Single-unit sympathetic discharge : quantitative assessment in human hypertensive disease.

Background-Reports demonstrating sympathetic hyperactivity in hypertension with the use of microneurography have been inconsistent. One possible reason is that previous studies have assessed muscle sympathetic nerve activity (MSNA) from integrated voltage waves ("bursts") recorded from multiunit discharges. We studied single units with defined vasoconstrictor properties (s-MSNA) to further characterize sympathetic output in hypertensive disease. Methods and Results-We examined 74 subjects with a wide range of arterial blood pressure that were considered to be either normal (NT), high normal (HN), or stages 1 to 3 essential hypertension (EHT-1, EHT-2/3). All had their peripheral sympathetic activity measured from both multiunit bursts and single-unit vasoconstrictor impulses. There was a significant correlation between s-MSNA and MSNA, and results of variability studies were similar. The EHT-1 and EHT-2/3 groups had greater s-MSNA and MSNA than did the matched NT group (always P<0. 01). The HN group also had greater s-MSNA and MSNA than did the NT group (mean+/-SEM; 43+/-5 vs 29+/-2 impulses/100 beats, P<0.05; 36+/-4 vs 24+/-2 bursts/100 beats, P<0.05). In addition, the EHT-1 group had significantly greater s-MSNA than did the EHT-2/3 group (63+/-6 vs 51+/-3 impulses/100 beats, P<0.05), which could not be demonstrated with MSNA bursts. Conclusions-Quantification from single vasoconstrictor units has provided additional evidence in established essential hypertension of increased central sympathetic output. Furthermore, in the mild or early stages of hypertension, this technique has provided new evidence of augmented sympathetic output compared with more severe hypertension.

Sympathetic neural mechanisms in normal and hypertensive pregnancy in humans.

BACKGROUND: Direct recordings from peripheral sympathetic nerves have shown an increased sympathetic drive in pregnancy-induced hypertension (PIH) and preeclampsia (PE). It is unknown whether sympathetic drive is altered in normal pregnancy, when arterial blood pressure can be normal or relatively low. The aim of this study was to measure and compare peripheral sympathetic discharge, its vasoconstrictor effect and its baroreceptor control, during pregnancy and postpartum in women with normal pregnancy (NP) and PIH and in normotensive nonpregnant (NN) women. METHODS AND RESULTS: Twenty-one women with NP, 18 women with PIH, and 21 NN women had muscle sympathetic nerve activity assessed from multiunit discharges (MSNA) and from single units with defined vasoconstrictor properties (s-MSNA). The s-MSNA in NP (38+/-6.6 impulses/100 beats) was greater (P<0.05) than in NN women (19+/-1.8 impulses/100 beats) despite similar age and body weight but less than in PIH women (P<0.001) (146+/-23.5 impulses/100 beats). MSNA followed a similar trend. Cardiac baroreceptor reflex sensitivity (BRS) was impaired in NP and PIH women relative to NN. After delivery, sympathetic activity decreased to values similar to those obtained in NN, and there was an increase in BRS. In women with NP, the decrease in sympathetic output occurred despite an insignificant change in blood pressure. CONCLUSIONS: Central sympathetic output was increased in women with normal pregnancy and was even greater in the hypertensive pregnant group. The findings suggest that the moderate sympathetic hyperactivity during the latter months of normal pregnancy may help to return the arterial pressure to nonpregnant levels, although when the increase in activity is excessive, hypertension may ensue.

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.

Detection of severity of coronary artery disease by the ST segment/heart rate relationship in patients on beta-blocker therapy.

Many patients presenting with anginal pain are on beta-blocker therapy and it has been suggested that noninvasive exercise tests for coronary artery disease are adversely affected by such therapy. Recently a new exercise test has been introduced claiming the ability accurately to detect the presence and severity of coronary heart disease in patients with anginal pain; the claim was based on results obtained in patients not undergoing beta-blocker therapy. Therefore using this test, the maximal rate of progression of ST segment depression relative to increases in heart rate during exercise (maximal ST/HR slope) as an index of the severity of myocardial ischaemia, 60 patients on beta-blocker therapy were studied and the results compared with results of coronary arteriography independently obtained. There was a complete agreement, without false results, between the maximal ST/HR slope and the number of significantly diseased coronary arteries. In 21 of these 60 patients the maximal ST/HR slopes obtained before and after beta-blockade were compared; the maximal ST/HR slopes after beta-blockade were not different from those before. It is concluded, that the maximal SR/HR slope can be used reliably to detect the pressure and the severity of coronary heart disease in patients with angina pectoris who are already on beta-blocker therapy.

Chronic I(1)-imidazoline agonism : sympathetic mechanisms in hypertension.

