coeluted with synthetic porcine galanin from Sephadex G-50. Moreover, synthetic porcine galanin inhibited glucose-stimulated insulin secretion from collagenase-isolated human islets at dose rates greater than 10(-8) M. Thus, (1) human pancreas is innervated by galanin-containing nerves, (2) human pancreatic GLIR is of similar size as synthetic porcine galanin, and (3) porcine galanin inhibits glucose-stimulated insulin secretion from human islets. Therefore, galanin could be an important local regulator of insulin secretion in man.
    Cell and Tissue Research 06/1991; 264(2):263-7. · 3.68 Impact Factor
  • S Lindskog, B Ahrén, B E Dunning, F Sundler
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    ABSTRACT: Galanin-containing nerve fibers have previously been observed in the human, dog, and pig pancreas. Whether the mouse and rat pancreas also contain galanin nerve fibers has been a matter of debate. Therefore, we examined the distribution of galanin in the mouse and the rat pancreas. Further, the possible localization of galanin to adrenergic nerves was studied using sequential immunostaining for galanin and tyrosine hydroxylase (TH). In the mouse pancreas, numerous galanin-immunoreactive (GIR) nerve fibers occurred around blood vessels. They were less numerous in the exocrine parenchyma and in association with the islets. In contrast, in the rat pancreas, only a few GIR nerves were found. They were located around blood vessels and scattered in the exocrine parenchyma. Occasionally, GIR nerves were also observed in the islets. There was a dense distribution of TH-immunoreactive fibers in both the mouse and the rat pancreas. Sequential immunostaining revealed co-localization of galanin and TH immunoreactivity in nerve fibers in both the mouse and the rat pancreas. Following chemical sympathectomy using 6-hydroxydopamine (6-OHDA), not all GIR nerves disappeared. In the mouse pancreas a remaining population of galanin nerves was found around blood vessels, and occasionally in the islets. In the rat pancreas, a few GIR nerves were seen also after chemical sympathectomy. We conclude that intrapancreatic GIR nerves also occur in the mouse and the rat. These findings suggest that many of the GIR nerves are adrenergic but that non-adrenergic, possibly intrinsic or sensory GIR nerves exist as well in both the mouse and the rat pancreas.
    Cell and Tissue Research 06/1991; 264(2):363-8. · 3.68 Impact Factor
  • B E Dunning, G J Taborsky
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    ABSTRACT: It is clear that the sympathoadrenal system has a role in the regulation of endocrine pancreatic function and that the sympathetic nerves of the pancreas can change pancreatic hormone secretion to increase the availability of metabolic fuels. It seems likely that the classical sympathetic neurotransmitter, NE, acts in concert with peptide co-transmitters, such as galanin and NPY. Each is released during the stimulation of pancreatic sympathetic nerves and each is capable of influencing either islet function or pancreatic blood flow. There is considerable indirect evidence that the sympathetic innervation of the pancreas is activated during acute stress and influences the endocrine pancreas. However, proving such a physiologic role is difficult because of redundant mechanisms that influence the secretion of the metabolically-crucial hormones, insulin and glucagon. Such definitive proof therefore awaits the development of new techniques to dissect and dissociate these mechanisms.
    Advances in experimental medicine and biology 02/1991; 291:107-27. · 1.83 Impact Factor
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    ABSTRACT: It is known that pig galanin inhibits insulin secretion in dogs, rats and mice. The present study examined whether species-specific, homologous, galanin inhibits insulin secretion. Thus, the effects of rat galanin were examined in the rat, and the effects of pig galanin were examined in the pig, both in vivo and in vitro. In conscious rats, synthetic rat galanin (2 nmol kg-1) abolished the glucose- (0.56 mmol kg-1) induced increase in plasma insulin levels. In vitro, rat galanin (10(-9) to 10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated rat islets. In anaesthetized pigs, 15 min infusion of synthetic pig galanin (207 pmol min-1) into the pancreatic artery decreased the insulin output with a subsequent recovery. In vitro, pig galanin (10(-6) mol l-1) inhibited glucose- (8.3 mmol l-1) stimulated insulin release from isolated pig islets. We conclude that homologous galanin inhibits insulin secretion in both the rat and the pig.
