Differentiated response of the sympathetic nervous system to angiotensin-converting enzyme inhibition in hypertension

Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (P<0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (P<0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved.     

Adrenaline infusion in man increases muscle sympathetic nerve activity and noradrenaline overflow to plasma

This study was conducted to determine if muscle sympathetic nerve activity (MSA) and/or the neuronal release of noradrenaline per impulse are modulated by adrenaline in the physiological plasma concentration range. We gave step-wise infusions of adrenaline (0.05-0.6 nmol/kg per min) to 10 healthy young men and measured: intra-arterial blood pressure; heart rate; central venous pressure (CVP); efferent MSA (microneurography in the peroneal nerve); arterial (brachial artery) and femoral venous plasma concentrations of noradrenaline, and the spillover of noradrenaline to arterial and venous plasma (radiotracer infusion). The infusion of adrenaline caused a fall in diastolic blood pressure and tachycardia, and was associated with increases in MSA and noradrenaline spillover. These observations suggest that part of the adrenaline-induced increase in transmitter release is due to enhanced nerve impulse activity, but such a conclusion rests on the absence of diffusion limitations from the site of noradrenaline infusion into the blood stream. After termination of adrenaline infusion the tachycardia and elevated plasma noradrenaline levels persisted, but these changes were probably due mainly to a profound increase in nerve activity. Concurrently, there was a reduction in CVP which may have triggered the increase in efferent sympathetic nerve activity. Infusions of adrenaline did not influence the clearance of noradrenaline from arterial plasma, but the fractional extraction over the leg was moderately reduced, indicating that more arterial noradrenaline is recovered in venous plasma during adrenaline infusion. The present data suggest that the reasons for the adrenaline-induced increase in noradrenaline release are complex, but they are consistent with the hypothesis that stress levels of adrenaline enhance sympathetic nerve activity, and that circulating adrenaline may modulate both haemodynamic and neural responses to stress.     

Absence of post exercise hypotension and sympathoinhibition in normal subjects: additional evidence for increased sympathetic outflow in borderline hypertension

OBJECTIVE: In young men (mean age 25 years) with borderline hypertension the authors have documented a reduction in systolic blood pressure and muscle sympathetic nerve activity 60 mins after 45 mins of submaximal treadmill exercise. The aim of this study was to determine if post exercise hypotension occurs in normotensive young men, and if so, if it is accompanied by a decrease in sympathetic nerve activity. DESIGN: Replicating a previous protocol, the authors recorded blood pressure, heart rate, plasma noradrenaline and muscle sympathetic nerve activity (microneurography; peroneal nerve) before and 60 mins after submaximal treadmill exercise. SUBJECTS: Ten healthy male volunteers (mean age 28 +/- 5 years). INTERVENTION: Forty-five minutes of treadmill exercise at 70% of resting heart rate reserve. MAIN RESULTS: In contrast to borderline hypertensive subjects, prior exercise had no effect on either systolic or diastolic blood pressure or muscle sympathetic nerve activity in healthy volunteers. Plasma noradrenaline concentrations were similar before and after exercise. Resting heart rate (56 +/- 3 versus 70 +/- 3 beats/min; P less than 0.002), and sympathetic burst frequency (10 +/- 4 versus 20 +/- 2 bursts/min; P = 0.026) were lower in normal than in borderline hypertensive men. CONCLUSIONS: At rest, discharge to muscle sympathetic nerves is increased in young borderline hypertensive men; and blood pressure and sympathetic nerve activity are decreased after exercise in borderline hypertensive but not normotensive men. These observations suggest that the depressor response to prolonged rhythmic exercise in young men with borderline hypertension may be due in part to transient suppression of augmented central sympathetic outflow.     

After-effects of exercise on haemodynamics and muscle sympathetic nerve activity in young patients with dilated cardiomyopathy.

