John B. Stoker

Impact of Type 2 Diabetes Mellitus on Sympathetic Neural Mechanisms in Hypertension

Background—Essential hypertension (EHT) is a major cardiovascular risk factor, and the additional presence of type 2 diabetes mellitus (DM2) increases this risk. However, although the sympathetic nerve hyperactivity of EHT is known to play a role in cardiovascular risk, the level of sympathetic nerve activity is known neither in DM2 nor in hypertensive type 2 diabetic patients (EHT+DM2). Therefore, we planned to quantify the vasoconstrictor sympathetic nerve activity in patients with EHT+DM2 and with DM2 relative to that in matched groups with EHT and normal blood pressure (NT). Methods and Results—In 68 closely matched subjects with EHT+DM2 (n=17), DM2 (n=17), EHT (n=17), and NT (n=17), we measured resting muscle sympathetic nerve activity as the mean frequency of multiunit bursts (MSNA) and of single units (s-MSNA) with defined vasoconstrictor properties. The s-MSNA in EHT+DM2 (97±3.8 impulses/100 beats) was greater (at least P <0.001) than in EHT (69±3.4 impulses/100 beats) and DM2 (78±4.1 impulses/100 beats), and all these were significantly greater (at least P <0.01) than in NT (53±3.3 impulses/100 beats) despite similar age and body mass index. The MSNA followed a similar trend. In addition, the level of insulin was also raised in EHT+DM2 (20.4±3.6 &mgr;U/mL) and DM2 (18.1±3.1 &mgr;U/mL; at least P <0.05) compared with HT or NT. Conclusions—Patients with EHT+DM2, EHT, or DM2 had central sympathetic hyperactivity, although plasma insulin levels were raised only in EHT+DM2 and DM2. The combination of EHT and DM2 resulted in the greatest sympathetic hyperactivity and level of plasma insulin, and this hyperactivity could constitute a mechanism for the increased risks of this condition.

Water ingestion increases sympathetic vasoconstrictor discharge in normal human subjects

A marked pressor response to water drinking has been observed in patients with autonomic failure and in the elderly, and has been attributed to sympathetic vasoconstrictor activation, despite the absence of such a pressor response in healthy subjects with intact sympathetic mechanisms. We investigated whether water drinking in normal subjects affected peripheral sympathetic neural discharge and its effect on vascular resistance. In nine normal human subjects, we examined the effect of water ingestion on muscle sympathetic neural activity from the peroneal nerve, as multi-unit bursts (muscle sympathetic nerve activity; MSNA) and as single-unit impulses (s-MSNA) with vasoconstrictor function, and on calf vascular resistance for 120 min. In each subject, water ingestion caused increases in s-MSNA and MSNA which peaked at 30 min after ingestion; they increased respectively (mean+/-S.E.M.) from 42+/-4 to 58+/-5 impulses/100 beats (P<0.01) and from 36+/-4 to 51+/-5 bursts/100 beats (P<0.001). There were corresponding increases in calf vascular resistance and in plasma noradrenaline levels. A significant correlation occurred between all of these data. In conclusion, measurement of MSNA has provided direct evidence that water drinking in normal human subjects increases sympathetic nerve traffic, leading to peripheral vasoconstriction. This sympathetic activation was not accompanied by significant changes in arterial blood pressure.