    Acta Physiologica Scandinavica 09/1990; 139(4):591-6. · 2.55 Impact Factor
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    ABSTRACT: To visualize the localization and potential co-localization of noradrenaline and the putative pancreatic sympathetic neurotransmitters, galanin and neuropeptide Y (NPY), immunofluorescent staining for galanin, NPY and tyrosine hydroxylase (TH) was performed on sections of canine pancreas and celiac ganglion. In the pancreas, galanin-immuno-fluorescent nerve fibers were confirmed as densely and preferentially innervating the islets, whereas numerous NPY-positive nerve fibers were found in the exocrine parenchyma, the surrounding of the blood vessels and within the islets. Double-staining for the peptides and TH indicated that most galanin-positive nerve fibers were adrenergic, most NPY-positive nerve fibers were adrenergic, and many islet nerves contained both galanin and NPY, although some galanin-positive nerve fibers appeared to lack NPY. In the celiac ganglion, virtually all cell bodies were positive for both galanin and TH; a large subpopulation of these cells were also positive for NPY. Radioimmunoassay (RIA) of galanin in extracts of dog celiac ganglion revealed a very high content (256 +/- 33 pmol/g wet weight) of galanin-like immunoreactivity (GLIR), consistent with the dense staining observed. This GLIR behaved in a similar manner to synthetic porcine galanin in the RIA. In addition, the majority of the GLIR in ganglion extracts co-eluted with the synthetic peptide upon gel filtration, although a minor peak of a larger apparent molecular weight was also observed, observations consistent with the presence of a precursor peptide. These findings suggest that galanin is a sympathetic post-ganglionic neurotransmitter in the canine endocrine pancreas and that NPY might serve a similar function.
    Cell and Tissue Research 08/1990; 261(1):49-58. · 3.68 Impact Factor
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    ABSTRACT: To address the hypothesis that the neutropeptide, galanin, functions as a sympathetic neurotransmitter in the endocrine pancreas, we sought to determine if galanin is released from pancreatic sympathetic nerves during their direct electrical stimulation in halothane-anesthetized dogs. During bilateral thoracic splanchnic nerve stimulation (BTSNS), both peripheral arterial and pancreatic venous levels of galanin-like immunoreactivity (GLIR) increased (delta at 10 min = +92 +/- 31 and +88 +/- 25 fmol/ml, respectively). Systemic infusions of synthetic galanin demonstrated that 1) the increment of arterial GLIR observed during BTSNS was sufficient to modestly restrain basal insulin secretion and 2) only 25% of any given increment of arterial GLIR appears in the pancreatic vein, suggesting that the pancreas extracts galanin, as it does other neurotransmitters. By use of 75% for pancreatic extraction of circulating galanin, it was calculated that pancreatic galanin spillover (output) increased by 410 +/- 110 fmol/min during BTSNS. To reinforce the conclusion that pancreatic sympathetic nerves release galanin, GLIR spillover was next measured during direct local stimulation of the pancreatic sympathetic input produced by electrical stimulation of the mixed autonomic pancreatic nerves (MPNS) in the presence of the ganglionic blocker, hexamethonium. During this local pancreatic sympathetic nerve stimulation, arterial GLIR remained unchanged, but pancreatic venous GLIR increased by 123 +/- 34 fmol/ml. Thus pancreatic GLIR spillover increased by 420 +/- 110 fmol/min during MPNS in the presence of hexamethonium. We conclude that galanin is released from both pancreatic and extrapancreatic sources during sympathetic neural activation in dogs.