OBJECTIVE: To determine the after-effects on sympathetic nerve activity and calf and systemic haemodynamics of symptom-limited exercise in young patients with dilated cardiomyopathy. PATIENTS: 14 young patients with dilated cardiomyopathy (mean (SEM) age 35 (2) yr) and 17 healthy controls (age 29 (2) yr). METHODS: Blood pressure, muscle sympathetic nerve activity, calf blood flow, plasma noradrenaline, and stroke volume were recorded during baseline rest and an hour after symptom-limited treadmill exercise (up to 45 min) at 70% of resting heart rate reserve. RESULTS: Before exercise, sympathetic nerve activity (45 (6) v 21 (2) bursts.min-1; P = 0.001) and calf vascular resistance (55 (5) v 31 (3) units; P < 0.0005) were higher in the dilated cardiomyopathy group, and there was a significant correlation between these two variables (r = +0.64; P < 0.001). Patients with ventricular dysfunction exercised for 31 (3) min. In both groups there were significant and similar reductions in diastolic blood pressure, total peripheral resistance, and calf vascular resistance after exercise. Sympathetic nerve activity and plasma noradrenaline were unchanged and there was no longer any relation between muscle sympathetic nerve activity and calf vascular resistance. Cardiac output increased in both groups but, in contrast to healthy controls, mean values for systolic blood pressure and stroke volume (P < 0.005) did not decrease in the cardiomyopathy group. For similar reductions in total peripheral resistance, there were two to three fold greater increases in stroke volume after exercise in patients with left ventricular dysfunction (P < 0.03). There was no relation between exercise duration and the magnitude of these after-effects of exercise in these patients. CONCLUSIONS: In young patients with dilated cardiomyopathy the haemodynamic after-effects of submaximal symptom-limited exercise resemble responses to pharmacological afterload reduction but are not accompanied by reflex sympathetic activation. Sustained calf and systemic vasodilation after exercise were not attenuated, as compared with healthy controls. These cardiac, peripheral, and sympathoneural after-effects provide further support for exercise training as a non-pharmacological adjunct to the management of chronic stable heart failure.     

Acute Effects of Short-term Fasting on Blood Pressure,Circulating Noradrenaline and Efferent Sympathetic Nerve Activity

ABSTRACT Eleven moderately obese women, aged 46–62 years, with a body mass index of 29–34 and with borderline hypertension (repeated diastolic blood pressure >90 mmHg) fasted for 48 hours. Before the fast and after 48 hours of fasting, plasma noradrenaline, urinary noradrenaline, urine potassium, urine sodium and weight were measured. In six of the patients muscle nerve sympathetic activity was recorded from the peroneal nerve by tungsten micro-electrodes for 15 min each time. The efferent muscle sympathetic activity (MSA) was expressed as the number of bursts/min. The recordings were done before the fast and after 48 hours of fasting. We found significant decreases in body weight from 88.4±2.5 kg to 86.4±2.5 kg. Systolic blood pressure (BP) was reduced from 158±3 mmHg to 146±5 mmHg (p<0.001) and diastolic BP from 96±3 mmHg to 89±3 mmHg (p<0.01) during the fast. MSA was significantly increased from 42.0±5.5 bursts/min to 44.5±5.8 (n=6), while plasma and urine noradrenaline concentrations (n = 11) showed a non-significant tendency to increase. We conclude that the hypotensive response during the first days of extensive caloric reduction is not due to a decreased sympathetic activity. If anything, there may be weak increase of efferent sympathetic nerve activity and venous plasma levels of circulating noradrenaline. The mechanisms behind the acute hypotensive response to negative caloric balance are thus still unclear, but obviously different from long-term adaptation of the blood pressure.     

Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings

Reports of elevated plasma catecholamine levels and augmented responses to autonomic blockade suggest increased sympathetic tone in borderline hypertension. It is not known if this reflects greater sympathetic neural outflow. We directly recorded muscle sympathetic nerve activity (microneurography) in 15 normotensive and 12 borderline hypertensive age-matched men to determine whether borderline hypertensive individuals have elevated sympathetic nerve activity. Supine heart rate, blood pressure, plasma norepinephrine, and efferent muscle sympathetic nerve activity (peroneal nerve) were measured after 6 days of both low and high dietary sodium intake (10 and 400 meq sodium/24 hr). Sympathetic nerve activity was elevated significantly in borderline hypertensive individuals on both low (37 +/- 1 in borderline hypertensive individuals vs. 29 +/- 1 bursts/min in normotensive individuals; p less than 0.01) and high (25 + 1 in borderline hypertensive individuals vs. 16 +/- 1 bursts/min in normotensive individuals; p less than 0.01) sodium diets. The borderline hypertensive group had higher systolic (p less than 0.01) and diastolic (p less than 0.05) blood pressures independent of sodium intake. Across both groups, high sodium intake reduced muscle sympathetic nerve activity (p less than 0.001), plasma norepinephrine (p less than 0.001), diastolic blood pressure (p less than 0.02), heart rate (p less than 0.002), and increased weight (p less than 0.005). A significant (p less than 0.05) group-by-diet interaction was observed for plasma norepinephrine levels. Specifically, compared with the normotensive group, plasma norepinephrine levels in the borderline hypertensive group tended to be higher on low sodium diet (p = 0.08) and lower on high sodium diet (p = 0.23).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for increased renal norepinephrine overflow during sodium restriction in humans

To investigate the differentiated pattern of efferent sympathetic nerve activity by means of analyzing norepinephrine kinetics in response to sodium restriction, cardiorenal sympathetic activity during rest and mental stress was studied in 12 subjects (33.3 +/- 2.6 years old, SEM) exposed to a low and a normal sodium diet; 5-40 mmol and 160-200 mmol/24 hours, respectively (crossover design). Organ norepinephrine release was calculated from organ plasma flow, arteriovenous plasma concentration gradient across the organ and the organ's fractional extraction of radiolabeled norepinephrine. Body weight and urinary sodium/24 hr fell significantly and urinary potassium/24 hr and both supine and standing blood pressure remained unchanged. Total norepinephrine release to plasma and norepinephrine plasma clearance were similar in both phases (approximately 460 ng/min and 1.90 l/min, respectively). A 138% increase in renal norepinephrine overflow was observed during sodium restriction (from 112 to 267 ng/min, p less than 0.025), which was due to elevated renal vein norepinephrine (434 versus 290 pg/ml, p less than 0.01) because renal plasma flow and renal norepinephrine extraction were unaltered. Similarly, sodium restriction caused a 168% elevation of renal renin secretion (p less than 0.05). Resting cardiac norepinephrine spillover and cardiac norepinephrine reuptake were unchanged between the two salt phases. Total and cardiac norepinephrine release, supine blood pressure, and heart rate increased to about the same extent in response to mental testing regardless of salt phase. In conclusion, sodium restriction induced a differential and physiological increase in resting renal sympathetic nervous activity, leaving cardiac norepinephrine overflow unchanged. Cardiac norepinephrine uptake was normal, which further supports the concept of a true increase of efferent renal nerve activity.     

Effects of the Calcium Antagonist Felodipine on the Sympathetic and Renin-Angiotensin-Aldosterone Systems in Essential Hypertension

ABSTRACT Studies were performed in 10 male patients with untreated essential hypertension, WHO grade I-II, aged 25–62 years, to explore the acute (single dose) and long-term (8 weeks) effects of felodipine on sympathetic activity—evaluated by plasma and urinary catecholamines—as related to blood pressure, heart rate and the activity in the renin-angiotensin-aldosterone system. The patients were hospitalized for 8 (acute) and 6 (long-term) days and were maintained on a standardized daily intake of sodium (150 mmol), potassium (75 mmol) and water (2500 ml). Acute felodipine administration (10 mg) significantly reduced blood pressure and increased heart rate. Plasma and urinary noradrenaline, plasma renin activity and angiotensin II increased, whereas plasma and urinary adrenaline, dopamine, aldosterone and plasma vasopressin were unaltered. Long-term felodipine treatment, 10 mg twice daily, reduced blood pressure to a similar extent as acute felodipine administration, but heart rate was not significantly changed. Plasma noradrenaline 3 and 12 hours after the last dose and urinary noradrenaline were increased, whereas plasma and urinary adrenaline and dopamine were unchanged. Plasma renin activity and angiotensin II were increased 3 hours, but unchanged 12 hours after the last dose. Plasma aldosterone was unchanged but urinary aldosterone increased. Plasma vasopressin was unchanged. The changes in plasma noradrenaline as related to blood pressure, heart rate, plasma renin activity and angiotensin II during long-term felodipine treatment may reflect decreased cardiac and renal β-adrenoceptor-mediated responses. Increased renal clearance of aldosterone could partly explain the unaltered plasma aldosterone level in spite of increased plasma angiotensin II following long-term felodipine treatment.     

