Homologous upregulation of human arterial alpha-adrenergic responses by guanadrel.

The purpose of this study was to test the hypothesis that there is homologous upregulation of arterial alpha-adrenergic responsiveness during suppression of sympathetic nervous system (SNS) activity in humans. 10 subjects (19-28 yr) were studied during placebo and when SNS activity was suppressed by guanadrel. Changes in forearm blood flow (FABF) mediated by the intraarterial infusion of norepinephrine (NE), angiotensin II (AII), and phentolamine were measured by plethysmography. During guanadrel compared with placebo, plasma NE levels (1.28 +/- 0.09-0.85 +/- 0.06 nM; P = 0.0001) and the extra vascular NE release rate derived from [3H]NE kinetics were lower (7.1 +/- 0.7-4.0 +/- 0.2 nmol/min per m2; P = 0.0004), suggesting suppression of SNS activity. During guanadrel, there was increased sensitivity in the FABF response to NE (analysis of variance P = 0.03). In contrast, there was no difference in the FABF response to AII (analysis of variance P = 0.81), suggesting that the upregulation observed to NE was homologous. The increase in FABF during phentolamine was similar during guanadrel compared with placebo (guanadrel: 141 +/- 37 vs. placebo; 187 +/- 27% increase; P = 0.33), suggesting that there was at least partial compensation to maintain constant endogenous arterial alpha-adrenergic tone. We conclude that there is homologous upregulation of arterial alpha-adrenergic responsiveness in humans when SNS activity is suppressed by guanadrel.

A preliminary study on T-786C endothelial nitric oxide synthase gene and renal hemodynamic and blood pressure responses to dietary sodium.

The purpose of the present study was to examine the role of the T-786C endothelial nitric oxide synthase (eNOS) gene polymorphism on changes in renal hemodynamics and blood pressure due to Na(+) loading. Twenty-eight older (63+/-1 years), moderately obese (39+/-2 % fat) hypertensives had their glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure (BP) and plasma nitric oxide (NO(x)) levels determined after eight days of low (20 mEq) and high (200 mEq) Na(+) diets. The two Na(+) diets were separated by a 1-week washout period. Subjects were genotyped for the eNOS-786 site and were grouped on whether they were homozygous or heterozygous for the C allele (TC+CC, n=13) or only homozygous for the T allele (TT, n=15). The TC+CC genotype group had a significantly greater increase in diastolic (P=0.021) and mean arterial (P=0.018) BP and a significant decline in both RPF (P=0.007) and GFR (P=0.029) compared to the TT genotype group with Na(+) loading. Furthermore, Na(+) loading resulted in a significant (P=0.036) increase in plasma NO(x) in the TT, but not in the TC+CC genotype group as well as a trend (P=0.051) for an increase in urine NO(x) in TC+CC, but not in the TT genotype group. The increase in BP during Na(+) loading in older hypertensives was associated with the eNOS genotype and may be related to changes in renal hemodynamics due to changes in NO metabolism.

Effect of aerobic exercise training on blood pressure sensitivity to dietary sodium in older hypertensives.

Although aerobic exercise training has been shown to lower blood pressure (BP) in older adults, its effect on BP sensitivity to dietary sodium (Na(+)) is unknown. Therefore, the present study was undertaken to examine the effect of aerobic exercise training on BP sensitivity to dietary Na(+) in older hypertensive individuals. Blood pressure was measured after 8 days of low (20 mEq) and high (200 mEq) Na(+) diets in 31 older (63+/-7 years, mean+/-standard deviation), hypertensive (152+/-11/88+/-5 mm Hg) individuals at baseline and following 6 months of aerobic exercise training (at 75% VO(2)max, 3 times/week, 40 min/session). Subjects were grouped on the basis of the difference in mean arterial BP (MAP) between diets (Na(+) sensitive: >or=5 mm Hg increase in MAP on high Na(+), n=20; Na(+) resistant: <5 mm Hg increase in MAP on the high Na(+) diet, n=11). Following 6 months of aerobic exercise training, there was a significant increase in maximal aerobic capacity (VO(2)max: 18.3+/-3.8 vs 20.7+/-4.2 ml/kg/min, P<0.017). Aerobic exercise training had a significant (P=0.02) effect on Na(+) sensitivity status, with the proportion of Na(+)-resistant individuals increasing from 35% at baseline to 61% following the 6-month aerobic exercise training programme. This study demonstrates the importance of physical activity on BP sensitivity to dietary Na(+).