Sympathetic neural mechanisms in white-coat hypertension

OBJECTIVES This study planned to establish whether sympathetic hyperactivity exists in white-coat hypertension (WHT) in the clinical setting, relative to matched groups with normotension (NT) and untreated essential hypertension (EHT). BACKGROUND White-coat hypertension differs from EHT by the presence of normal ambulatory blood pressure. Sympathetic hyperactivity exists in patients with EHT in the clinical setting and is believed to contribute to the development of target organ damage. Similar organ damage has been reported in WHT, yet little is known about sympathetic neural activity in this condition. METHODS Using microneurography, we examined groups of 12 matched subjects with WHT, EHT and NT during the same clinical setting to quantify muscle sympathetic nerve activity as multiunit discharge (MSNA) and single units (s-MSNA). RESULTS The s-MSNA in WHT (54 +/- 4.2 impulses/100 beats) was greater (p < 0.05) than in NT (37 +/- 5.4 impulses/100 beats) despite similar age and body mass index (BMI). The EHT values of s-MSNA (73 +/- 5.2 impulses/100 beats) were significantly (p < 0.05) greater than in WHT despite similar age, BMI and blood pressure levels. The MSNA followed a similar trend. White-coat hypertension had a similar cardiac baroreceptor reflex sensitivity to NT, but this was impaired in EHT relative to both NT and WHT. CONCLUSIONS It was shown, in the clinical setting, that central sympathetic hyperactivity exists in WHT, albeit to a lesser degree than EHT. These findings suggest that WHT may not be entirely benign and that the observed sympathetic hyperactivity may be responsible for development of target organ damage in this group of patients.

Hypertensive left ventricular hypertrophy: Relation to peripheral sympathetic drive

OBJECTIVES This study was designed to examine whether the occurrence of left ventricular hypertrophy (LVH) in moderate to severe essential hypertension (EHT) was associated with alteration in peripheral sympathetic drive. BACKGROUND In hypertension, LVH is an independent predictor of increased morbidity and mortality. The reported mechanisms leading to LVH remain unclear but include hemodynamic and humoral factors. The sympathetic nervous system may be important, particularly as catecholamines have been shown to have trophic properties. We tested the hypothesis that sympathetic activity measured using microneurography could be different in patients with hypertension depending on the presence of LVH. METHODS We examined 28 subjects with moderate to severe EHT (stages 2 to 3; Joint National Committee [JNC]-VI classification). Fourteen had echocardiographic evidence of LVH (EHT + LVH), while the other 14 subjects (EHT) did not. Subjects were matched in terms of age, body mass index and levels of arterial blood pressure. Peripheral muscle sympathetic nerve activity was measured from both multiunit bursts (MSNA) and single unit (s-MSNA) vasoconstrictor impulses via the peroneal nerve. RESULTS The mean frequency of s-MSNA and MSNA was greater in the EHT + LVH group than it was in the EHT group (mean +/- SEM; 75.9 +/- 6.9 impulses/100 beats vs. 52.1 +/- 2.9 impulses/100 beats, p < 0.001 and 64.2 +/- 5.7 bursts/100 beats vs. 48.9 +/- 2.8 bursts/100 beats, p < 0.05). CONCLUSIONS These results indicate that, in subjects with moderate to severe hypertension, the presence of LVH is associated with higher sympathetic discharge, evidenced by an increase in unitary firing frequency and also by fiber recruitment.

Time Course of Sympathetic Neural Hyperactivity After Uncomplicated Acute Myocardial Infarction

Background—Little information is available on sympathetic activity after acute myocardial infarction (AMI), despite the belief that sympathetic drive is important in relation to morbidity and mortality. Indirect indices such as plasma catecholamines are transiently elevated after uncomplicated AMI, whereas other prognostically important autonomic indices may be affected longer. We planned to quantify central sympathetic output to the periphery after uncomplicated AMI and to investigate its progress over time. Methods and Results—After uncomplicated AMI, 13 patients had muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units with defined vasoconstrictor properties (s-MSNA). Measurements were obtained 2 to 4 days after AMI and were repeated after 3 and 6 months. We also examined 3 matched control groups comprising normal subjects, patients with coronary artery disease, and hospitalized patients without AMI. MSNA and s-MSNA after AMI (84±4.6 bursts/100 beats and 95±5.8 impulses/100 beats) were unchanged at 3 months but decreased (P <0.01 and P <0.001) after 6 months (75±4.0 bursts/100 beats and 80±4.4 impulses/100 beats). These were still greater (at least P <0.01) than values in normal subjects, patients with coronary artery disease, and hospitalized patients without AMI (51±3.9 bursts/100 beats, 58±4.7 impulses/100 beats ; 56±2.2 bursts/100 beats, 61±2.2 impulses/100 beats; and 55±3.6 bursts/100 beats, 61±3.3 impulses/100 beats, respectively). This sympathetic hyperactivity was inversely correlated to left ventricular ejection fraction but not to changes in blood pressure. Conclusions—A protracted state of sympathetic hyperactivity was shown to occur after uncomplicated AMI. It is suggested that this hyperactivity may explain delayed cardiovascular morbidity and mortality and that it arises because of an impairment of reflexes from cardiac receptors.

