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PubMed1997

Activation of autonomic nerves and the adrenal medulla contributes to increased glucagon secretion during moderate insulin-induced hypoglycemia in women.

Despite evidence that the autonomic nervous system (ANS) makes a significant contribution to increased glucagon secretion during insulin-induced hypoglycemia in several animal species, including a recent study in nonhuman primates, the role of the ANS in mediating this important counterregulatory response in humans remains controversial. Therefore, glucagon responses to insulin-induced hypoglycemia were examined in seven nondiabetic women (BMI, 28.0 +/- 2.0 kg/m2) with and without the presence of the ganglionic nicotinic receptor antagonist trimethaphan. Trimethaphan impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia and in the adrenal medulla and, therefore, markedly impairs autonomic activation during insulin-induced hypoglycemia. The studies were performed in random order at least 4 weeks apart. Trimethaphan was infused at a variable rate (0.3-0.6 mg/min) to modestly lower blood pressure (approximately 10 mmHg) without producing hypotension. Regular human insulin was infused (0.28 pmol x m(-2) x min(-1)) with a variable rate glucose infusion to lower the plasma glucose from 4.9 +/- 0.2 to 2.6 +/- 0.2 mmol/l in the control study and from 4.9 +/- 0.2 to 2.5 +/- 0.2 mmol/l in the trimethaphan study. Trimethaphan impaired parasympathetic and sympathoadrenal activation during insulin-induced hypoglycemia as assessed by 70% reductions of the plasma pancreatic polypeptide response and epinephrine response (both P < 0.05 vs. control study). Glucagon secretory responses during insulin-induced hypoglycemia were assessed as peak responses and as the area under the curve (AUC) above baseline values during insulin-induced hypoglycemia. Plasma glucagon increased in the control study from 44 +/- 5 ng/l to a peak of 76 +/- 9 ng/l (delta = 32 +/- 8 ng/l; P < 0.005 vs. baseline) and in the trimethaphan study from 41 +/- 3 to 50 +/- 7 ng/l (delta = 10 +/- 5 ng/l; P < 0.02 vs. control subjects). The glucagon response to insulin-induced hypoglycemia as assessed by the AUC was 948 +/- 272 ng x 1(-1) x 45 min(-1) in the control study (P < 0.01 vs. baseline), but was reduced by 75% in the trimethaphan study (AUC = 203 +/- 94 ng x 1(-1) x 45 min(-1); P < 0.02 vs. control subjects). Trimethaphan did not affect the glucagon response to arginine administration. These results demonstrate that the ANS mediates the majority of the glucagon response to insulin-induced hypoglycemia of 2.5 mmol/l in postmenopausal nondiabetic women.

Adrenal Medulla↗
PubMed2001

Activation of the parasympathetic nervous system is necessary for normal meal-induced insulin secretion in rhesus macaques.

Meal-induced insulin secretion is thought to be regulated primarily by absorbed nutrients and incretin hormones released from the gastrointestinal tract. In addition, the parasympathetic nervous system (PNS) is known to mediate preabsorptive, or cephalic phase, insulin secretion. Despite evidence that the PNS remains activated during the absorptive phase of the meal, its role in mediating postprandial insulin secretion has not been established. To study the role of the PNS in absorptive phase insulin release, we measured plasma concentrations of glucose as well as islet hormones and incretins in six healthy rhesus monkeys before and for 60 min after meals while they were infused with saline (control), atropine (muscarinic blockade), or trimethaphan (nicotinic blockade). During the infusion of saline, plasma levels of glucose, pancreatic polypeptide (PP), insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 increased promptly after meal ingestion and remained elevated throughout the 60 min of the study. The PP response was nearly abolished in animals treated with trimethaphan, indicating functional blockade of PNS input to the islet, and in contrast to the control study, there were minimal changes in plasma concentrations of glucose, incretin hormones, and insulin. Because trimethaphan inhibited glycemic and incretin stimuli in addition to blocking PNS input to the islet, it was not possible to discern the relative roles of these factors in the stimulation of insulin secretion. Atropine also significantly decreased PNS transmission to the islet, as reflected by PP levels similar to those observed with trimethaphan. Unlike the trimethaphan study, plasma glucose levels rose normally during atropine treatment and were similar to those in the control study over the course of the experiments (114 +/- 22 and 132 +/- 23 mmol/L.60 min, respectively). In addition, the rise in plasma glucagon-like peptide-1 following the meal was not suppressed by atropine, and the glucose-dependent insulinotropic polypeptide responses were only modestly decreased. Despite the significant increases in circulating glucose and incretins, plasma insulin levels were greatly attenuated by atropine, so that the 60 min responses were more comparable to those during trimethaphan treatment than to those in the control study (atropine, 3,576 +/- 1,284; trimethaphan, 4,128 +/- 2,616; control, 15,834 +/- 5,586 pmol/L.60 min; P: < 0.05). Thus, muscarinic blockade markedly suppressed the meal-induced insulin response despite normal postprandial glycemia and significant elevations of incretins. These results indicate that activation of the PNS during the absorptive phase of meals contributes significantly to the postprandial insulin secretory response.

Animals↗
PubMed2004

Differential pressor response to intravenous ephedrine during recovery from deliberate hypotension.