Heart rate variability and circulating catecholamine concentrations during steady state exercise in healthy volunteers.

OBJECTIVES--To assess whether exercise induced suppression of heart rate variability in the low frequency domain (0.06-0.15 Hz) is related to the increase in circulating catecholamine concentrations. DESIGN--Randomised crossover trial of three exercise tests characterised by different workloads. Pharmacological simulation of exercise-induced changes in vagal and sympathetic activity. PARTICIPANTS--Six healthy men with a mean age of 31.2 (SD 3.0) years. INTERVENTIONS--Three different workloads of steady state cycling ergometry: control state without cycling, cycling at a target heart rate of 100 beats/min, and cycling at a target heart rate of 150 beats/min. Intravenous infusion of atropine (target heart rate 100 beats/min) followed by the additional infusion of adrenaline and noradrenaline. MAIN OUTCOME MEASURES--Fast Fourier analysis of heart rate variability; blood pressure; and venous plasma concentrations of lactate, adrenaline, and noradrenaline. RESULTS--During the control exercise period there were no changes in the assessed variables compared with the preceding resting period. During exercise at a heart rate of 100 beats/min systolic blood pressure increased and heart rate variability decreased. During exercise at a heart rate of 150 beats/min systolic blood pressure and lactate, adrenaline, and noradrenaline concentrations increased. In addition, low frequency (LF) was lower than during exercise at 100 beats/min, high frequency (HF 0.15-0.80 Hz) resembled that during exercise at 100 beats/min, and diastolic blood pressure was reduced. Infusion of atropine caused no changes in blood pressure or plasma concentrations of lactate, adrenaline, and noradrenaline and decreased heart rate variability. The additional infusion of adrenaline and noradrenaline completely suppressed heart rate variability and increased blood pressure. CONCLUSIONS--The reduction in LF and HF during exercise at a heart rate of 100 beats/min, which is not characterised by increased plasma catecholamine concentrations, and during atropine infusion suggests that heart rate variability in the supine state is largely influenced by vagal activity. The additional reduction in LF during exercise at 150 beats/min and during catecholamine infusion may reflect a negative feedback of circulating catecholamines on the sympathetic control of heart rate.     

Contributions of central sympathetic neural activity to furosemide-induced increases in plasma renin activity and noradrenaline

To evaluate the role of the central nervous system on the furosemide-induced increases in plasma noradrenaline (PNA), renin activity (PRA), and aldosterone concentration (PAC), central vasoactive sympathetic structures were inhibited by intravertebral artery infusion of colnidine. Intravertebral artery infusion of clonidine (0.06 microgram/Kg/min) significantly reduced basal PNA, heart rate, and arterial pressure, while both PRA and PAC were increased. Intravenous infusion of the same dose of clonidine caused no significant changes in PNA, PRA, and PAC. Intravertebral artery infusion of clonidine (0.02 or 0.1 microgram/Kg/min) significantly suppressed the furosemide-induced increases in PNA and heart rate, and induced a drop in arterial pressure. Although the furosemide-induced increase in PRA was suppressed by intravertebral artery infusion of clonidine, the furosemide-induced increase in PAC was not affected. These results suggest that the furosemide-induced increase in PNA may be mediated by the central sympathetic nervous system and that some of the furosemide-induced increase in PRA may be mediated by central sympathetic neural activation.     

