Flow dependence of forearm noradrenaline overflow, as assessed during mental stress and sodium nitroprusside infusion

OBJECTIVE: To evaluate the influence of blood flow on measurements of regional sympathetic nerve activity by radiotracer methodology ([3H]noradrenaline). DESIGN: Ten healthy men were studied under two conditions of elevated forearm blood flow: mental stress (Stroop colour word conflict test) and an intra-arterial infusion of sodium nitroprusside. METHODS: Arterial blood pressure was measured invasively and forearm blood flow with strain-gauge plethysmography. Arterial and venous plasma adrenaline and noradrenaline were measured with high-performance liquid chromatography, and regional and total noradrenaline spillover were calculated. RESULTS: During mental stress, mean arterial pressure increased by 17%, heart rate by 16 beats/min, forearm blood flow by 117%, while forearm vascular resistance decreased by 44% (P < 0.001 for all). Sodium nitroprusside increased forearm blood flow dose-dependently, but elicited only minor effects on systemic haemodynamics. Mental stress increased arterial plasma noradrenaline by 52% (P < 0.001), and total body noradrenaline spillover by 75% (P < 0.001). During sodium nitroprusside infusion, arterial plasma noradrenaline increased only slightly and total body noradrenaline spillover was unaffected Forearm noradrenaline overflow increased from 5.4 +/- 0.9 to 16.9 +/- 2.6 pmol/min per I (P < 0.001) during mental stress and from 6.6 +/- 0.8 to 16.9 +/- 3.7 pmol/min per I (P < 0.001) during the second dose-step of sodium nitroprusside infusion. By intra-individual comparisons of forearm noradrenaline overflow increases during mental stress and during sodium nitroprusside infusion, with similar forearm blood flow increases, the flow dependence of forearm noradrenaline overflow was estimated. During mental stress, about 60% (median value, range 29-112%) of the increase in forearm noradrenaline overflow was attributed to the increase in forearm blood flow, whereas 40% was considered to reflect increased sympathetic nerve activity. CONCLUSIONS: There seems to be a considerable flow dependence of the regional overflow of noradrenaline, that is, a component of simple wash-out of noradrenaline from the forearm tissues during vasodilation. However, the present results still indicate that sympathetic nerve activity in the forearm is increased during mental stress, justifying the radiotracer technique for semiquantitative measurements, also during vasodilation.     

Magnesium sulphate infusion suppresses the cardiac release of noradrenaline during a handgrip stress test

BACKGROUND: Magnesium has several important cardiovascular effects, but its effect on cardiac sympathetic efferent neuron activity has not been clarified. Objectives: To examine the effect of magnesium sulphate infusion on cardiac sympathetic efferent postganglionic neuronal liberation of noradrenaline. PATIENTS AND METHODS: Twenty-two patients who underwent cardiac catheterization were randomly allocated to the control group or the magnesium group. Plasma noradrenaline and adrenaline concentrations in the aorta and the coronary sinus were measured. Noradrenaline or adrenaline release from the heart was calculated by dividing the difference in noradrenaline or adrenaline concentration between the aorta and the coronary sinus by that of the aorta. After baseline blood sampling, the control patients and the patients in the magnesium group received intravenous infusion of saline or magnesium sulphate (10 mmol). All patients were then subjected to 3 min of handgrip exercise stress test to augment sympathetic efferent neuronal activity, and the blood sampling was repeated. RESULTS: Although blood pressure was increased by the handgrip stress test, there were no differences in heart rate and blood pressure between the two groups, both at baseline and during the handgrip stress test. The plasma noradrenaline and adrenaline concentrations and noradrenaline or adrenaline release from the heart did not differ between the two groups in the baseline condition. However, the handgrip stress increased plasma noradrenaline concentrations and the cardiac noradrenaline release was increased in the control group, whereas the cardiac noradrenaline release was not increased by the handgrip stress in the magnesium group (P<0.02). CONCLUSIONS: These data indicate that magnesium sulphate infusion suppresses the release of catecholamines by the heart, which is an indirect index of sympathetic efferent neuronal activity.     

Reflexogenic neuronal and humoral responses to selective stimulation of low-pressure cardiopulmonary receptors in man.

