Effect of adrenaline on A N P Clinical Autonomic Research 2, 303-307 (1992)

Research Paper THE levels of plasma atrial natriuretic peptide in response to graded adrenaline infusion were determined in six patients with essential hypertension and six healthy normotensive subjects (controls). Basal plasma adrenaline concentration was similar in both groups and rose progressively and to a similar level d u r i n g adrenaline infusion. Plasma noradrenaline rose in both groups and to the same extent during the 26 and 39 n g l k g / m i n adrenaline infusion rates. Basal plasma atrial natriuretic peptide levels were higher in the hypertensives than in the controls. Graded adrenaline infusion had no effect on atrial natriuretic peptide levels in the controls but significantly raised atrial natduretic peptide levels in the hypertensives. Systolic blood pressure rose progressively during adrenaline infusion at a lower infusion rate in the hypertensives than in the controls. Similarly, while heart rate rose during adrenaline infusion in both groups, there was a greater rise in the hypertensives. The increased cardiovascular, responsiveness to adrenaline infusion in patients with essential hypertension may explain why plasma atrial natriuretic peptide levels rose only in this group and not the normotensive subjects.

Elevation of plasma atrial natriuretic peptide occurs during adrenaline infusion in hypertensive but not normotensive subjects Terry J. Tunny, Richard D. Gordon cA, Anthony W . Bachmann and Shelley A. Klemm Endocrine-Hypertension Research Unit, Greenslopes Hospital, Brisbane, Australia 4120.

CACorresponding Author

Key words: Atrial natriuretic peptide, Adrenaline, Hypertension, Normal subjects, Renin, Aldosterone, Human

Introduction It has been suggested that an increase in circulating adrenaline levels in man in response to stress might lead to an elevated blood pressure through stimulation of presynaptic beta-adrenoceptors, with resultant increased co-release of noradrenaline from sympathetic nerves. 1'2 The role of stress in the development of hypertension remains controversial. >5 Increased sympathetic activity in essential hypertension has been suggested in some studies 6'v and increased sympathetic outflow in the heart and kidneys may be particularly important. 8 Atrial stretch has been reported as the major stimulus for atrial natriuretic peptide (ANP) secretion in humans. 9'1° However, atrial stretch is not the sole determinant of ANP secretion, since increased ANP concentrations have been observed either in vitro or in vivo in response to a variety of hormonal stimuli, including adrenaline, n'12 noradrenaline, ~>14 angiotensin II, 1>16 endothelin 17 and prostaglandins TM. Atrial natriuretic peptide is a potent natriuretic and diuretic agent with the concurrent effect of relaxation of vascular smooth muscle ceils, and may have a physiological role in the regulation of blood pressure. 19 ANP may therefore assist in limiting the blood pressure rise in response to hypertensive stimuli. We therefore examined the response of arterial ANP, adrenaline, noradrenaline, renin, aldosterone, blood pressure and heart rate to graded infusions © Rapid Communications of Oxford Ltd.

of adrenaline in order to achieve circulating levels seen during mild to moderate stress, and compared the responses observed between essential hypertensive and normal subjects.

Subjects and Methods Six male patients with essential hypertension (EHT) aged 27-47 years (40 ___6 years), taking no antihypertensive medications, and six healthy male normotensive subjects (NLS), aged 21-26 years (23 -t- 2 years) took part in the study. The protocol was approved by the Greenslopes Hospital Ethics Committee, and informed consent was obtained from all participants. All subjects had normal levels of plasma creatinine and liver enzymes. Standing systolic and diastolic blood pressures were 143 ___6 m m H g and 96 _.+ 2 m m H g respectively for the E H T group, and 124 __+11 m m H g and 62 ___4 m m H g respectively for the NLS group. Smoking, alcohol and caffeine were avoided for at least 12 h prior to the study. The radial artery of the non-dominant arm was cannulated for subsequent blood sampling and monitoring of arterial blood pressure and heart rate. After 30 min of recumbency, adrenaline (6 #g/ml in 5% dextrose solution with 0.5 mg/ml ascorbic acid) was infused into the antecubital vein in the opposite arm at rates of 6.5, 13.0, 19.5, 26.0 and 39.0 ng/kg/min for 30 min each. Basally, at the end of each infusion period, and 20 min after the cessation of the infusion, blood was collected for determination of plasma atrial natriuretic peptide (ANP), Clinical Autonomic Research. vol 2.1992

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T. J. Tunny et al. plasma adrenaline (ADR) and noradrenaline (NA), plasma renin activity (PRA) and plasma aldosterone (PA) concentrations. Plasma ANP was measured by double antibody radioimmunoassay after prior extraction on SepPak C18 cartridges. 2° Plasma ADR and NA were measured by a radioenzymatic method. 21 Plasma renin activity was measured using a radioimmunoassay for generated angiotensin I at pH 6.0 in a modification of the method of Haber eta/. 22 Plasma aldosterone was measured by radioimmunoassay (Diagnostic Products Corporation, Los Angeles, CA, USA). Results were expressed as means and SEM and were analysed non-parametrically using the Mann-Whitney U-test and the Friedman test.

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ADR INFUSION RATE ( n g / k g / m i n ) FIG. 2. Heart rate (HR) responsesto graded adrenaline (ADR) infusion in normotensive subjects (solid circles) and in patients with essential hypertension (open circles). (*p < 0.05, ~ p < 0.01, compared with zero basal time.)

Results Basal plasma adrenaline levels were almost identical in the EHT group (44 + 9 pg/ml) and the NLS group (39 ± 7 pg/ml), and rose progressively with increasing ADR infusion rates in both groups (Fig. 1). Twenty minutes after cessation of the infusion ADR had fallen to baseline in both groups. Basal plasma NA concentrations were also ADR( p g / m l ) tO00

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comparable ( 1 7 7 ± 2 3 p g / m l in E H T group, 179 + 12 pg/ml in NLS group). Plasma NA rose significantly (p < 0.01) in both groups at the 26.0 and 39.0 ng/kg/min infusion rates (Fig. 1), and fell on cessation of the infusion. Heart rate rose significantly in the hypertensive group during infusion at the 13.0 ng/kg/min and higher rates and in the normotensive group at the 19.5 ng/kg/min and higher rates (Fig. 2). Systolic blood pressure rose progressively and diastolic blood pressure fell progressively with increasing rates of ADR infusion in the E H T group (Fig. 3). Changes in both systolic and diastolic blood pressure were less marked in the NLS, reaching significance" at only 39 ng/kg/min for systolic blood pressure and at 26 ng/kg/min for diastolic blood pressure (Fig. 3). Basal plasma ANP was significantly (p < 0.01) higher in E H T than in the NLS group (59 +_ 5 vs. 3 6 _ 6 pg/ml, Fig. 4), and remained significantly

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FIG. 1. Plasma adrenaline (ADR), upper panel, and noradrenaline (NA) levels, lower panel, during progressively increasing ADR infusion rates in normotensive subjects (solid circles) and in patients with essential hypertension (open circles). (=~p