Adenosine increases sympathetic nerve traffic in humans

BACKGROUND. Adenosine is an effective hypotensive agent in experimental animals and in anesthetized patients, producing little if any evidence of reflex sympathetic activation. In contrast, adenosine increases systolic blood pressure and heart rate in conscious subjects. To determine whether this response is related to sympathetic activation, we studied the cardiovascular and respiratory effects of adenosine in normal subjects while measuring muscle sympathetic nerve traffic through direct recordings from a peroneal nerve. METHODS AND RESULTS. Adenosine (80 micrograms/kg/min i.v.) increased heart rate (+32 +/- 3 beats/min), systolic blood pressure (+10 +/- 2 mm Hg), and minute ventilation (+7 +/- 1 l/min). This was accompanied by a dose-dependent increase in muscle sympathetic nerve activity (from 198 +/- 52 to 451 +/- 92 units/min). Adenosine also produced a small, but consistent, decrease in diastolic blood pressure (-6 +/- 3 mm Hg). Adenosine produced a greater increase in sympathetic nerve traffic (145 +/- 32% above baseline) than did nitroprusside (65 +/- 16%) at doses that resulted in equivalent decreased in diastolic blood pressure. Arterial baroreceptor unloading, therefore, could not totally explain the increase in sympathetic traffic produced by adenosine. CONCLUSIONS. Given the constellation of findings of increased ventilation and sympathetic activity, we, therefore, propose that adenosine increases sympathetic tone by activating afferent nerves, including arterial chemoreceptors. Contrary to the known inhibitory actions of adenosine on central and peripheral efferent systems, this and other reports suggest that adenosine-induced activation of afferent nerves, leading to sympathetic activation, may be a more widespread phenomenon than previously recognized.     

Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings

OBJECTIVE: To determine if central sympathetic outflow is increased in patients with cirrhosis and ascites. PATIENTS: Eleven patients with cirrhosis and ascites, 8 patients with cirrhosis but without ascites, and 7 age-matched and 8 young healthy volunteers. METHODS: With subjects supine, direct microneurographic recordings of efferent post-ganglionic muscle sympathetic nerve activity were obtained from the peroneal nerve, and sympathetic burst frequency was compared with subjects' blood pressure, heart rate, sodium excretion, catecholamines, and plasma renin activity. All patients with cirrhosis were studied at least 5 days after withdrawal from all medications and after 7 days of a 20 mmol/d sodium, 1-L fluid-restricted diet. Age-matched volunteers were studied after 7 days of 20 mmol/d sodium intake and young healthy volunteers after 7 days of 150 mmol/d sodium intake. RESULTS: Sympathetic nerve activity in ascitic patients (65 +/- 15 bursts/min; mean +/- SD) was markedly increased, whether compared with patients with cirrhosis but without ascites (34 +/- 16 bursts/min; P less than 0.001), age-matched healthy volunteers on similar sodium intake (27 +/- 22 bursts/min; P less than 0.001), or young healthy subjects (21 +/- 10 bursts/min; P less than 0.001). The frequency of muscle sympathetic nerve discharge was directly related to plasma norepinephrine and epinephrine concentrations, plasma renin activity, and heart rate, all of which were increased in those patients with cirrhosis and ascites, and inversely related to 24-hour urinary sodium excretion, the fractional excretion of sodium, and subjects' pulse pressures. Sympathetic nerve activity fell from 78 to 6 bursts/min in one patient after liver transplantation. CONCLUSIONS: This study provides the first direct evidence that elevated plasma norepinephrine concentrations in patients with cirrhosis and ascites are due to increased central sympathetic outflow. Sympathetic nerve activity is not increased in patients with cirrhosis but without ascites. Because there were direct positive correlations of sympathetic nerve activity with plasma norepinephrine concentrations, plasma epinephrine concentrations, plasma renin activity, and heart rate, the increase in central sympathetic outflow in patients with cirrhosis and ascites appears generalized and not restricted to muscle nerves. The anti-natriuretic effects of parallel increases in renal and muscle sympathetic nerve activity could account for the inverse correlation between muscle sympathetic nerve activity and sodium excretion.     