This study was conducted to determine the relative importance of efferent muscle sympathetic nerve activity (MSA), vasopressin (ADH) and atrial natriuretic peptide (ANP) in the short-term neurohumoral response to moderate changes in low-pressure cardiopulmonary receptor activity. The low-pressure receptors were stimulated and unloaded, respectively, by autotransfusion of blood (450 ml) and the application of lower body negative pressure (LBNP, -20 mmHg), and in 11 healthy men we measured MSA in the left peroneal nerve, indirect blood pressure, ECG, central venous pressure (CVP) and venous plasma concentrations of ANP and ADH (radioimmunoassay). Total MSA rose by 30% during LBNP and decreased during a rapid autotransfusion of blood, and the changes in MSA were significantly related to changes in CVP. The plasma concentrations of ADH and ANP were not significantly affected by either procedure. It is suggested that during moderate short-term changes in venous return, MSA responded more rapidly and/or at a lower threshold than the ADH and ANP systems.     

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.     

Stress levels of adrenaline amplify the blood pressure response to sympathetic stimulation

The possibility that sympathetic pressor responses are modulated by adrenaline-mediated facilitation of neuronal noradrenaline release was explored in 17 subjects with borderline hypertension. Infusion of adrenaline, which raised plasma adrenaline by a factor of 8 to 9, augmented the rise in systolic and diastolic arterial pressure induced by standardized cold pressor and isometric exercise tests. The heart rate response to these tests was not affected. When a low dose of propranolol was given on top of the adrenaline infusion before the cold pressor test, the blood pressure response to cold exposure was not different from the response observed when the test was performed during saline infusion. Plasma noradrenaline was higher during adrenaline infusion then during saline infusion, both before and after the cold pressor and isometric exercise tests, and the effect of adrenaline on plasma noradrenaline was antagonized by propranolol. These observations are consistent with the hypothesis that stress levels of circulating adrenaline may amplify sympathetic pressor responses by facilitation of the release of transmitter noradrenaline.     

Effect of saralasin upon plasma catecholamines in hypertensive patients

The effect of saralasin, a clinically employed angiotensin antagonist, upon hemodynamics and plasma catecholamine concentration was compared to the infusion of noradrenaline. These studies were carried out to determine if a transient pressor effect frequently observed during saralasin infusion might be mediated by release of catecholamines from the adrenal medulla. After five minutes of saralasin infusion, mean arterial pressure rose significantly, pulse rate fell slightly, and plasma noradrenaline increased by 115 +/- 28 pg./ml. Plasma adrenaline was unchanged. After 30 minutes of saralasin infusion, mean arterial pressure was at control levels and plasma catecholamine concentrations were also no different from pre-infusion levels. Infusion of noradrenaline produced a hemodynamic pattern similar to that observed during the first five minutes of saralasin infusion. However, there was a thirteen-fold increase of plasma noradrenaline observed when compared to the first five minutes of saralasin infusion. It was concluded that the transient pressor action of saralasin could not be explained by release of catecholamines from the adrenal medulla. However, the very slight increase in plasma norepinephrine observed during the first five minutes of saralasin infusion may imply altered function of sympathetic neurons.     

Total and renal sympathetic nervous system activity in alcoholic cirrhosis

Basal sympathetic nervous system activity was assessed in 8 unmedicated patients with alcoholic cirrhosis using a previously developed radiotracer method for measuring total and renal noradrenaline release to, and clearance from, plasma. Compared to the control group total noradrenaline clearance was significantly increased in the patients with advanced alcoholic cirrhosis (Pugh grade C) [1.89 +/- 0.13 vs 1.51 +/- 0.11 l/min, P less than 0.05) indicating that endogenous plasma noradrenaline levels underestimate total sympathetic nervous system activity in these patients. Renal noradrenaline clearance was similar to controls independent of the severity of the liver disease. Both total and renal noradrenaline release were significantly increased in the patients with cirrhosis. The ratio of renal to total noradrenaline release was similar in cirrhotic (26 +/- 7%) and control (23 +/- 5%) groups. Increased arterial plasma adrenaline levels, indicative of adrenal medullary stimulation, were also evident in the patients with cirrhosis and correlated significantly with total noradrenaline spillover (r = 0.732, P less than 0.05). These results strongly suggest that in patients with cirrhosis, rather than a preferential increase in renal sympathetic tone, the increase is part of a pattern of generalized sympathoadrenomedullary activation. Although renal renin secretion was significantly increased in the cirrhotic group no correlation with renal noradrenaline release was seen (r = 0.199), raising the possibility that in cirrhosis renal sympathetic tone is not a major determinant of renal renin secretion. Finally, renal noradrenaline release did not correlate with renal blood or plasma flow but an influence of the sympathetic nervous system on renal function was suggested by the correlation observed between total noradrenaline spillover and impaired salt (r = -0.683, P less than 0.05) and water excretion (r = -0.702, P less than 0.05) demonstrated in the cirrhotic patients.     