Evidence exists for a state of sympathetic hyperactivity in essential hypertension, and moxonidine, a new central sympathetic inhibitor, has been introduced for its treatment. Acute administration of moxonidine lowers peripheral sympathetic neural output. This study examined the effect of chronic moxonidine therapy, at increasing therapeutic doses, on resting peripheral sympathetic activity and vascular resistance and their responses to physiological reflex maneuvers. Twelve newly diagnosed patients with essential hypertension were studied sequentially at least 1 month apart, initially on no therapy, then on 200 microg, and finally on 400 microg of oral moxonidine daily. Changes in heart rate, arterial blood pressure, calf vascular resistance, and peripheral sympathetic drive were assessed at rest and during reflex maneuvers. Peroneal microneurography was used to quantify peripheral sympathetic vasoconstrictor activity by single-unit and multiunit techniques. Moxonidine therapy progressively reduced resting mean arterial pressure (P<0.0001) without affecting heart rate. At 200 microg daily, there was a significant reduction in sympathetic nerve activity (P<0.001) and calf vascular resistance (P<0.01). At 400 microg daily, further reductions were smaller and insignificant. Responses to cold stimulus and isometric handgrip exercise showed a similar pattern, with the greatest magnitude of change at 200 microg daily. In patients with essential hypertension, chronic moxonidine therapy inhibited resting sympathetic vasoconstrictor drive and also its reflex responses. The magnitude of inhibition became less as the therapeutic dose was increased, suggesting that moxonidine may be more effective under conditions of high sympathetic activity.

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 pre-eclampsia 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.

Blockade of peripheral vascular responses to isoprenaline by three beta-adrenoceptor antagonists in the anaesthetized dog.

1 A dog's hind limb was vascularly isolated by strong nylon snares and its sympathetic nerve supply interrupted. Blood was perfused at constant flow into the femoral artery and drained from the femoral vein. In some dogs the cardiac nerves were cut.2 Isoprenaline infused intravenously caused an increase in heart rate and a decrease in arterial resistance.3 Practolol (2 mg/kg) effectively blocked heart rate responses to isoprenaline infused at up to 10 mug/min but was relatively ineffective in blocking arterial responses. ICI 66082 (2 mg/kg) reduced vasomotor responses and propranolol (0.5 mg/kg) abolished vasomotor responses.4 Small cumulative doses of beta-adrenoceptor antagonists were given to some dogs. Practolol blocked heart rate responses in lower doses than were required to block vasomotor responses. Propranolol preferentially blocked vasomotor responses and ICI 66082 was intermediate between the other two in its effects.

Mechanisms of the renal vasodilation caused by insulin in anesthetized pigs.

The present study was planned to determine the mechanisms involved in the renal vasodilation caused by insulin. Changes in flow caused by the intravenous infusion of 0.004 IU/kg/min of insulin at constant heart rate, aortic blood pressure, left ventricular contractility and blood levels of glucose and potassium in the left renal artery were assessed using an electromagnetic flowmeter. In ten pigs, infusion of insulin caused an increase in renal blood flow which averaged 12.8% of the control values. After hemodynamic variables had returned to control values, insulin infusion was repeated in five pigs following blockade of alpha-adrenergic receptors with injection of phentolamine into the renal artery and in the other five pigs following blockade of nitric oxide formation with injection in the same artery of Nomega-nitro-L-arginine methyl ester (L-NAME). After blockade of alpha-adrenergic receptors, insulin infusion caused an increase in renal blood flow which averaged 18.1% of the control values, being significantly enhanced with respect to the increase previously obtained in the same pigs. On the contrary, after blockade of nitric oxide formation insulin infusion caused a decrease in renal blood flow which averaged 6.5% of the control values. These responses were respectively abolished by the subsequent injection into the renal artery of L-NAME and phentolamine. The present study showed that the renal vasodilation caused by insulin in the anesthetized pig was the result of two opposite effects which involved a predominant vasodilation mediated by the release of nitric oxide from the endothelium and a sympathetic vasoconstrictor mechanism mediated by alpha-adrenergic receptors.

Changes in myocardial ischaemia during isosorbide dinitrate or indoramin therapy in patients with stable angina using relations between the ST segment and heart rate.

The effect of isosorbide dinitrate or indoramin on myocardial ischaemia was examined in patients with stable angina pectoris. In a prospective trial, randomization resulted in 8 and 9 patients, respectively, given isosorbide dinitrate in a dose of 30-90 mg daily, and indoramin in a dose of 75-225 mg daily; 2 of these patients were serially examined during the two types of therapy. Changes in myocardial ischaemia were assessed by exercise testing using 12 standard electrocardiographic leads and a bipolar lead CM5. Individual and group comparisons showed that isosorbide dinitrate resulted in an increase in ST segment depression, the maximal ST/heart rate slope and the ratio of net ST segment depression to increases in heart rate (at least P less than 0.01). In contrast, with indoramin therapy there were no significant changes in these indices. The results in these patients suggest that isosorbide dinitrate leads more consistently to increases in the severity of myocardial ischaemia than indoramin, although this effect on ischaemia is apparently less than the benefit of these agents on exercise performance.

