Hypoglycaemia increases aldosterone in a dose-dependent fashion.

AIMS: Intensive glycaemic control increases the incidence of hypoglycaemia. We sought to define the effects of hypoglycaemia on aldosterone, a hormone involved in cardiovascular injury and baroreflex impairment. METHODS: To contrast the effects of hypoglycaemia and euglycaemia on aldosterone and plasma renin activity, in Study 1, we assessed hormone levels in 13 subjects who participated in euglycaemic (5.0 mmol/l) and hypoglycaemic (2.8 mmol/l) hyperinsulinaemic clamp protocols in random order. To determine the relationship between aldosterone and the depth of hypoglycaemia, in Study 2, we assessed hormone levels in an additional 13 subjects who participated in a 3-h stepped hypoglycaemic hyperinsulinaemic clamp protocol; blood glucose was reduced in 0.55 mmol/l steps from 5.0 to 2.2 mmol/l. Subjects were healthy and consumed controlled sodium diets. RESULTS: In Study 1, aldosterone increased approximately 2.5-fold during hypoglycaemic hyperinsulinaemia, P<0.001, but did not rise with euglycaemic hyperinsulinaemia. Plasma renin activity increased during both hyperinsulinaemic clamps; however, the increase was greater during hypoglycaemia (Δ=1.5 ± 0.2 ng ml(-1) h(-1) ) vs. euglycaemia (Δ=0.5 ± 0.1 ng ml(-1) h(-1) ), P<0.005. In Study 2, aldosterone increased significantly at glucose levels of 2.8 mmol/l; this increase was amplified with glucose of 2.2 mmol/l. Aldosterone increases paralleled those of ACTH. CONCLUSIONS: Hypoglycaemia increases aldosterone in a dose-dependent fashion. This increase is likely attributable to activation of the renin-angiotensin-aldosterone system and increases in ACTH. Because aldosterone activation of the mineralocorticoid receptor is implicated in the pathophysiology of cardiovascular injury, including vascular dysfunction, inflammation, baroreflex impairment and cardiac arrhythmias, these findings may be of relevance in individuals who experience hypoglycaemia.

The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy.

Twenty-eight patients with sensory complaints of unknown etiology had repeated skin biopsies. Patients with large nerve fiber swellings on initial biopsy showed a decline in epidermal nerve fiber density on repeated biopsies (p < 0.05 within group; p < 0.05 vs those without swellings). Patients without nerve fiber swellings did not have changes in nerve fiber density between biopsies. Patients with large nerve fiber swellings were most likely to present clinically with paresthesias (p < 0.05).

Effect of vasoactive drugs on carotid diameter in humans.

We studied whether vasoactive drugs used to determine baroreflex sensitivity influence baroreceptor firing by affecting carotid sinus smooth muscle or simply by stretching the sinus wall through changes in pressure. In six young healthy subjects, the diameter of the carotid artery and its change with arterial pulse were measured with ultrasonography. Blood pressure was measured by Finapres. Phenylephrine and nitroglycerin doses were injected intravenously to raise and lower pressure by approximately 15-25 mmHg. Carotid dimensions increased in all subjects during the phenylephrine-induced rise and decreased during the nitroglycerin-induced fall in pressure. Diastolic diameter changed more than systolic diameter; changes were significantly different from the control value (assessed by single-factor analysis of variance and Scheffé's post hoc test). The systolic pressure-diameter relationship appeared to be nonlinear, with a steeper slope above than below baseline, and contributed significantly to the nonlinearity of the R-R interval-systolic pressure relationship. It is concluded that during drug-induced changes in blood pressure, baroreceptor activity in humans is influenced more by passive stretch than by local smooth muscle contraction.

Relation between baroreflex sensitivity and carotid artery elasticity in healthy humans.

We investigated whether physiological variability in arterial baroreflex sensitivity (BRS) was related to differences in carotid elastic behavior among 19 young healthy subjects (age 18-26 yr). The diameter of the carotid artery (D) and its change during the arterial pulse (delta D) were monitored by a phase-locked echotracking device (UT-4 Hokanson), and pulse pressure (delta P) was measured in the brachial artery by sphygmomanometry. Distensibility coefficient (DC) for the common carotid artery was calculated using the formula DC = (2 x delta D/D)/delta P. Dynamic elastic parameters such as the maximum and mean rate of carotid artery expansion and the dominant harmonic frequency of the diameter curve were also determined. BRS was assessed by regressing R-F.intervals against systolic blood pressure, monitored by finger arterial pressure (FINAPRES), during an elevation of pressure, induced by intravenous bolus injection of phenylephrine. Using correlation and stepwise regression analysis, we found that BRS was significantly related to carotid artery distensibility (r = 0.778, P < 0.001) but was not related to any of the dynamic parameters of carotid pulsation.