Increased arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism during hypothyroid as compared to euthyroid state.

The use of venous plasma noradrenaline levels as a marker of general sympathetic tone has been questioned as changes in local sympathetic activity may influence the venous levels. To compare arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism, arterial and venous blood were sampled during strictly standardized conditions during hypothyroid and euthyroid states. The patients were hospitalized for 5 days at a metabolic ward on a standardized sodium and potassium intake. On the fourth day catheters were positioned in the axillary artery and vein. Blood samples were drawn simultaneously for noradrenaline and adrenaline determinations during resting conditions. The arterial and venous plasma noradrenaline levels did not differ significantly, neither during hypothyroidism nor during euthyroidism. The arteriovenous difference in plasma adrenaline was similar during hypothyroidism compared to euthyroidism, indicating similar peripheral extraction rate of catecholamines during hypothyroidism as compared to euthyroidism. During hypothyroidism venous and arterial noradrenaline were significantly higher as compared to euthyroidism. In conclusion, there is no difference between arterial and venous noradrenaline levels either in the hypothyroid or the euthyroid state, and the peripheral extraction rate of plasma noradrenaline seems to be similar in hypothyroidism and euthyroidism. The local contribution of noradrenaline from the arm, reflecting local sympathetic nervous activity, is limited during resting conditions. In hypothyroid patients plasma noradrenaline levels are increased as compared to the euthyroid state, indicating increased general sympathetic activity in hypothyroidism.     

Noradrenaline release and sympathetic nervous system activity

Measurements of the plasma concentration of noradrenaline, or more specifically the rate at which noradrenaline enters plasma, provide a useful guide to sympathetic nervous system function in humans. The overall rate of release of noradrenaline to plasma gives an overview of sympathetic nervous system activity (integrated nerve firing rate), detecting generalized changes, whether occurring as a reflex response, produced by drugs, or accompanying disease processes. The pattern of sympathetic nervous activation, however, is not delineated, only the net change in neurotransmitter release. Measurement of regional rates of noradrenaline release allows the clinical assessment of organ-specific sympathetic nervous tone, and consequently more penetrating analysis of sympathetic nervous system pathophysiology in disease states. The major problem in interpreting regional noradrenaline spillover measurements lies in the difficulty in differentiating those changes in noradrenaline spillover due to altered nerve firing, from those due to extraneous factors which might also affect spillover, such as the possible influence of blood flow on noradrenaline washout.     

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.     

Cardiac and whole body [3H]noradrenaline kinetics in ischaemic heart disease: contrast between unstable anginal syndromes and pacing induced ischaemia.

Radiotracer kinetics were used to evaluate the activity of the sympathetic nervous system in 10 patients who had had unstable ischaemic symptoms within the previous 12 weeks and 10 with stable angina. Patients with recent unstable angina or angina after recent acute myocardial infarction had higher basal cardiac noradrenaline spillover than patients with stable angina. This represents a selective increase in cardiac sympathetic tone because whole body noradrenaline spillover was not significantly increased in the patients with recent unstable angina. Atrial pacing in 15 patients caused angina in 13 but did not significantly alter cardiac noradrenaline spillover in either patients with stable or unstable angina. The flow of plasma in the coronary sinus increased during pacing but because cardiac noradrenaline extraction decreased cardiac noradrenaline clearance was not significantly altered. Both whole body noradrenaline spillover and clearance were modestly increased by pacing, and arterial noradrenaline concentration was unchanged. Patients with recent symptoms of unstable ischaemia had a sustained and selective increase in cardiac efferent sympathetic tone compared with patients with stable angina, and angina induced by atrial pacing did not cause important cardiac sympathetic activation.     