Baroreceptor dysfunction induced by nitric oxide synthase inhibition in humans

OBJECTIVES: We sought to investigate baroreceptor regulation of sympathetic nerve activity and hemodynamics after inhibition of nitric oxide (NO) synthesis. BACKGROUND: Both the sympathetic nervous system and endothelium-derived substances play essential roles in cardiovascular homeostasis and diseases. Little is known about their interactions. METHODS: In healthy volunteers, we recorded muscle sympathetic nerve activity (MSA) with microneurography and central hemodynamics measured at different levels of central venous pressure induced by lower body negative pressure. RESULTS: After administration of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min), systolic blood pressure increased by 24 mm Hg (p = 0.01) and diastolic blood pressure by 12 mm Hg (p = 0.009), while stroke volume index (measured by thermodilution) fell from 53 to 38 mL/min/m2 (p < 0.002). Administration of L-NMMA prevented the compensatory increase of heart rate, but not MSA, to orthostatic stress. The altered response of heart rate was not due to higher blood pressure, because heart rate responses were not altered during infusion of the alpha-1-adrenoceptor agonist phenylephrine (titrated to an equal increase of systolic blood pressure). In the presence of equal systolic blood pressure and central venous pressure, we found no difference in MSA during phenylephrine and L-NMMA infusion. CONCLUSIONS: This study demonstrates a highly specific alteration of baroreceptor regulation of heart rate but not muscle sympathetic activity after inhibition of NO synthesis in healthy volunteers. This suggests an important role of NO in reflex-mediated heart rate regulation in humans.     

Effects of incremental infusions of atrial natriuretic factor on aldosterone, renin, and blood pressure in humans

To evaluate the physiological effects of human atrial natriuretic factor-(99-126) (ANF), we infused ANF, 0.1, 0.3, and 1.0 micrograms/min, or placebo for 125 minutes on different days into six sodium-deprived normal men. During the last 45 minutes of infusion, angiotensin II, 6 ng/kg/min, was infused. Blood pressure, heart rate, plasma concentrations of ANF, aldosterone, and cortisol, and plasma renin activity (PRA) were measured before and during infusion. Steady state mean plasma ANF levels during infusion were 26.2 (placebo), 68.8 (0.1 micrograms ANF/min), 221 (0.3 micrograms ANF/min), and 648 pg/ml (1.0 microgram ANF/min). Systolic blood pressure fell significantly (with 1.0 microgram ANF/min), and diastolic pressure tended to rise in a dose-dependent manner, while heart rate was unchanged. PRA and plasma aldosterone fell during ANF infusion in a dose-dependent manner (significant with 0.3 and 1.0 microgram ANF/min infused). The blood pressure-raising and aldosterone-stimulating effects of angiotensin II were blunted by ANF (significant only with 1.0 microgram ANF/min). It is concluded that effects of ANF on blood pressure and the renin-aldosterone system occur with plasma ANF levels close to the physiological range, as well as with slightly elevated ANF levels, as observed in congestive heart failure and renal insufficiency.     

The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target?

Polycystic ovary syndrome (PCOS) is a common endocrine condition associated with long‐term health risks, including type 2 diabetes and vascular dysfunction in addition to reproductive sequelae. Many of the common features of PCOS, such as central obesity, hyperinsulinaemia and obstructive sleep apnoea (OSA), are associated with chronic sympathetic overactivity, suggesting that sympathoexcitation may be involved in the pathogenesis of this condition. Rodent models of polycystic ovaries have shown that ovarian sympathetic outflow may be increased, accompanied by elevated intra‐ovarian synthesis of nerve growth factor (NGF) which may be involved in initiation of ovarian pathology. Patients with PCOS have evidence of increased muscle sympathetic nerve activity (MSNA), altered heart rate variability and attenuated heart rate recovery postexercise, compared with age‐ and BMI‐matched controls, suggesting a generalized increase in sympathetic nerve activity. Active weight loss can reduce MSNA and whole body noradrenaline spillover, whereas low‐frequency electroacupuncture decreased MSNA in overweight women with PCOS. Treatment of OSA with continuous positive airways pressure may reduce plasma noradrenaline levels and diastolic blood pressure and improve cardiac sympathovagal balance. Renal sympathetic denervation also reduced MSNA, noradrenaline spillover and blood pressure in two PCOS subjects with hypertension, accompanied by improved insulin sensitivity. The sympathetic nervous system may thus offer a new therapeutic target in PCOS but larger and longer‐term studies are needed before these treatments can be considered in clinical practice.     

