Journal of Human Hypertension (2006) 20, 510–516 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Decreased pituitary response to - induced hypoglycaemia in young lean male patients with essential hypertension

Z Radikova1, A Penesova1, E Cizmarova2, M Huckova1, R Kvetnansky1, M Vigas1 and J Koska1 1Institute of Experimental , Slovak Academy of Sciences, Bratislava, Slovakia and 2Department of Cardiology, Out-patient Clinic Karlova Ves, Bratislava, Slovakia

Essential hypertension is associated with changes in 45, 60 and 90 min after insulin administration. Increased central catecholaminergic pathways which might also baseline levels of norepinephrine (Po0.05), increased be reflected in the pituitary response to stress stimuli. response of norepinephrine (Po0.001) and decreased The aim of this study was to determine whether the response of (Po0.001), prolactin response of pituitary hormones, , plasma renin (Po0.001), adrenocorticotropic hormone (Po0.05) and activity, aldosterone and catecholamines to insulin- cortisol (Po0.001) were found in hypertensive patients induced hypoglycaemia is changed in hypertension. when compared to normotensive controls. Increased We studied 22 young lean male patients with newly norepinephrine levels and a decreased pituitary res- diagnosed untreated essential hypertension and 19 ponse to metabolic stress stimuli may represent another healthy normotensive, age- and body mass index manifestation of chronically increased sympathetic tone (BMI)-matched controls. All subjects underwent an in early hypertension. insulin tolerance test (0.1 IU insulin/kg body weight Journal of Human Hypertension (2006) 20, 510–516. intravenously) with blood sampling before and 15, 30, doi:10.1038/sj.jhh.1002026; published online 13 April 2006