Functional uncoupling of the platelet alpha 2-adrenergic receptor-adenylate cyclase complex in the elderly.

Elderly humans demonstrate decreased responsiveness in several hormone-receptor systems, including adrenergic receptors. Studies of the beta-adrenergic receptor (beta-AR) system have shown that reduced beta-adrenergic sensitivity in the elderly may be due to reduced beta-AR affinity for agonists. To determine the mechanisms underlying altered alpha-adrenergic sensitivity in the elderly, we assessed the relationships between age and platelet membrane alpha 2-adrenergic receptor (alpha 2-AR)-binding properties, receptor-linked adenylate cyclase (AC) activity, and the affinity of the alpha 2-AR-AC complex for agonists in 18 young (mean age, 24 yr; range 19-34) and 13 elderly (mean age, 69 yr; range, 63-85) normal subjects. In platelet membrane preparations from elderly compared to young subjects, we found similar antagonist-binding properties and similar activity of the catalytic unit of platelet AC, as indicated by the cAMP response to sodium fluoride stimulation. However, mean epinephrine-mediated inhibition of sodium fluoride-stimulated platelet AC activity was less in the elderly [20 +/- 4% (+/- SEM) vs. 31 +/- 2% inhibition; P less than 0.005). In addition, platelet alpha 2-AR affinity for agonist was lower in the elderly, as indicated by the higher concentration of epinephrine needed to inhibit 50% of specific [3H]yohimbine binding (IC50, 3.2 +/- 0.6 vs. 1.4 +/- 0.3 microM; P less than 0.02). These data provide evidence that platelet membranes from elderly humans have decreased responsiveness to alpha-adrenergic stimulation, which can be attributed to reduced alpha 2-AR-AC affinity for agonists. Similarly to reported age-related alterations in beta-adrenergic receptor function, these results suggest that there is also functional uncoupling of the alpha 2-AR-AC complex in elderly humans.

Age differences in the plasma clearance mechanisms for epinephrine and norepinephrine in humans.

There is an age-related increase in plasma norepinephrine (NE) in humans that is due to both an increase in NE appearance into plasma and a decrease in plasma NE clearance. However, previous studies demonstrated no difference in plasma epinephrine (EPI) in young and old subjects, and the effect of aging on plasma EPI appearance and clearance is unclear. To study age differences in basal NE and EPI metabolism we infused eight young (aged 19-26 yr) and eight old (aged 64-74 yr) normal subjects with [3H]NE or [3H]EPI (15 microCi/m2 bolus dose plus 0.35 microCi/m2/min for 50 min) to achieve steady state conditions on separate days. The old subjects had higher arterialized plasma NE levels [mean, 217 +/- 13 (+/- SE) vs. 149 +/- 12 pg/mL; P less than 0.005] and plasma NE appearance. In contrast, neither plasma EPI levels (98 +/- 8 vs. 104 +/- 10 pg/mL; P = NS) nor EPI appearance rates were different in the old and young subjects. The plasma clearance rates of EPI and NE were nearly identical in the young subjects (1.63 +/- 0.14 vs. 166 +/- 0.09 L/min X m2; P = NS). Plasma NE clearance was lower in the old compared to the young subjects (1.38 +/- 0.06 vs. 1.64 +/- 0.10 L/min X m2; P less than 0.05) and was lower than EPI plasma clearance in the same subjects. Although NE and EPI can be removed by both neuronal and nonneuronal uptake mechanisms, and mean plasma clearance values for NE and EPI are the same in the young, the age-related decline in catecholamine clearance is specific for NE. This finding implies a differential effect of age on a catecholamine removal mechanism that is specific for NE.

Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity.