Heart rate variability after complete autonomic blockade in man.

In a number of studies, using the autoregressive model for frequency domain analysis of R-R interval fluctuations, the low frequency (LF) component (centered at about 0.1 Hz) is claimed to index sympathetic activity level. The aim of this study was to investigate the mediation mechanism of the LF component by pharmacological blockade. Our results support earlier findings, obtained with the use of fast Fourier transformation, that in supine subjects spectral components of R-R interval variability at around 0.1 Hz are mediated mainly by cholinergic mechanisms. Therefore, the use of the LF component as sympathetic index appears questionable.

Cardiac vagal hyperactivity in adolescent anorexia nervosa.

Adolescent anorexia nervosa, a psychiatric disease with high mortality, is often associated with bradycardia. We studied the vagal control of sinus node function in anorexic subjects, to investigate the mechanism of anorexic bradycardia. Cardiac vagal tone was determined in a group of 11 adolescent anorexic girls and in 11 age- and height-matched controls. Cardiac vagal tone in the anorexic patients was measured as the change in R-R interval in response to complete cholinergic blockade; in addition, non-invasive indices of cardiac vagal tone and baroreflex sensitivity were determined in both anorexic and control subjects. Cardiac vagal tone in anorexic subjects was 465 +/- 52 (SE) ms, about 30% higher than values reported for healthy subjects. Vagal tone values were directly related to percent weight loss (R = 0.69, P = 0.017). Non-invasive indices of both cardiac vagal activity and baroreflex sensitivity were significantly higher in the anorexic group as compared to controls; the percent increase of cardiac vagal tone, however, exceeded the increase of baroreflex sensitivity. Cardiac vagal hyperactivity significantly contributes to the bradycardia of anorexic subjects. The excess vagal activity is only partly explained by enhanced baroreflex sensitivity.

Relation between tonic sympathetic and vagal control of human sinus node function.

BACKGROUND: Clinical conditions, such as heart failure or myocardial infarction are associated with enhanced sympathetic and reduced parasympathetic activity as compared to normal controls. The reciprocal alteration in cardiac autonomic tone likely contributes to the electrical instability of the myocardium. Little information is available on the relation between sympathetic and vagal cardiac control in healthy human subjects. METHODS AND RESULTS: Heart period changes in response to autonomic blockades were measured in 16 young, healthy human subjects. Adrenergic and cholinergic blockades were induced by i.v. propranolol (0.2 mg/kg) and atropine (0.04 mg/kg) in two opposite orders on two occasions; interindividual correlations were performed between the R-R interval responses to propranolol and to atropine obtained under the various blockade conditions, and the magnitude of the responses were compared by a drug x order two factorial ANOVA design. It was found, that previous adrenergic blockade did not reduce the extent of cardioacceleration produced by subsequent cholinergic blockade and that the R-R interval responses to atropine and to subsequently given propranolol did not share significant variance across subjects (r = 0.22, P = 0.234). Also, no interindividual correlation was found between the R-R interval responses to propranolol and to atropine, with the influence of the other, respective, autonomic division already blocked (r = 0.42, P = 0.114). CONCLUSIONS: Under resting conditions, activity levels of cardiac vagal and sympathetic outflows are not related across young, healthy human subjects and peripheral interaction is not manifest between the autonomic divisions.

Relation between baroreflex sensitivity and cardiac vagal tone in humans.

The extent of dependence of cardiac vagal tone on arterial baroreceptor input has been studied in 12 healthy, young adult subjects. Cardiac vagal tone was defined as the chang in R-R interval after complete cholinergic blockade by atropine. Baroreflex sensitivity was determined with the "Oxford-method": R-R interval was regressed against systolic pressure. The interindividual correlation between cardiac vagal tone and baroreflex sensitivity for falling pressures was found to be significant, but not close (R = 0.81, P = 0.002). In each subject, the baroreflex regression line for falling pressures was extrapolated to the post-atropine R-R interval level; 50 mmHg was considered as minimum and 80 mmHg as maximum threshold level for the integrated baroreflex. From the relation between the individual regression lines and the minimum and maximum threshold levels, it was concluded that cardiac vagal tone could be generated by both baroreflex-dependent and -independent mechanisms, the ratio of which varies in different individuals, with the baroreflex-dependent mechanism being the dominant factor.