Keywords: hypoglycaemia; ACTH; growth hormone; prolactin; catecholamines

Introduction hypothalamic centres of hypertensive (HT) subjects. Central catecholaminergic pathways transmit neural Hypertension is a risk factor for cardiovascular stimuli to neuroendocrine hypothalamic centres morbidity and mortality. Already a modest elevation that regulate endocrine activity of pituitary cells.10,11 of blood pressure (BP) in grade 1 hypertension Somatotropic, lactotropic and adrenocorticotropic and high normal BP, prehypertension (previously axes are activated differently by various stress borderline hypertension), is associated with multi- stimuli.12,13 Therefore, we hypothesize hypertension ple rheologic, haemodynamic, endocrine and meta- 1,2 to be associated with changes in central catechol- bolic changes. aminergic pathways, and that these changes are Increased sensitivity to stress stimuli is presumed reflected by changes in the pituitary response to to play an important role in the ethiopathogenesis 3–5 stress stimuli. of essential hypertension. Adaptation to stress Amerena and Julius3 observed increased neuro- situations is mediated predominantly by the sym- endocrine response during exercise in young HT pathoadrenal system and the hypothalamic– 6,7 patients. However, the stress stimulus used (exer- pituitary–adrenocortical axis. Increased peripheral cise) is dependent upon efficiency of the cardio- sympathetic activity is suggested to play a key role vascular system; it is possible that increased especially in the early phases of hypertension in neuroendocrine responses are due to a decreased young subjects.3,8 Furthermore, as reviewed by 9 level of cardiovascular fitness in HT patients. For DeQuattro and Feng, several research groups found that reason, we chose to utilize a metabolic stimulus increased norepinephrine levels in cerebrospinal which acts via a hypothalamic pathway (insulin- fluid and increased norepinephrine turnover in induced hypoglycaemia) to determine whether responses of growth hormone, prolactin, adreno- Correspondence: Dr Z Radikova, Laboratory of Human Endocri- corticotropic hormone (ACTH) and cortisol (as nology, Institute of Experimental Endocrinology, Slovak Academy a measure of pituitary–adrenocortical function), of Sciences, Vlarska 3, Bratislava SK 833 06, Slovakia. E-mail: [email protected] plasma renin activity (PRA) and aldosterone (as a Received 15 December 2005; revised 1 March 2006; accepted 2 measure of mineralocorticoid function) and cate- March 2006; published online 13 April 2006 cholamines (epinephrine and norepinephrine) are Endocrine response in hypertension Z Radikova et al 511 altered in young non-obese males with newly Slovakia. After explanation of the procedure, writ- diagnosed untreated hypertension. ten informed consent was obtained from all partici- pants. Subjects and methods Methods We studied 22 young non-obese male patients with The subjects were asked to refrain from the use essential hypertension (HT) recruited from the of tobacco, alcohol, caffeine, any medication and registry of the Department of Cardiology, Out-patient heavy physical activity for 12 h before the study. The Clinic Karlova Ves, Bratislava, Slovakia. The diag- investigations started at 0800 after a 12-h overnight nosis of HT was confirmed by 24-h BP measurement. fast. An indwelling catheter was inserted into a Secondary HT was excluded by clinical examina- cubital vein and the subjects were asked to rest tion, routine blood and urine analysis, and hormo- in a comfortable armchair. After a 30 min rest, BP nal measurements before the study and only was measured using Dinamap Vital Signs Monitor individuals with confirmed diagnosis of essential (model 845 XT; Critikon Inc., Tampa, FL, USA) and HT were enrolled. The patients had not been baseline blood samples were taken. An intravenous previously treated with antihypertensive drugs. bolus of insulin (0.1 IU/kg, Actrapid HM, Novo Blood pressure was measured again in our labora- Nordisk, Denmark) was injected afterwards. Blood tory on two separate occasions in duplicate seated samples were taken 15, 30, 45, 60 and 90 min after measurements after 30 min stabilization period. All insulin administration into polyethylene tubes con- patients fulfilled the criteria of the European Society taining ethylenediaminetetraacetic acid (EDTA) or of Hypertension/European Society of Cardiology14 heparin as anticoagulants, and immediately placed (ESH/ECS) for high normal BP (systolic BP: 130– on ice. After centrifugation at 41C, plasma aliquots 139 mm Hg and/or diastolic BP: 85–89 mm Hg) and were stored frozen at À201C until assayed. Plasma grade 1 hypertension (systolic BP: 140–159 mm Hg glucose concentrations were measured using an and/or diastolic BP: 90–99 mm Hg). Nineteen automatic biochemical analyser by the glucose healthy normotensive (NT) subjects matched for oxidase method (Hitachi 911, Japan). Plasma renin age and body mass index (BMI) (within 5 years of activity, aldosterone, ACTH and cortisol concentra- age and 2 kg/m2 of BMI of their HT counterparts) tions were determined by radioimmunoassay (RIA); served as controls. growth hormone and prolactin levels were measured None of the patients or controls had a history of by immunoradiometric assay (IRMA); all using or impaired glucose tolerance (as shown commercial kits (Immunotech, Marseille, France). before the study by standard oral glucose tolerance Epinephrine and norepinephrine were measured testing).15 Clinical characteristics of the groups with a radioenzymatic assay according to Peuler and are shown in Table 1. Except HT, all patients and Johnson.16 controls were in very good physical and mental Statistical evaluation was completed using the health condition, taking no medication, non- Sigma Stat 2.0 program (Jandel Scientific, San smokers. The study was approved by the Ethics Rafael, CA, USA) and SPSS 11.5 program (SPSS Committee of the Institute of Experimental Endocri- Inc., Chicago, IL, USA). Comparison of single nology, Slovak Academy of Sciences, Bratislava, variables was performed using the Mann–Whitney

Table 1 Clinical characteristics of the hypertensive patients and normotensive controls

Normotensives (n ¼ 19) Hypertensives (n ¼ 22)P

Age (years) 23.171.0 21.070.6 0.066 BMI (kg/m2) 23.370.4 22.870.4 0.425 SBP (mm Hg) 117.672.9 141.372.0 o0.001 DBP (mm Hg) 65.971.8 72.571.6 0.011 HR (beats/min) 67727573 0.042 Fasting glucose (mmol/l) 4.970.1 5.170.1 0.253 Glucose 120 min OGTT (mmol/l) 4.570.3 5.470.2 0.017 Epinephrine (pg/ml) 28.375.5 42.876.4 0.111 Norepinephrine (pg/ml) 344.5737.2 479.2740.1 0.023 PRA (ngAT1/ml/h) 0.6470.11 0.8570.10 0.173 Aldosterone (pmol/l) 147.3731.1 162.1734.4 0.773 ACTH (pg/ml) 33.276.3 34.074.4 0.924 Cortisol (mg/100 ml) 19.571.3 20.271.2 0.726 Prolactin (ng/ml) 8.870.6 7.570.8 0.190 Growth hormone (mIU/l) 1.970.7 7.072.7 0.092