Cardiac and whole body [3H]noradrenaline kinetics in ischaemic heart disease: contrast between unstable anginal syndromes and pacing induced ischaemia

Radiotracer kinetics were used to evaluate the activity of the sympathetic nervous system in 10 patients who had had unstable ischaemic symptoms within the previous 12 weeks and 10 with stable angina. Patients with recent unstable angina or angina after recent acute myocardial infarction had higher basal cardiac noradrenaline spillover than patients with stable angina. This represents a selective increase in cardiac sympathetic tone because whole body noradrenaline spillover was not significantly increased in the patients with recent unstable angina. Atrial pacing in 15 patients caused angina in 13 but did not significantly alter cardiac noradrenaline spillover in either patients with stable or unstable angina. The flow of plasma in the coronary sinus increased during pacing but because cardiac noradrenaline extraction decreased cardiac noradrenaline clearance was not significantly altered. Both whole body noradrenaline spillover and clearance were modestly increased by pacing, and arterial noradrenaline concentration was unchanged. Patients with recent symptoms of unstable ischaemia had a sustained and selective increase in cardiac efferent sympathetic tone compared with patients with stable angina, and angina induced by atrial pacing did not cause important cardiac sympathetic activation.     

Plasma catecholamines determination using high pressure liquid chromatography and their roles in blood pressure regulation and experimental hypertension in rats.

Plasma catecholamine levels have been used experiemtally and clinically as the indices of the sympathetic nerve activity. We measured plasma catecholamines using high pressure liquid chromatography in rats to assess the significance of plasma catecholamines as an index of the sympathetic nerve activity and its role in hypertension. Pentobarbital anesthesia depressed plasma catecholamine levels, especially plasma adrenaline. Sodium loading for 5 weeks suppressed plasma noradrenaline, while administration of furosemide (1 mg/kg) produced the elevation of plasma noradrenaline. Experimental hypertension, one-kidney and two-kidney types of Goldblatt hypertension and DOCA-salt hypertension, raised plasma noradrenalines both in acute and chronic phases. The infusion of pressor doses of angiotensin II suppressed plasma noradrenaline by the reflex mechanism. Sar1, Ile8-angiotensin II and SQ 14,225 did not suppress plasma cathecholamine elevation due to hemorrhage. L-Hydroxyldopamine produced elevation of plasma catecholamines in experimental nypertension and controls in rats. After adrenal demedullation, plasma noradrenaline was decreased by the administration of 6-hydroxy-dopamine. Acute reduction of circulating blood volume and blood pressure fall produced the elevation of plasma catecholamine, especially plasma adrenaline. In rats, the adrenal medulla plays an important role in the regulation of blood pressure.     

Pathophysiologic levels of atrial natriuretic factor do not alter reflex sympathetic control: direct evidence from microneurographic studies in humans

To determine if circulating levels of atrial natriuretic factor comparable with those seen in pathophysiologic states alter autonomic control of the circulation, direct recordings of hemodynamic variables and efferent sympathetic nerve activity to muscle (microneurography) were obtained during two separate protocols in a total of 21 normal men (age 25 +/- 1 years). In protocol 1, the responses of 10 men were compared during incremental mechanical unloading of cardiopulmonary baroreceptors with lower body negative pressure versus responses to comparable unloading during infusion of alpha-human atrial natriuretic factor. Lower body negative pressure decreased pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure or heart rate and increased muscle sympathetic nerve activity from 205.2 +/- 36.3 to 438.7 +/- 100.2 units/min (p less than 0.01). Intravenous infusion of atrial natriuretic factor (25 ng/kg per min) increased plasma levels of the hormone from 24 +/- 4 to 322 +/- 34 pg/ml (p less than 0.01, n = 6), produced similar decreases in pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure, increased heart rate and increased sympathetic nerve activity from 233.1 +/- 35.6 to 387.2 +/- 64.9 units/min (p less than 0.05). Thus, during similar hemodynamic perturbations produced by lower body negative pressure or infusion of atrial natriuretic factor at the dose used in this study, these subjects exhibited comparable sympathoexcitatory responses, with a 109 +/- 23% increase in sympathetic activity during lower body negative pressure and a 76 +/- 19% increase during atrial natriuretic factor infusion (p = NS). In protocol 2, the responses of 11 additional men were examined during lower body negative pressure performed before and again during infusion of atrial natriuretic factor (12.5 ng/kg per min). During baseline (prehormone) trials, lower body negative pressure (-14.5 +/- 1.6 mm Hg) decreased central venous pressure, did not change arterial pressure or heart rate and increased sympathetic nerve activity from 215 +/- 47.7 to 372.3 +/- 64.3 units/min (p less than 0.001). Infusion of atrial natriuretic factor increased plasma levels of the hormone from 39 +/- 8 to 313 +/- 18 pg/ml (p less than 0.01, n = 7); central venous pressure was held constant during hormone infusion by intravenous infusion of saline solution.(ABSTRACT TRUNCATED AT 400 WORDS)     