Effects of low-dose nifedipine GITS on sympathetic activity in young and older patients with hypertension

BACKGROUND: Dihydropyridines have both sympathoexcitatory and sympathoinhibitory effects. To date, the latter have been characterized only in animals. During chronic treatment with long-acting dihydropyridines, sympathoexcitatory effects mediated via the arterial baroreflex are unlikely. However, increases in plasma angiotensin II in response to dihydropyridines could contribute to increases in sympathetic activity during chronic treatment. Such increases may be less in older than in young patients. METHODS: We evaluated the effects of 4 weeks of treatment with low-dose nifedipine gastrointestinal therapeutic system (GITS; 20 mg/day) compared with placebo on muscle sympathetic nerve activity and plasma noradrenaline, in relation to changes in plasma renin activity and plasma angiotensin II and blood pressure in young and older patients with mild hypertension. RESULTS: Nifedipine GITS decreased systolic and diastolic blood pressures significantly, by 10 +/- 3 mmHg and 7 +/- 2 mmHg respectively, in older patients (age 67 +/- 2 years), but not in younger patients (age 45 +/- 2 years) (decreases of 1 +/- 3 mmHg and 1 +/- 2 mmHg, respectively). Nifedipine GITS caused only minor changes in plasma renin activity and plasma angiotensin II in young and older patients. Compared with changes in response to placebo (-5.7 +/- 2.4 bursts/min), sympathetic activity was increased significantly by nifedipine GITS in the young patients (2.0 +/- 1.7 bursts/min; P < 0.05), but not in older patients (5.4 +/- 1.3 bursts/min by placebo compared with 4.1 +/- 3.5 bursts/min by nifedipine GITS). CONCLUSION: We conclude that age-related differences in the response of muscle sympathetic nerve activity (and plasma noradrenaline) to low-dose nifedipine GITS in patients with mild hypertension are unlikely to be mediated by plasma angiotensin II. An increase in sympathetic activity may contribute to the absent blood pressure response in young patients with hypertension.     

Platelet-activating factor and anti-platelet-aggregating factor in acute reduction of blood pressure following percutaneous transluminal renal angioplasty in patients with renovascular hypertension

The mechanism of the acute fall of BP following percutaneous transluminal renal angioplasty (PTRA) was studied in four patients with renovascular hypertension caused by fibromuscular dysplasia. One hour after PTRA, systemic blood pressure and plasma renin activity in the ipsilateral renal venous blood decreased significantly (P less than 0.05), but the plasma noradrenaline level in ipsilateral renal venous blood increased significantly (P less than 0.05). At the same time, a platelet-activating factor (PAF) and an unidentified factor that inhibited the aggregation of rabbit platelets induced by PAF, arachidonic acid or ADP were detected in the ipsilateral renal venous blood, but were not found in the contralateral renal venous blood. Plasma noradrenaline level in cubital venous blood decreased significantly (P less than 0.05) after 24 hours as compared with that before PTRA and BP also maintained the normal level. These results suggest that the reduction in plasma renin activity is associated with the acute reduction in BP following PTRA. PAF and an unidentified factor blocking the aggregation of platelets may be involved in ipsilateral renal venous blood following PTRA in patients with renovascular hypertension. The reduction in plasma noradrenaline level is an additional mechanism involved in maintaining normal BP following PTRA in the late stage.     