In subjects with type 2 diabetes in whom an impaired response to an endothelial-dependent vasodilator has been characterized, the populations have also been at least moderately obese. Obesity has been characterized as an independent predictor of endothelial dysfunction in nondiabetic subjects. We hypothesized that in normotensive subjects with type 2 diabetes compared with age-matched control subjects, 1) endothelium-dependent vasodilation, as demonstrated by the forearm blood flow (FABF) response to intraarterial acetylcholine, would be decreased; 2) endothelium-independent vasodilation, as demonstrated by the FABF response to intraarterial nitroprusside, would be similar; 3) the degree of insulin resistance, as measured by the insulin sensitivity index (SI), would predict greater impairment in the FABF response to acetylcholine; and 4) these relationships would be independent of obesity. We measured FABF by venous occlusion plethysmography during brachial arterial infusions of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroprusside in 20 control and 17 subjects with type 2 diabetes. We measured SI using the frequently sampled i.v. glucose tolerance test. Among the diabetic relative to the control subjects we identified a decrease in the acetylcholine-mediated percent increase in FABF (P = 0.02). Using the absolute FABF response to acetylcholine and including adjustments for body mass index and other covariates, the overall group difference remained and was noted to be greatest in those subjects who had lower baseline FABFs. In contrast, no significant difference in the nitroprusside-mediated increase in the percent change FABF was identified between groups (P = 0.30). Finally, the degree of insulin resistance, as measured by SI, did not independently predict greater impairment of the FABF response to acetylcholine. This study is the first to identify specific endothelial cell dysfunction that remains significant after adjustment for obesity in a population of normotensive subjects with type 2 diabetes.

Sensitization of human alpha 1- and alpha 2-adrenergic venous responses by guanadrel sulfate.

The alpha 1- and alpha 2-adrenergic venoconstriction in dorsal hand veins of normal subjects was determined by infusion of phenylephrine or clonidine. Oral administration of prazosin reduced the constriction response to phenylephrine but not to clonidine. Subjects were treated for 3 weeks in a randomized crossover design with placebo or guanadrel sulfate. Guanadrel reduced sympathetic tone (i.e., plasma norepinephrine and norepinephrine release rate), whereas venous responses to phenylephrine and clonidine were both augmented during guanadrel treatment. The effect on phenylephrine responses was primarily attributable to a decrease in the median effective concentration with a small increase in maximum response. Clonidine showed a markedly increased maximum response with a small increase in the median effective concentration. Platelet alpha 2-adrenergic receptors increased slightly but there was no change in the amount of platelet pertussis toxin substrate during guanadrel treatment. Thus reduction in sympathetic tone in normal young men results in increased venous responses to both alpha 1- and alpha 2-agonists.

The effects of ramipril on sympathetic nervous system function in older patients with hypertension.

BACKGROUND: There are important interactions between the renin-angiotensin system and the sympathetic nervous system. Therapy with angiotensin-converting enzyme (ACE) inhibitors may suppress sympathetic nervous system activity. OBJECTIVE: To test the hypothesis that long-term ACE inhibition by ramipril will suppress sympathetic nervous system activity and up-regulate alpha-adrenergic receptor responsiveness in older patients with hypertension. METHODS: This placebo-controlled, double-blind randomized study was conducted at the University Hospital, General Clinical Research Center, University of Michigan Medical Center. Fifteen healthy older patients with mild to moderate hypertension received 8 weeks of ramipril therapy with doses ranging from 5 mg to 20 mg. The following measurements were obtained: plasma norepinephrine levels; norepinephrine kinetic parameters derived from plasma norepinephrine and 3H-norepinephrine levels obtained during infusion and disappearance of 3H-norepinephrine, including the extravascular norepinephrine release rate, norepinephrine clearance, spillover fraction, and volume of distribution; forearm blood flow; platelet membrane alpha2-receptor binding characteristics, and adenylyl cyclase activity. RESULTS: Although plasma norepinephrine levels increased in the subjects treated with ramipril, there were no significant differences from baseline in the rate of norepinephrine appearance into the vascular compartment (P = .76) or in the rate of norepinephrine release into the extravascular compartment (P = .92). In addition, no differences were observed in other norepinephrine kinetic parameters (norepinephrine spillover fraction, norepinephrine volume of distribution, or clearance) between the ramipril and placebo groups. Consistent with this, there was no apparent change in measures of vascular or platelet alpha-adrenergic receptor responsiveness. CONCLUSIONS: Ramipril therapy did not suppress systemic sympathetic nervous system activity, alter other norepinephrine kinetic parameters, or alter alpha-adrenergic responsiveness in older patients with hypertension.