STUDY OBJECTIVE: To determine whether nitroglycerin or trimethaphan alters pressor response to intravenous (i.v.) ephedrine. DESIGN: Prospective, randomized study. SETTING: Operating room of a university hospital. PATIENTS: 60 ASA physical status I female patients scheduled for mastectomy. INTERVENTIONS: Patients were assigned to one of six groups (n = 10 in each). Group 1: nitroglycerin + normal saline (NS) i.v., Group 2: nitroglycerin + ephedrine 0.1 mg/kg i.v., Group 3: nitroglycerin + ephedrine 0.15 mg/kg i.v., Group 4: trimethaphan + NS i.v., Group 5: trimethaphan + ephedrine 0.1 mg/kg i.v., and Group 6: trimethaphan + ephedrine 0.15 mg/kg i.v. MEASUREMENTS: Hemodynamic responses to ephedrine following withdrawal of vasodilators were observed for 15 minutes. MAIN RESULTS: Ephedrine increased heart rate and mean blood pressure. After ephedrine 0.1 mg/kg i.v., the maximum pressor response in the trimethaphan group was approximately twofold that of the nitroglycerin group (p = 0.038). CONCLUSIONS: Ephedrine restored BP more easily in those patients who had received trimethaphan compared with those who had received nitroglycerin for deliberate hypotension.

Blood Gas Analysis↗
PubMed1996

Acute and chronic angiotensin hypertension: neural and nonneural components, time course, and dose dependency.

We examined the mechanisms mediating hypertension in conscious rats during acute and chronic infusion of angiotensin II (ANG II) at pressor doses (50, 100, and 200 ng.kg-1.min-1). Trimethaphan-induced blood pressure reduction was inversely related to the acute dose of ANG II, consistent with a constrictor action of ANG II on vascular smooth muscle and withdrawal of sympathetic tone. During chronic ANG II infusion, the entire increase in mean arterial pressure (MAP) was inhibited by trimethaphan, consistent with neural mediation. During acute ANG II hypertension, the AT1-specific receptor blocker losartan induced a large fall in MAP (64 +/- 4 mmHg) in ganglion-blocked (chlorisondamine) rats, whereas, during chronic ANG II hypertension, losartan had only a small hypotensive effect (11 +/- 3 mmHg). To determine the time course of the change from vascular smooth muscle action to neural action, we measured MAP in response to trimethaphan during the first 24 h of ANG II infusion. After 5 h, the minimal MAP in response to trimethaphan was significantly higher than that before ANG II. After 10 h of infusion, trimethaphan decreased MAP to pre-ANG II levels. That is, the neural component was fully active after only 10 h of infusion in rats. Finally, chronic administration of ANG II resulted in a dose-related increase in MAP that, at all doses, was completely inhibited by trimethaphan. These findings are consistent with ANG II acting primarily on vascular smooth muscle during acute infusion and via neural pathways during chronic treatment. The transition from direct smooth muscle to indirect neural action is rapid in rats (< 10 h), and the MAP and neural responses to ANG II are dose related during chronic hypertension.

Acute Disease↗
PubMed2000

The effects of anesthetics on stress responses to forebrain ischemia and reperfusion in the rat.

UNLABELLED: Rats exposed to forebrain ischemia have reduced injury when anesthetized with isoflurane versus fentanyl + N(2)O. The protection caused by isoflurane is reversed by trimethaphan. We hypothesized that these anesthetic-dependent effects on ischemic outcome can be associated with altered stress responses to ischemia. Rats were randomized to four treatments: isoflurane; fentanyl + N(2)O; isoflurane + trimethaphan; or isoflurane + metyrapone. Severe forebrain ischemia was then induced for 10 min. Plasma and brain corticosterone, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were assayed. Plasma corticosterone concentrations were similar in the isoflurane and isoflurane + trimethaphan groups, but greater than in the fentanyl + N(2)O and isoflurane + metyrapone groups. Brain corticosterone was similar among all groups except isoflurane + metyrapone, in which values were markedly reduced. The addition of metyrapone to isoflurane also reduced plasma TNF-alpha; however, values among other groups were similar. There were no differences among groups for brain TNF-alpha. Plasma IL-6 concentrations were below the limit of detection. Brain IL-6 concentrations were increased by ischemia; however, there was no difference among groups. In conclusion, there were no differences between the isoflurane and isoflurane + trimethaphan groups for any of the measured stress markers. Further, there was little difference between the isoflurane and fentanyl + N(2)O groups, except for plasma corticosterone concentration. Accordingly, isoflurane neuroprotection and its reversal by trimethaphan appear to be independent of effects on the stress responses measured in this study. IMPLICATIONS: Differential anesthetic effects on ischemic outcome are independent of effects on adrenergic/noradrenergic responses to ischemia. The absence of a consistent differential effect of anesthetics on either corticosterone or cytokine responses to ischemia serves to further refute the hypothesis that isoflurane neuroprotection can be attributed to dampening of adverse stress responses to ischemic insults.

Anesthetics↗
PubMed2000

Sympathetically mediated hypertension in autonomic failure.

BACKGROUND: Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity. METHODS AND RESULTS: In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of alpha(1)-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248+/-543 versus 467+/-209 mm Hg. min; P=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874+/-809 versus 785+/-189 mm Hg. min; P=0. 0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67+/-8 and 12+/-6 mm Hg in MSA and PAF patients, respectively (P<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4+/-5.8% and 40.7+/-9.5%, respectively (P=0. 0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (r=0.98; P=0.001). CONCLUSIONS: Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.

Adrenergic alpha-Antagonists↗