Sympathetic nerve discharge in normal pregnancy and pregnancy-induced hypertension.

Background Microneurographic assessment of processed bursts that represent multi-unit nerve discharge has suggested that sympathetic hyperactivity occurs in pregnancy induced hypertension and preeclampsia in comparison with normal pregnancy. Objective To examine the differences between peripheral sympathetic outputs in pregnancy-induced hypertension and normal pregnancy by directly measuring single impulses of neural discharge. Design We compared the sympathetic neural discharge at rest and its reflex responses in subjects with pregnancy-induced hypertension and normal pregnancy and re-examined their progress at least 6 weeks post partum. The patients with pregnancy-induced hypertension were hospital in-patients for whom the diagnosis could be strictly defined and the normally pregnant women were recruited to match the former. Methods Standard microneurography was performed to quantify single impulses of action potentials, together with the processed multi-unit bursts from fibres innervating the leg muscles. We measured neural discharge with vascular vasoconstrictive properties, heart rate and finger arterial blood pressure at rest and their responses to standard isometric hand-grip exercise and cold pressor tests. Results As expected, patients with pregnancy-induced hypertension (n = 13) had higher levels of finger arterial blood pressure than did women with normal pregnancies (n = 11). The number of single impulses of action potentials (per min and per 100 cardiac beats) in resting patients with pregnancy-induced hypertension was more than three times greater than that in resting women with normal pregnancies, and the number of multi-unit bursts was twofold greater. After delivery of their child, sympathetic activity and heart rate in nine patients decreased, but finger arterial blood pressure decreased in patients with pregnancy-induced hypertension only. Conclusions From results of cross-sectional and longitudinal studies, pregnancy-induced hypertension is associated with a greater resting sympathetic output than that of women with normal pregnancies. Follow-up data after parturition suggest that this hyperactivity is not the only cause of hypertension. J Hypertens 16:617–624

INSULIN SECRETION FOLLOWING MYOCARDIAL INFARCTION WITH PARTICULAR RESPECT TO THE PATHOGENESIS OF CARDIOGENIC SHOCK

Abstract Plasma-insulin and blood-glucose were measured before and after the intravenous injection of tolbutamide in patients with acute myocardial infarction. Patients in circulatory shock showed a marked suppression of insulin secretion, compared with patients with uncomplicated myocardial infarction or with normal subjects. Improvement in their clinical condition was associated with a return to normal in the plasma-insulin level and the insulin-secretion response. This suppression of insulin secretion is probably due to the reduced blood-flow to the pancreas in combination with the high level of circulating catecholamines.

The magnitude of sympathetic hyperactivity in pregnancy-induced hypertension and preeclampsia*

BACKGROUND It is unclear whether pregnancy-induced hypertension (PIH) and preeclampsia (PE) are separate conditions or represent opposite ends of a spectrum of a single disease entity. Sympathetic hyperactivity exists in both PIH and PE; however, only the latter is characterized by multiorgan involvement, particularly renal impairment. As there is evidence in hypertension that target organ damage is associated with increased sympathetic drive, this study was designed to test the hypothesis that the magnitude of sympathetic hyperactivity in PE is greater than that in PIH. METHODS Microneurography was used to compare peripheral sympathetic neural discharge, its reflex control and end-organ effect (plethysmographic measurement of calf blood flow) in 33 women with PIH, PE, and normal pregnancy (NP) who were matched for age, body weight, and gestation. RESULTS As expected, patients with PIH and PE had higher levels of mean arterial pressure than those with NP. The frequency of sympathetic neural discharge was greater in the hypertensive disorders of pregnancy compared with NP; however, it was not increased in PE compared with PIH as might be expected. CONCLUSIONS Based on the study results, PE is not associated with greater sympathetic hyperactivity than PIH, suggesting that any renal impairment in PE involves mechanisms that are not solely dependent on sympathetic hyperactivity.