Dobutamine pharmacokinetics during dobutamine stress echocardiography.

Many patients fail to achieve target heart rate during dobutamine stress echocardiography (DSE). We evaluated the pharmacokinetics of dobutamine during DSE to determine whether patients with an impaired chronotropic response have higher rates of dobutamine clearance and consequently relatively lower plasma dobutamine levels. Plasma dobutamine levels, heart rate, and left ventricular (LV) ejection fraction (EF) were measured in 13 male patients referred for DSE at baseline and at the end of stepped 3-minute dobutamine infusions of 5, 10, 20, and 30 microg/kg/min. Dobutamine levels increased with doses: 27 +/- 10, 111 +/- 17, 275 +/- 17, and 403 +/- 28 ng/ml (mean +/- SEM). There was no relation observed between the plasma dobutamine level achieved at the 30-microg infusion dose and the increase in heart rate from baseline (r = 0.066; p = 0.83). Baseline LVEF and a measure of chronotropic beta responsivity were identified as independent predictors of dobutamine clearance, together accounting for 73% of the variance in dobutamine clearance. In conclusion, (1) there is a dose-dependent increase in plasma dobutamine levels during DSE, (2) dobutamine clearance is positively related to baseline LVEF and is partially mediated by a beta-receptor mechanism, and (3) an impaired chronotropic response during DSE is not due to failure to achieve a sufficiently high dobutamine level. We conclude that in patients who lack an adequate heart rate response during the early stages of DSE (e.g., up to 20 microg/kg/min infusion), administration of atropine rather than progressively higher amounts of dobutamine may provide a more effective strategy to achieve target heart rate.

Relation of systemic sympathetic nervous system activation to echocardiographic left ventricular size and performance and its implications in patients with mitral regurgitation.

We have previously demonstrated that the systemic sympathetic nervous system (SNS) is activated in proportion to an increase in cineventriculographic left ventricular (LV) end-systolic volume and decrease in ejection fraction (EF) in patients with chronic mitral regurgitation (MR). However, the relation between noninvasive echocardiographic measures of LV size and performance and systemic SNS activation and their clinical implications in patients with MR is not known. We studied 17 MR patients with echocardiography, arterial norepinephrine (NE) sampling, and [3H]-NE infusions and arterial blood sampling to determine NE kinetic parameters using a 2-compartment analysis, including extravascular NE release rates (NE2, index of SNS activity) and the metabolic clearance rate from the vascular compartment. The arterial NE values correlated with LV end-systolic dimensions (r = 0.50, p = 0.04), but not with LV end-diastolic dimensions, and EF or fractional shortening measures. The NE2 values correlated with LV end-systolic dimensions (r = 0.53, p = 0.03) and inversely with LVEF (r = -0.45, p = 0.07) and fractional shortening (r = 0.43, p = 0.08) measures, but not with LV end-diastolic dimensions. The metabolic clearance rate values showed an inverse correlation with LV end-diastolic (r = -0.52, p = 0.03) and end-systolic (r = -0.49, p = 0.04) dimensions, but not with LV performance measures. The increase in NE2 values was progressive as the LV endsystolic dimensions increased and more marked at LV end-systolic dimensions > or = 40 mm. Thus, activation of the SNS is related to an increase in echocardiographic LV end-systolic dimensions and a decrease in LV performance measures in chronic MR. Medica, Inc.

Glucose metabolism in older adults: a study including subjects more than 80 years of age.