Adrenaline and Hypertension

In man, circulating adrenaline has little or no direct effect on the control of blood pressure. A small proportion of adrenaline secreted by the adrenal medulla is accumulated in sympathetic nerve endings and may be re-released by sympathetic nerve stimulation. Recent pharmacological studies have suggested that adrenaline acts on a presynaptic β-receptor on sympathetic nerve endings to facilitate noradrenaline release, and it has been proposed that adrenaline re-released from these nerve endings is therefore a functionally important “co-transmitter”. Intermittently elevated secretion of adrenaline from the adrenal medulla could therefore lead indirectly to a sustained increase in neuronal release of noradrenaline and hence to hypertension.     

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.     

The 'adrenaline hypothesis' of hypertension revisited: evidence for adrenaline release from the heart of patients with essential hypertension

OBJECTIVE: Whether adrenaline acts as a sympathetic nervous cotransmitter in humans and stimulates beta2-adrenoceptors to augment neuronal noradrenaline release remains a subject of considerable dispute. The aim of this study was to test if adrenaline is released from regional sympathetic nerves (in the heart) in patients with essential hypertension, and to investigate whether locally released adrenaline might enhance cardiac noradrenaline release. METHODS: Using dual isotope dilution methodology, adrenaline and noradrenaline plasma kinetics was measured for the whole body and in the heart in 13 untreated patients with essential hypertension and 27 healthy volunteers. All research participants underwent cardiac catheterization under resting conditions. RESULTS: At rest, there was negligible adrenaline release from the sympathetic nerves of the heart in healthy subjects, 0.27 +/- 1.62 ng/min. In contrast, in patients with essential hypertension, adrenaline was released from the heart at a rate of 1.46 +/- 1.73 ng/min, equivalent on a molar basis to approximately 5% of the associated cardiac noradrenaline spillover value. Cardiac noradrenaline spillover was higher in hypertensive patients, 24.9 +/- 17.0 ng/min compared to 15.4 +/- 11.7 ng/min in healthy volunteers (P< 0.05). Among patients, rates of cardiac adrenaline and noradrenaline spillover correlated directly (r= 0.59, P< 0.05). CONCLUSIONS: This study, in demonstrating release of adrenaline from the heart in patients with essential hypertension, and in disclosing a proportionality between rates of cardiac adrenaline and noradrenaline release, provides perhaps the most direct evidence to date in support of the 'adrenaline hypothesis' of essential hypertension.     

Continuous recording of muscle nerve sympathetic activity during percutaneous transluminal angioplasty in renovascular hypertension in man

We have previously shown that during percutaneous transluminal renal angioplasty (PTRA) there is a transient increase in plasma renin activity (PRA) that is partly mediated by adrenergic beta-receptors. Despite a concomitant increase in plasma aldosterone, no increase in blood pressure occurred. The aim of this study was to record sympathetic outflow in man during PTRA as reflected by muscle nerve sympathetic activity and arterial plasma noradrenaline. Nine patients with hypertension and unilateral renal artery stenosis underwent PTRA by the Grüntzig technique and simultaneous microelectrode recording of muscle nerve sympathetic activity in the peroneal nerve. Blood pressure and heart rate were recorded and blood specimens were drawn for determination of noradrenaline and PRA. During total occlusion of the renal artery, muscle nerve sympathetic activity and the heart rate were unchanged. In the first 6 min after occlusion PRA increased transiently, but there was no significant change in muscle nerve sympathetic activity, arterial noradrenaline, heart rate or blood pressure. From 10 min after PTRA, muscle nerve sympathetic activity was significantly increased and after 40 min there was a significant increase in noradrenaline. The heart rate remained unchanged throughout the procedure, but the blood pressure decreased progressively and the diastolic blood pressure was significantly reduced at 40 min, indicating successful dilation. Despite activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, two strong pressor systems, the only circulatory reaction was a decrease in diastolic blood pressure. These findings indicate simultaneous activation of a potent depressor mechanism during PTRA.     