Sympathetic neural hyperactivity and its normalization following unstable angina and acute myocardial infarction.

Impaired autonomic function occurs after AMI (acute myocardial infarction) and UA (unstable angina), which may be important prognostically. However, the pattern of sympathetic nerve hyperactivity has been investigated only after AMI. We aimed to quantify central sympathetic output to the periphery in patients with UA, investigate its progress over time relative to that after uncomplicated AMI and to explore the mechanisms involved. Muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units (s-MSNA) was obtained in matched patients with UA ( n =9), AMI ( n =14) and stable CAD (coronary artery disease, n =11), patients with chest pain in which AMI was excluded (NMI, n =9) and normal controls (NCs, n =14). Measurements were obtained 2-4 days after UA or AMI, and repeated at 3 monthly intervals until they returned to normal levels. The respective MSNA and s-MSNA early after UA (72+/-4.0 bursts/100 beats and 78+/-4.2 impulses/100 beats respectively) were less than those after AMI (83+/-4.4 bursts/100 beats and 93+/-5.5 impulses/100 beats respectively). Relative to the control groups of NCs (51+/-2.7 bursts/100 beats and 58+/-3.4 impulses/100 beats respectively) and patients with CAD (54+/-3.7 bursts/100 beats and 58+/-3.9 impulses/100 beats respectively) and NMI (52+/-4.5 bursts/100 beats and 59+/-4.9 impulses/100 beats respectively), values returned to normal after 6 months in UA (55+/-5.0 bursts/100 beats and 62+/-5.5 impulses/100 beats respectively) and 9 months after AMI (60+/-3.8 bursts/100 beats and 66+/-4.2 impulses/100 beats respectively). In conclusion, both UA and AMI result in sympathetic hyper-activity, although this is of smaller magnitude in UA and is less protracted than in AMI. It is suggested that this hyperactivity is related to the degree of left ventricular dysfunction and reflexes.

Sympathetic Drive in Anterior and Inferior Uncomplicated Acute Myocardial Infarction

Background—The sympathetic activation that follows acute myocardial infarction (AMI) has been associated with increased morbidity and mortality. Because the prognosis after anterior AMI (ant-AMI) is worse than that after inferior AMI (inf-AMI), we planned to determine whether the magnitude of sympathetic hyperactivity differs between the two. Methods and Results—Thirty-nine patients with uncomplicated AMI, comprising 2 matched groups of 17 patients with ant-AMI, and 22 patients with inf-AMI were examined. Measurements were obtained 2 to 4 days after AMI and compared with 20 normal subjects (NC) who were matched in terms of age and body weight to the AMI groups. Resting muscle sympathetic nerve activity was quantified from multiunit bursts (MSNA) and from single units (s-MSNA). Both groups of AMI patients were matched with regard to hemodynamic variables, left ventricular function, and infarct size. Both groups had greater (at least P <0.01) sympathetic nerve activity than NC (60±4.3 bursts/100 cardiac beats and 68±4.9 impulses/100 cardiac beats), but the magnitude of sympathetic nerve hyperactivity in ant-AMI (81±4.0 bursts/100 cardiac beats and 91±4.9 impulses/100 cardiac beats) was similar (P >0.05) to that in inf-AMI (80±3.2 bursts/100 cardiac beats and 90±4.0 impulses/100 cardiac beats) Conclusions—Both ant-AMI and inf-AMI resulted primarily in a similar magnitude of sympathetic nerve hyperactivity. These findings suggest that the worse prognosis after ant-AMI compared with after inf-AMI would not be related primarily to the degree of sympathetic hyperactivity.