OBJECTIVE: This study was undertaken to understand the dynamics of glucose metabolism in healthy non-diabetic subjects older than age 80 (old-old) compared with subjects aged 61 to 79 (young-old), as well as to compare healthy older subjects with impaired glucose tolerance (IGT) with older subjects with normal glucose tolerance (NGT). DESIGN: A cross sectional, observational study. SETTING: A university hospital clinical research center. PARTICIPANTS: There were 28 community-dwelling adults, 10 older than age 80 and 18 aged 61 to 79. Thirteen of these people had NGT and 15 had IGT. Subjects were not taking any medication that interfered with glucose tolerance. MEASUREMENTS: Status of glucose tolerance was determined by an oral glucose tolerance test categorized as NGT or IGT according to WHO criteria. Insulin sensitivity (SI) and glucose effectiveness (SG) were assessed using a tolbutamide-assisted intravenous glucose tolerance test (IVGTT). The data were analyzed using the Minmod modeling program. Glucose tolerance (K(g)) and the acute insulin response to glucose (AIRg) were calculated from the IVGTT. RESULTS: There were no significant differences between the young-old and old-old in body mass index or in plasma glucose, insulin, or C-peptide levels in the fasting state or during the OGTT. Values for K(g), SI, SG, and AIRg from the IVGTT were similar in the two age groups. When the subjects were classified by glucose tolerance status, the subjects with NGT had age, gender, and body mass index similar to the subjects with IGT. Older people with IGT had a lower K(g) and tended to have higher fasting glucose and similar fasting insulin compared with people with NGT. IGT subjects had lower SI and tended to have lower SG. The AIRg in IGT subjects tended to be low rather than high when compared with older people with NGT. CONCLUSION: Otherwise healthy adults more than 80 years of age have measures of glucose metabolism similar to people aged 61 to 79. The presence of IGT in older adults is associated with insulin resistance, regardless of patient age. We hypothesize that the lack of pancreatic islet compensation for insulin resistance may contribute to impaired glucose tolerance in older adults.

Role of angiotensin converting enzyme genotype in sodium sensitivity in older hypertensives.

BACKGROUND: Individuals differ in their blood pressure (BP) response to changes in dietary sodium (Na+) intake. It is possible that differences in BP responses to dietary Na+ are influenced by genes. METHODS: A total of 35 older (62.9 +/- 1.2 years) hypertensive subjects had their mean arterial blood pressure (MABP) determined after 8 days of low (20 mmol/day) and high (200 mmol/day) Na+ intake. The insertion/ deletion polymorphism of the angiotensin converting enzyme (ACE) gene was genotyped with standard polymerase chain reaction methods. RESULTS: Of the 35 subjects, 24 were classified as sodium-sensitive (> or = 5 mm Hg increase in MABP in response to the increase in dietary Na+) and 11 were classified as sodium-resistant (<5 mm Hg increase in MABP). Those homozygous for the insertion allele of the ACE gene (insertion/insertion [II]; n = 8) had lower (P = .04) MABP responses to the increase in dietary Na+ (0 +/- 3 mm Hg) compared to heterozygotes (insertion/deletion [ID]; n = 20) (9 +/- 2 mm Hg; P = .0001) and those homozygous for the deletion allele (deletion/deletion [DD]; n = 7) (9 +/- 3 mm Hg; P = .05). The prevalence of sodium sensitivity was higher (P = .0083) in DD (71%) and ID (83%) compared to II (25%) genotype groups. CONCLUSIONS: Based on these data in older hypertensive individuals, we conclude that the ACE gene ID and DD genotypes are associated with an increase in BP during a high Na+ diet, which is consistent with the phenotypic characteristic of sodium sensitivity.

Sodium-sensitive hypertension is not associated with higher sympathetic nervous system activity in older hypertensive humans.

The majority of older hypertensive humans are sodium sensitive and they are characterized by increased alpha-adrenergic responsiveness relative to their level of sympathetic nervous system (SNS) activity. To test the hypothesis that heightened SNS activity and/or increased alpha-adrenergic receptor responsiveness during sodium loading may play a role in the sodium-dependent increase in blood pressure in older sodium-sensitive hypertensives, we used compartmental analysis of [3H]norepinephrine (NE) kinetics to determine the release rate of NE into an extravascular compartment (NE2) as an index of systemic SNS activity and determined forearm blood flow responses to graded intrabrachial artery NE and angiotensin II (ANG II) infusions and platelet membrane alpha2-receptor properties in 24 older (age 64 +/- 7 years) hypertensive subjects. Subjects were studied at the end of 1 week of a low (20 mmol/day)- and again at the end of 1 week of a high (200 mmol/day)-sodium diet. Subjects were categorized as sodium sensitive (SS) if they had a > or = 5 mm Hg increase in mean arterial blood pressure (MABP) with dietary sodium loading (n = 16), or sodium-resistant (SR) if their MABP increased by < 5 mm Hg (n = 8). Neither dietary sodium intake nor sodium-sensitivity status significantly affected arterial plasma NE levels, NE2, or other NE kinetic parameters. Forearm blood flow responses to NE or to ANG II, and platelet alpha2-receptor properties were similar between the SS and SR groups. These results suggest that the sodium-dependent increase in MABP that characterizes SS hypertension among older humans is not because of an increase in systemic SNS activity or increased arterial adrenergic receptor responsiveness.