Abbreviations: ACTH, adrenocorticotropic hormone; BMI, body mass index; DBP, diastolic blood pressure; HR, heart rate; OGTT, oral ; PRA, plasma renin activity; SBP, systolic blood pressure. Parameters are expressed as means7s.e.m.

Journal of Human Hypertension Endocrine response in hypertension Z Radikova et al 512 U-test. The general linear model (multiple analyses Po0.001, F ¼ 151.674) with similar nadir reached of variance) was used to determine the differences in 30 min after insulin bolus (NT: 2.070.1 mmol/l vs endocrine response to insulin-induced hypoglycae- HT: 2.070.1 mmol/l; NS); however, earlier recovery mia between HT and NT subjects with Student– from hypoglycaemia was noted in HT subjects in Newman–Keuls post hoc test. All data are expressed 60 and 90 min only (effect of diagnosis Po0.05, as mean7s.e.m. unless indicated. Differences were F ¼ 5.506). The interactive differences were over considered significant at Po0.05. the limit of statistical significance (effect of diag- nosis  time P ¼ 0.061, F ¼ 2.147). An increase in HR (Figure 1) was observed in both Results groups during hypoglycaemia (effect of time Po0.001, F ¼ 5.086). Hypertensive patients had a The plasma levels of norepinephrine at baseline higher HR during insulin-induced hypoglycaemia were significantly higher in HT subjects than in (effect of diagnosis Po0.01, F ¼ 9.16). NT controls (Table 1). Baseline heart rate (HR) and Systolic and diastolic BP increased during hypo- BP were also significantly higher in HT than in glycaemia (Figure 1) (effect of time Po0.05, F ¼ 2.5). NT subjects (Table 1). Plasma levels of aldosterone, The systolic and diastolic BP were higher in HT ACTH, cortisol, prolactin, growth hormone, epi- subjects than in NT subjects during the entire nephrine and PRA at baseline did not differ between investigation (effect of diagnosis Po0.001, the groups (Table 1). F ¼ 25.6), with interactive differences in systolic As shown in Figure 1, insulin administration BP (effect of diagnosis  time P ¼ 0.04, F ¼ 2.402). resulted in a significant decrease in plasma glucose Hypoglycaemia resulted in an increase in epi- concentrations in both groups (effect of time nephrine in HT and in NT subjects (effect of time

Figure 1 Changes in plasma glucose, epinephrine and norepinephrine levels, as well as systolic and diastolic blood pressure and heart rate during insulin tolerance test in hypertensive patients (black circle) and normotensive controls (white circles). Statistical significance as revealed by two-way analysis of variance ANOVA for factors time, diagnosis (dg) and their interactions (time  dg). Post hoc tests for significant differences in time vs diagnosis interactions: *Po0.05 for particular time intervals.