    The American journal of physiology 04/1990; 258(3 Pt 1):E436-44. · 3.28 Impact Factor
  • B E Dunning, G J Taborsky
    Diabetologia 03/1990; 33(2):125. · 6.49 Impact Factor
  • B E Dunning, G J Taborsky
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    ABSTRACT: To determine if galanin is released during pancreatic neural activation, we measured galanin-like immunoreactivity (GLIR) in pancreatic venous and peripheral arterial plasma during 10 min of electrical stimulation of the mixed autonomic pancreatic nerves in halothane-anesthetized dogs, using a sensitive and specific radioimmunoassay. During mixed pancreatic nerve stimulation (MPNS), pancreatic venous GLIR increased by 174 +/- 20 fmol/ml, whereas arterial GLIR did not change. By use of the arteriovenous concentration difference and measurements of pancreatic venous blood flow, pancreatic spillover of GLIR was calculated and found to increase by 640 +/- 90 fmol/min during MPNS. This MPNS inhibited the output of immunoreactive insulin (IRI; delta = -53 +/- 9%) and somatostatin-like immunoreactivity (SLI, delta = -49 +/- 13%) and stimulated that of immunoreactive glucagon (IRG, delta = +600 +/- 200%). To determine if the amount of GLIR released during MPNS was sufficient to elicit these changes of pancreatic hormone secretion, we compared the effect of MPNS on IRI, SLI, and IRG output with the effect of synthetic galanin infused directly into the pancreatic artery at a rate that reproduced the MPNS-induced spillover of GLIR. Exogenous infusion of synthetic galanin (2.7 pmol/min) increased pancreatic venous levels of GLIR by 169 +/- 38 fmol/ml, did not change arterial GLIR levels, and thus increased calculated spillover (appearance) by 550 +/- 160 fmol/min, which was nearly identical to the increment produced by MPNS. This matched infusion of galanin inhibited IRI (delta = -58 +/- 3%) and SLI output (delta = -35 +/- 3%) and modestly stimulated IRG output (delta = +62 +/- 10%).(ABSTRACT TRUNCATED AT 250 WORDS)
    The American journal of physiology 02/1989; 256(1 Pt 1):E191-8. · 3.28 Impact Factor
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    ABSTRACT: Evidence for peptidergic innervation of the islets of Langerhans is increasing, yet the role of neuropeptides in mediating neurally induced changes of islet function is not clear. To determine if nonadrenergic transmitters make an important contribution to sympathetic neural effects on basal pancreatic hormone secretion, we examined the effect of local sympathetic nerve stimulation (SNS) on the output of immunoreactive insulin (IRI), immunoreactive glucagon (IRG), and somatostatin (SLI) from the duodenal lobe of the pancreas in situ in halothane-anesthetized dogs, under conditions where the actions of the classical transmitter norepinephrine (NE) should be blocked by propranolol (PROP) and yohimbine (YO). In the absence of adrenergic antagonists, SNS rapidly reduced the output of IRI (delta = -1.34 +/- 0.91 mU/min) and SLI (delta = -600 +/- 350 fmol/min) and stimulated that of IRG (delta = +1.39 +/- 0.57 ng/min). In the presence of PROP and YO, SNS induced similar changes of hormone secretion: delta IRI, -1.30 +/- 0.53 mU/min; delta SLI, -480 +/- 180 fmol/min; delta IRG = +1.89 +/- 0.63 ng/min. Because PROP and YO abolished the pancreatic effects of high dose infusions of NE (1 microgram.kg-1.min-1 iv), we suggest that the antagonists produced sufficient, combined adrenergic blockade at the level of the islet, and we conclude that a nonadrenergic neurotransmitter or modulator plays a major role in mediating sympathetic neural effects on basal islet hormone secretion.