Effect of aging and obesity on insulin responsiveness and glut-4 glucose transporter content in skeletal muscle of Fischer 344 x Brown Norway rats.

This study investigated the metabolic changes with age in the Fischer 344 x Brown Norway rat and its suitability as an animal model of postmaturational insulin resistance. Specifically, we determined whether an age-associated decrease in glucose disposal is associated with diminished whole body insulin responsiveness and/or a decrease in glucose transporter (GLUT-4) protein and mRNA content in medial gastrocnemius muscle of male Fischer 344 x Brown Norway rats of ages 8, 18, and 28 months. Fasting plasma glucose was unchanged with age. There was a significant age effect on visceral adiposity, fasting plasma insulin levels, insulin responsiveness, and GLUT-4 protein content. Insulin responsiveness and GLUT-4 protein were lower in the 18-month-old rats than in the 8-month-old rats. The findings of age-associated increases in visceral adiposity and insulin resistance, and decreases in GLUT-4 in the Fisher 344 x Brown Norway rat, suggest that this rat strain may be an appropriate model for studying the effects of aging on glucose homeostasis.

Effect of age and neurovascular grafting on the mechanical function of medial gastrocnemius muscles of Fischer 344 rats.

Both aging and grafting of whole skeletal muscle are associated with decreased specific force and resistance to fatigue. This study tested the hypothesis that the recovery of mechanical function in nerve-repair skeletal muscle grafts in senescent rats would be impaired compared with recovery in similar grafts in younger animals. Following a 120-day recovery period, the contractile properties of grafted medial gastrocnemius (MGN) muscles from young-mature (6 months), middle-aged (12 months), and senescent (24 months) Fischer 344 rats were measured and compared to age-matched controls. Although there was full recovery of muscle mass, grafting and aging alone both were associated with diminished maximum twitch and tetanic tension, maximum power, and maximum sustained power. In addition, the deleterious effect of grafting on maximum tetanic tension, specific force, and sustained power of MGN muscle was significantly greater in old animals. These findings suggest that aging limits full recovery of the quality of muscle contractions from the nerve-repair grafting procedure, possibly due to an age-related impairment of reinnervation.

Heightened norepinephrine-mediated vasoconstriction in type 2 diabetes.

Adrenergic responsiveness (AR) appears to be increased in subjects with diabetes, but measurement of arterial AR in normotensive people with type 2 diabetes mellitus has not been previously reported. We sought to determine whether, compared with control subjects, there is increased arterial AR in type 2 diabetes mellitus and its relationship to the level of systemic sympathetic nervous system activity (SNSa). We studied 15 type 2 diabetic subjects aged 57 +/- 3 years without hypertension or clinical signs of autonomic neuropathy and 13 age-matched control subjects aged 55 +/- 2 years. We assessed vascular alpha-AR by measuring forearm blood flow (FABF) by venous occlusion plethysmography during intrabrachial artery norepinephrine (NE) and phentolamine infusions, as well as arterial plasma NE levels and the extravascular NE release rate (NE2) derived from 3H-NE kinetics, as estimates of systemic SNSa. The vasoconstricting effect of NE during intrabrachial artery NE infusion was greater in type 2 diabetes compared with control subjects (P = .02). The vasodilating effect of phentolamine was greater in type 2 diabetics compared with control subjects (P = .05), suggesting increased endogenous arterial alpha-adrenergic tone. Arterial plasma NE levels (control v type 2, 1.8 +/- 0.10 v 1.84 +/- 0.14 nmol/L, P = .86) and NE2 (control vtype 2, 11.8 +/- 1.54 v 13.3 +/- 0.89 nmol/min/m2, P = .39) were similar in the two groups. In summary, in type 2 diabetes compared with control subjects, (1) the vasoconstriction response to intraarterial NE is greater, (2) plasma NE and NE2 are similar, suggesting similar levels of systemic SNSa, and (3) arterial alpha-adrenergic tone is greater. We conclude that subjects with type 2 diabetes demonstrate inappropriately increased alpha-AR for their level of systemic SNSa.