Journal of Human Hypertension Endocrine response in hypertension Z Radikova et al 513 Po0.001, F ¼ 32.8). The response of epinephrine to significantly lower in HT subjects when compared hypoglycaemia in HT was the same as in NT to NT controls (effect of diagnosis Po0.001, (Figure 1). F ¼ 14.246) (Figure 2). Increased norepinephrine levels were observed in Adrenocorticotropic hormone levels significantly both groups during hypoglycaemia (effect of time increased during hypoglycaemia (Figure 2; effect of Po0.01, F ¼ 3.873). The response of norepinephrine time Po0.001, F ¼ 14.169). The ACTH response was during insulin-induced hypoglycaemia was higher lower in HT subjects than in NT subjects (effect of in HT subjects compared to NT controls (effect of diagnosis Po0.05, F ¼ 4.655). diagnosis Po0.001, F ¼ 13.6); however, the incre- Hypoglycaemia caused a significant increase in ments from baseline to maximal response being plasma cortisol levels in both groups (effect of time comparable in both groups (P ¼ 0.45) (Figure 1). Po0.001, F ¼ 36.8). The cortisol response was lower Hypoglycaemia caused a significant increase in in HT subjects than in NT subject (effect of diagnose plasma growth hormone (GH) levels (Figure 2) in Po0.001, F ¼ 14.541; effect of diagnose  time both groups (effect of time Po0.001, F ¼ 39.797). The Po0.01, F ¼ 3.104). GH response was significantly lower in HT than in Hypoglycaemia resulted in an increase in PRA in NT subject (effect of diagnosis Po0.001, F ¼ 16.639; HT and in NT subjects (effect of time Po0.05, effect of diagnosis  time Po0.001, F ¼ 4.058). F ¼ 2.738). The response of PRA to hypoglycaemia A significant increase in prolactin (PRL) levels in HT was not different from that found in NT. was observed in both groups during hypoglycaemia No significant changes in plasma aldosterone (effect of time Po0.001, F ¼ 15.746). The response of concentrations were observed in the two groups PRL during insulin-induced hypoglycaemia was during hypoglycaemia.

Figure 2 Changes in plasma renin activity (PRA), plasma aldosterone, growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH) and cortisol levels during insulin tolerance test in hypertensive patients (black circle) and normotensive controls (white circles). Statistical significance as revealed by two-way analysis of variance ANOVA for factors time, diagnosis (dg) and their interactions (time  dg). Post hoc tests for significant differences in time vs diagnosis interactions: *Po0.05 for particular time intervals.