Lack of Influence of Circulating Adrenaline on Blood Pressure in Normotensive and Hypertensive Rats

The relationship between circulating adrenaline and blood pressure was examined by manipulating plasma adrenaline levels in both normotensive and hypertensive rats: bilateral adrenalmedullectomy was performed in spontaneously hypertensive rats and stroke-prone spontaneously hypertensive rats; adrenaline bitartrate was infused chronically (25-32 μg/kg/h s.c.) into Wistar Kyoto, Sprague Dawley and stroke-prone rats via osmotic minipumps. Arterial and venous catheters were subsequently implanted for direct measurement of mean arterial pressure, blood sampling and drug administration in conscious rats. Adrenaline infusion for 5-6 weeks in Wistar Kyoto rats did not affect resting blood pressure (118 ± 3 versus 119 ± 1 mmHg in controls) even though plasma adrenaline was elevated 12-fold. Plasma noradrenaline was marginally elevated. Blood pressure was also unaffected by adrenaline infusion in Sprague Dawley or stroke-prone hypertensive rats. One week after adrenal medullectomy, plasma adrenaline was reduced 89% in spontaneously hypertensive rats, but blood pressure was unaffected. Ten weeks after adrenal medullectomy in young stroke-prone rats, resting blood pressure was slightly higher (167 ± 2 mmHg) than in control rats (157 ± 2 mmHg), although adrenaline was reduced by 34% in plasma and 67% in adrenal glands. Nitroprusside was infused acutely to lower blood pressure and reflexly elevate plasma noradrenaline. Neither of these responses were affected by chronic adrenaline infusion or adrenal medullectomy. In both adrenaline-infused Wistar Kyoto and medullectomised stroke-prone rats, autonomic blockade reduced blood pressure to a similar extent as in controls, indicating that the degree of sympathetic vasoconstriction was not altered by either treatment. Moreover, pressor responses to i.v. phenylephrine were similar in all groups, indicating that changes in plasma adrenaline did not affect post-synaptic receptor sensitivity. We conclude that elevated plasma adrenaline seen in spontaneous hypertensive rats is unlikely to contribute to their hypertension.     

Increase in plasma noradrenaline concentration after the administration of phentolamine in the patients with "latent" left-sided heart failure

We measured increments of peripheral venous pressure induced by dynamic leg exercise (delta VP) in 10 healthy subjects (Group C) and 70 patients with heart diseases which primarily affect the left-side of the heart. None of the subjects showed apparent symptoms of left- or right-sided heart failure. The patients were divided into 2 groups on the basis of delta VP, namely, Group N (delta VP less than 35 mmH2O, n = 30, normal reaction) and Group H (delta VP greater than or equal to 35 mmH2O, n = 40, abnormal reaction). We measured the increments of plasma concentrations of noradrenaline (delta NAPH) and adrenaline (delta APH) with infusion of phentolamine (PH). Parallel studies with nitroglycerin and prazosin supplied strong evidence that delta NAPH was brought about mainly by the blockade of alpha 2-receptors at the sympathetic nerve terminals. Thus, we estimated the degree of sympathetic nerve activity from the central nervous system by opening using PH the negative feed-back loop for noradrenaline (NA) release at the sympathetic nerve terminals, and this degree of sympathetic nerve activity was compared with the degree of delta VP. The results obtained were 1) there was a rough overall correlation between delta VP and delta NAPH in the subjects of Groups C, N and H, and 2) delta NAPH was significantly higher in Group H than in Groups C and N. These results suggest that much reliance can be placed on the measured increment of plasma NA concentration in response to the administration of PH in assessing the degree of enhanced sympathetic nerve activity in the patients with "latent" left-sided heart failure.