Acute effects of adrenergic-mediated ischemia on nerve conduction in subjects with type 2 diabetes.

Several lines of evidence support peripheral nerve ischemia as a contributing factor in the etiology of human diabetic neuropathy. We questioned whether diabetic subjects with relatively normal nerve function in the baseline state would be more likely than healthy control subjects to show either improvement of ulnar nerve function with acute intraarterial infusion of nitroprusside (vasodilation) or be more sensitive than control subjects to worsening of nerve function with acute intraarterial infusion of norepinephrine (vasoconstriction). We measured forearm blood flow (FABF) using venous occlusion plethysmography and assessed ulnar nerve function at baseline and during two intrabrachial artery infusions. Six nondiabetic control subjects (mean age, 56 years) and 11 subjects with type 2 diabetes (mean age, 58 years) in good general health participated. Only three type 2 diabetic subjects had peripheral sensory neuropathy, which was mild. Among control subjects, there was no significant change in sensory distal latency, motor distal latency, motor proximal latency, or sensory or motor conduction velocity during norepinephrine infusion. In contrast, among type 2 diabetic subjects, there was a significant increase in sensory (baseline vnorepinephrine, 2.73+/-0.10 v 2.94+/-0.10 milliseconds [MS], P< or =.01) and motor distal latencies (baseline v norepinephrine, 2.90+/-0.06 v 3.18+/-0.1 ms, P< or =.001) and motor proximal latency (baseline v norepinephrine, 7.15+/-0.18 v 7.60+/-0.23 ms, P<.01) and a decrease in sensory conduction velocity (baseline v norepinephrine, 52.1+/-2.0 v 47.7+/-1.6 m/s, P<.01) during norepinephrine infusion. There were no consistent changes in nerve function during nitroprusside infusion in either group. In summary, we found that subjects with type 2 diabetes, but not control subjects, demonstrate a decrement in nerve function with vasoconstriction during intraarterial infusion of norepinephrine, but no consistent change during nitroprusside-induced vasodilation. These findings suggest there may be enhanced sensitivity of nerve function to ischemia in type 2 diabetic subjects with mild or absent clinical neuropathy.

Functional deficits in medial gastrocnemius grafts in rats: relation to muscle metabolism and beta-AR regulation.

This study tested the hypothesis that alterations in the metabolic integrity of grafted muscle contribute to its diminished ability to sustain power. Compared with control muscles, muscles studied 120 days after the grafting procedure had lower specific force and sustained power. The sustained power protocol resulted in a depletion of muscle glycogen in control (83%) and grafted (85%) animals. Grafts had lower pre- and poststimulation glycogen, diminished citrate synthase activity, and greater hexokinase activity. No differences were observed in phosphofructokinase activity, glucose transporter GLUT-4 content, fiber type, beta-adrenergic-receptor (beta-AR) density, or binding affinity. Isoproterenol-stimulated adenylyl cyclase activity was lower in grafted vs. control muscle, suggesting an uncoupling of the beta-AR-effector complex. Thus the diminished ability of the grafted muscle to sustain power may be explained, in part, by a decrease in energy available from glycogen stores and/or a decrease in oxidative capacity.

Transient dobutamine-mediated pulsus alternans.

Pulsus alternans, alternating weak and strong beats occurring in a heart beating at a constant rate, has most often been reported in patients with severe, end-stage heart failure. This patient with New York Heart Association functional class I heart failure developed pulsus alternans during the inotropic stimulation of dobutamine that subsequently resolved in a time course consistent with dobutamine clearance. Thus, in the setting of mildly impaired myocardial contractility, the inotropic stimulus of dobutamine may precipitate the development of reversible pulsus alternans.