Effects of low-dose epinephrine infusion on cardiovascular and renal responses to water immersion in humans

Elevated plasma epinephrine concentrations may impair blood pressure homeostasis and renal sodium and volume excretion in response to central hypervolemia. We studied the effects of a low-dose epinephrine infusion (12 ng/kg/min) on cardiovascular and renal responses to a thermoneutral head-out water immersion in eleven healthy men.Responses to water immersion without epinephrine were characterized by significant suppression of plasma renin activity (PRA), plasma aldosterone concentration, and renal norepinephrine excretion, and an augmentation of natriuresis and diuresis. Epinephrine infusion, which raised mean plasma epinephrine concentration 4.3-fold, slightly increased plasma norepinephrine and renal norepinephrine excretion, markedly stimulated PRA (+66.7%), but decreased plasma aldosterone (−11.7%), and augmented renal sodium and volume excretion. Despite the presence of the epinephrine infusion, water immersion continued both to suppress PRA and aldosterone, and to increase natriuresis and diuresis in a qualitatively similar pattern. During all conditions blood pressure and heart rate remained unchanged.It is concluded that physiologic responses to central hypervolemia are not impaired at stress levels of circulating epinephrine. During epinephrine infusion, despite a concomitant increase in plasma norepinephrine and a stimulation of PRA, blood pressure remained constant in response to water immersion due to an augmentation of natriuresis and diuresis.     

Inhibition of adrenergic neurotransmission in ischaemic regions of the canine left ventricle

To test hypothesis that adrenergic neurotransmission is impaired in acute myocardial ischaemia, we studied contractile function of normal and ischaemic myocardium after coronary artery occlusion. For each area we compared the contractile response to left sympathetic nerve stimulation (LSS) with the response to exogenous noradrenaline (NA). Contractile response was measured with intramyocardial sonomicrometers. LSS increased aortic pressure and heart rate. NA was infused to achieve an aortic pressure equivalent to LSS and simultaneous atrial pacing matched the heart rate during LSS. In normal zones both interventions produced increased shortening equivalently. In ischaemic zones systolic expansion was unchanged during LSS, while NA improved contractile function of the same zones by decreasing systolic expansion. These responses occurred during ischaemia produced by either anterior or posterior descending coronary occlusion. Changes in regional blood flow, measured by 8 microns radiolabelled microspheres, could not account for the difference between the ischaemic regional response to LSS or NA. We conclude that acute regional ischaemia impairs adrenergic nerve transmission.     

Alcohol stimulation of renin release in man: its relation to the hemodynamic, electrolyte, and sympatho-adrenal responses to drinking

Alcohol stimulation of the renin-angiotensin axis has been proposed as an explanation for the higher blood pressure in drinkers. This study examines the acute effects of moderate alcohol intake on PRA in relation to change in fluid and electrolyte balance, sympatho-adrenal activity, blood pressure, and heart rate in 20 normal men, aged 20-24 yr. They consumed either 750 ml nonalcoholic beer as a control or the same beverage with 1 ml/kg alcohol added, which increased the plasma alcohol concentration to 16.7 +/- 1.0 (+/- SE) mM within 70 min. PRA increased more than 2-fold 90 min after the ingestion of alcohol. This was accompanied by a decrease in diastolic blood pressure and a fall in plasma potassium, both possible stimuli to the rise in PRA. A late increase in plasma sodium, also occurring 90 min after alcohol ingestion, was attributed to plasma volume contraction after an alcohol-induced diuresis. This may have been an additional factor in stimulating renin release. Norepinephrine levels increased during both alcohol and control studies. In contrast, plasma epinephrine decreased significantly during the control study, but did not change after alcohol ingestion. Hence, alcohol stimulation of sympathetic nervous activity is unlikely to have mediated the renin release. We conclude that the acute increase in PRA associated with moderate alcohol consumption is predominantly a secondary response to changes in fluid and electrolyte balance and blood pressure. Although a direct action of alcohol on renin release was not excluded, the possibility that repeated activation of the renin-angiotensin system mediates the pressor effect of regular moderate alcohol consumption is, therefore, diminished.