Long-term comparison of metoprolol and methyldopa in the treatment of hypertension.

The effect of the cardioselective beta-adrenoreceptor blocking compound, metoprolol, was compared with methyldopa in the long-term management of hypertension. Thirty patients given metoprolol and twenty-six given methyldopa were treated for 2 years. The maximum dose of metoprolol was 200 mg twice daily (average 308 mg) and of methyldopa 1,000 mg twice daily (average 1,120 mg). Blood pressure was similar at entry to the study (metoprolol 177/110 mmHg and methyldopa 181/111 mmHg). After 2 years of treatment the blood pressure levels were again similar (metoprolol 149/91 mmHg and methyldopa 148/91 mmHg). Erect pressures were lower in the methyldopa group, but there was no difference between supine and erect blood pressure levels in those on metoprolol. At an exercise load of 300 and 600 kpm the increase in systolic pressure was significantly less in the metoprolol group. The proportional increase in systolic and diastolic pressure in response to a standardized stress situation was reduced by treatment with metroprolol but not by methyldopa. Tolerance to therapy did not develop in either group. The main difference between metoprolol and methyldopa was in the incidence and severity of side effects. Four patients were withdrawn from the metoprolol group. Seventeen were withdrawn from the methyldopa mainly because of side effects including drowsiness, depression, skin rash, and impotence. Six patients on metoprolol and seventeen on methyldopa continued on therapy although side effects were present. It is concluded that metoprolol and methyldopa lower blood pressure to the same extent, but metoprolol is advantageous because of a lower incidence of side effects.

Nuclear magnetic moment of the 57Cu ground state.

The nuclear magnetic moment of the ground state of (57)Cu(Iota(pi) = 3/2(-), T(1/2) = 196.3 ms) has been measured to be /mu((57)Cu)/ = (2.00 +/- 0.05)mu(N) using the beta-NMR technique. Together with the known magnetic moment of the mirror partner (57)Ni, the spin expectation value was extracted as = -0.078 +/- 0.13. This is the heaviest isospin mirror T = 1/2 pair above the (40)Ca region for which both ground state magnetic moments have been determined. The discrepancy between the present results and shell-model calculations in the full f p shell giving mu((57)Cu) approximately 2.4mu(N) and approximately 0.5 implies significant shell breaking at (56)Ni with the neutron number N = 28.

The influence of aortic baroreceptors on venous tone in the perfused hind limb of the dog.

1. The aortic arch and both carotid sinuses were vascularly isolated and perfused. A hind limb was vascularly isolated and blood was pumped at constant flows into the femoral artery and the central end of a superficial metatarsal vein. 2. Large increases in aortic arch pressure resulted in decreases in arterial blood pressure, heart rate and femoral arterial perfusion pressure. The average response of the vein was a decrease of 11% in the pressure gradient between the perfused vein and the femoral vein. Similar responses were obtained when carotid sinus pressure was increased. 3. Crushing or cooling the lumbar sympathetic trunk caused responsed similar to those induced by increasing baroreceptor perfusion pressure. Stimulation at 1 HZ resulted in venous responses four times as great as the average reflex response, whereas frequencies of 2-5 Hz were required to produce changes in arterial resistance as great as those induced reflexly. 4. These experiments indicate, that although the large superficial veins of the dog's hind limb participate in the baroreceptor reflexes, the activities in the nerves supplying arterioles and veins must have been different.

The activity of single vasoconstrictor nerve units in hypertension.

AIM: It has long been established from controlled experiments in anaesthetized animals that it is more accurate to quantify the mean frequency of efferent sympathetic nerve activity from single unit than from multi-unit bursts recordings. More recently, sympathetic nerve hyperactivity has been reported in patients with essential hypertension (EHT) when using microneurographic recordings from peripheral efferent nerves. This review will focus on the mean frequency of single unit of muscle sympathetic nerve activity (s-MSNA) in relation to that of multi-unit bursts (MSNA) as obtained by microneurography in EHT. RESULTS: We have shown that the resting levels of s-MSNA and MSNA were increased in uncomplicated EHT, white coat hypertension and in EHT complicated by left ventricular hypertrophy. There was a relatively greater increase in s-MSNA than in MSNA in mild hypertension and in complicated EHT. We also found that both s-MSNA and MSNA were increased to a similar extent in conditions known to affect reflexes emanating from the heart and influencing sympathetic output, such as acute myocardial infarction. In other preliminary studies, the increase of s-MSNA in response to the discomfort of cold pressor test was greater than that of MSNA and this difference was abolished by the centrally sympatholytic agent moxonidine. CONCLUSION: These results are consistent with the hypothesis that an increase in the mean frequency of central sympathetic discharge to the periphery (greater s-MSNA than MSNA) is involved in the pathogenesis and complications of EHT. Target organ damage may in turn lead to an increase in overall sympathetic output (excessive MSNA increase) through the operation of peripheral reflex mechanisms.