    The American journal of physiology 01/1989; 255(6 Pt 1):E785-92. · 3.28 Impact Factor
  • L J Klaff, B E Dunning, G J Taborsky
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    ABSTRACT: Somatostatin-28 (S-28) is a naturally occurring N-terminally extended form of the tetradecapeptide somatostatin (S-14). The concept has arisen that S-28 is a gut hormone that regulates insulin secretion. This concept is based on 1) reports that S-28 is a more potent inhibitor of insulin secretion than S-14; 2) the finding that S-28 is present in D-cells of the intestine and is released after a meal; and 3) the demonstration of selective binding of S-28 to B-cells of the rat islet. To critically test this hypothesis we have 1) measured the circulating levels of somatostatin-like immunoreactivity (SLI) during infusions of S-28 and S-14 to accurately compare their potencies to inhibit insulin and glucagon secretion from the in vivo dog pancreas, and 2) measured the circulating levels of endogenous SLI released after a meal and compared these to the circulating levels of infused S-28 needed to inhibit insulin secretion. Infusion of S-28 at rates of 170 and 500 pmol/min raised arterial SLI levels by 282 +/- 26 and 885 +/- 98 fmol/ml, respectively. Immunoreactive insulin (IRI) output was inhibited by 20 +/- 11% (P less than 0.05) and 52 +/- 7% (P less than 0.0005), respectively. Immunoreactive glucagon (IRG) output was not significantly altered by either dose. Pancreatic SLI output was inhibited by 32 +/- 5% (P less than 0.0005) by the 500 pmol/min infusion. Infusion of S-28 at 50 pmol/min increased arterial SLI by 108 +/- 17 fmol/ml, but did not alter IRI output (+4 +/- 20%). In comparison, infusion of S-14 (100 pmol/min) raised arterial SLI levels by a similar amount (110 +/- 21 fmol/ml), but, unlike S-28, inhibited both IRI (-50 +/- 6%, P less than 0.0005) and IRG output (-17 +/- 8%; P less than 0.05). Thus, comparable increments in arterial S-28 failed to reproduce the inhibition of IRI secretion seen during the S-14 infusion, while similar inhibition was seen with an 8-fold increment. This suggests that S-28 is significantly less potent than S-14 in the dog. After a mixed meal, endogenous SLI levels increased by 35 +/- 3 fmol/ml in arterial plasma.(ABSTRACT TRUNCATED AT 400 WORDS)
    Endocrinology 01/1989; 123(6):2668-74. · 4.72 Impact Factor
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    ABSTRACT: To determine if acute stress activates pancreatic noradrenergic nerves, pancreatic norepinephrine (NE) output (spillover) was measured in halothane-anesthetized dogs. Central neuroglucopenia, induced by intravenous 2-deoxy-D-glucose [( 2-DG] 600 mg/kg + 13.5 mg/kg-1 per min-1) increased pancreatic NE output from a baseline of 380 +/- 100 to 1,490 +/- 340 pg/min (delta = +1,110 +/- 290 pg/min, P less than 0.01). Surgical denervation of the pancreas reduced this response by 90% (delta = +120 +/- 50 pg/min, P less than 0.01 vs. intact innervation), suggesting that 2-DG activated pancreatic nerves by increasing the central sympathetic outflow to the pancreas rather than by acting directly on nerves within the pancreas itself. These experiments provide the first direct evidence of stress-induced activation of pancreatic noradrenergic nerves in vivo. In contrast, neither hemorrhagic hypotension (50 mmHg) nor hypoxia (6-8% O2) increased pancreatic NE output (delta = +80 +/- 110 and -20 +/- 60 pg/min, respectively, P less than 0.01 vs. neuroglucopenia) despite both producing increases of arterial plasma NE and epinephrine similar to glucopenia. The activation of pancreatic noradrenergic nerves is thus stress specific. Furthermore, because both glucopenia and hypotension increased arterial NE, yet only glucopenia activated pancreatic nerves, it is suggested that a regionally selective pattern of sympathetic activation can be elicited by acute stress, a condition in which sympathetic activation has traditionally been thought to be generalized and nondiscrete.
    Journal of Clinical Investigation 12/1988; 82(5):1538-45. · 12.81 Impact Factor

Publication Stats

398 Citations
104.32 Total Impact Points

Institutions

  • 1991–1997
    • University of California, Davis
      • • Department of Anatomy, Physiology and Cell Biology (VM)
      • • School of Veterinary Medicine
      Davis, CA, United States
    • University of Everett Washington
      Seattle, Washington, United States
  • 1988–1992
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 1990–1991
    • Swedish Medical Center Seattle
      Seattle, Washington, United States
  • 1988–1991
    • Lund University
      • Department of Surgery
      Lund, Skane, Sweden