Journal of Human Hypertension Endocrine response in hypertension Z Radikova et al 514 Discussion responses in HT and NT subjects. Several investiga- tors9,28–30 proposed an important role of the nervous In the present study we found decreased responses system in the aetiology and pathogenesis of essential of growth hormone, ACTH, cortisol and PRL in hypertension, particularly of the abnormalities of young, lean, untreated male patients with hyper- the sympathetic nervous system in the early phases tension during insulin-induced hypoglycaemia of hypertension. Sustained increase in sympathetic when compared to those in age- and BMI-matched activity was associated with decreased receptor NT controls. density or decreased response to adrenergic agonists In a traditional view, a reduction of stress res- in several studies.31–33 Circulating norepinephrine ponse has been thought to be favourable.17,18 How- under euglycaemia is derived mostly from adrener- ever, our results and previously found lower gic sympathetic postganglionic neurons. However, concentrations of ACTH, cortisol, prolactin and under hypoglycaemia, plasma norepinephrine is catecholamines in anxious subjects during psycho- derived largely from adrenal medulla together with social stress19 do not support this suggestion. main adrenal catecholamine–epinephrine.34 There- Altered neuroendocrine responsiveness of HT sub- fore, we found a discrepancy in epinephrine and jects to stress stimuli might also therefore be related norepinephrine response to hypoglycaemia in both to the state of the mood; however, our subjects did HT and NT subjects. Increased baseline norepi- not suffer from any mood disorder. nephrine concentrations observed in HT subjects Insulin-induced hypoglycaemia activates the could reflect the increased norepinephrine levels in neuroendocrine system by stimulation of central cerebrospinal fluid.35–37 The elevated norepinephr- regulatory mechanisms. Glucopenia registered by ine levels in cerebrospinal fluid and in the internal glucosensitive neurons in the hypothalamus jugular venous overflow from subcortical brain through monoamine transmission activates post- regions38,39 may cause an alteration in noradrenergic synaptic alpha-adrenergic receptors on peptidergic receptors in several brain structures, including those hypophyseotropic neurons20 and initiates the secre- responsible for release of pituitary hormones. It tion of growth hormone, PRL and ACTH (leading has been proposed that HT patients may have to cortisol response)10,21,22 and neural stimulation altered sensitivity of central alpha-adrenergic recep- of the adrenal medulla and of adrenergic nerve tors on associated hypothalamic neurons.40,41 This endings.23 Glycemic thresholds for hormone release hypothesis is supported by the data showing are 3.770.1 mmol/l for growth hormone,24,25 decreased response of growth hormone to a central 3.270.2 mmol/l for cortisol24 and 2.470.1 mmol/l pre-synaptic alpha-2 adrenergic agonist in for PRL (means7s.d. all).26 Following the pharma- HT patients.27,42 Clonidine stimulates growth hor- cological dose of insulin, the glucose concentration mone secretion from the through the in our subjects decreased to an average of 2.2 mmol/l endogenous release of growth hormone-releasing in the minute 30 of the insulin tolerance test, hormone by the hypothalamus.43,44 Therefore, the showing that HT as well as NT subjects had a suffi- decreased growth hormone response to hypogly- cient decrease in plasma glucose levels to activate caemia seen in our study may be explained by the the hypothalamic–pituitary axis.24–26 The stimulus desensitization of alpha-2 adrenergic receptors on for endocrine activation is the decrease of glycemia growth hormone-releasing hormone neurons in the below glycemic thresholds, which was the same in hypothalamus. HT patients and NT controls. A comparable degree Intravenous infusion of alpha-adrenergic blockers of hypoglycaemia was observed in both groups also causes a suppressed plasma cortisol response to at 45 min, when the majority of hormonal responses insulin-induced hypoglycaemia in healthy males.45 had already reached the peak of their concentra- However, the role of alpha-adrenergic receptors in tions. Therefore, the observed trend to a faster ACTH and PRL secretion has been investigated with recovery of plasma glucose to normal values in several discrepant outcomes. Karhuvaara et al.46 and the 60–90 min after insulin administration in HT Al-Damluji21 found that alpha-2 adrenergic recep- subjects did not influence the peak of hormonal tors are not involved in the secretion of PRL in responses. Decreased pituitary response to hypogly- humans. However, several animal studies showed caemia, as a result of an alteration in the sensitivity equivocal effects of alpha-2 agonists and alpha-2 of hypothalamic glucoreceptors for neuroglucope- antagonists on PRL11,47–50 and ACTH secretion.11,51 nia, is also unlikely because of the comparable On the other hand, intravenous infusion of alpha-1 nadirs of hypoglycaemia, and the similar and adrenergic agonist stimulated PRL and ACTH secre- adequate increase of epinephrine and angiotensin I tion in healthy male volunteers, suggesting that during hypoglycaemia. the stimulated alpha-1 receptors are located cen- In general, functional secretory capacity of the trally and not on the pituitary gland or in the pituitary gland is large in humans; the finding of periphery.19,21 a normal growth hormone response to the adminis- On the basis of present knowledge, the clinical tration of growth hormone-releasing hormone in significance of attenuated responses of growth HT patients27 also does not support the possibility hormone, ACTH and PRL to stress stimuli in that secretory defect underlies different hormonal hypertension is not known. Some influence on the

Journal of Human Hypertension Endocrine response in hypertension Z Radikova et al 515 development of associated metabolic complications characteristics and cardiovascular risk factors. J Hum in hypertension cannot be excluded. Conversely, Hypertens 2004; 18: 333–341. decreased pituitary response may only be a conse- 5 Touyz RM, Campbell N, Logan A, Gledhill N, Petrella quence of a modified effect of central neurotrans- R, Padwal R. Canadian Hypertension Education Pro- mitters on hypothalamic releasing hormones. gram: the 2004 Canadian recommendations for the management of hypertension: Part III – Lifestyle Nonetheless, our results do not support the gener- modifications to prevent and control of hypertension. ally accepted hypothesis of enhanced endocrine Can J Cardiol 2004; 20: 55–59. reactivity to any stress stimulus in patients with 6 Elenkov IJ, Wilder RL, Chrousos GP, Vizi S. The early hypertension.3–5 sympathetic nerve – an integrative interface between The results of our study showed an increased two supersystems: the brain and the immune system. concentration of norepinephrine and decreased Pharmacol Rev 2000; 52: 595–638. response of growth hormone, prolactin, ACTH 7 Tsigos C, Chrousos GP. Hypothalamic–pituitary– (and cortisol) during hypoglycaemia in HT subjects. adrenal axis, neuroendocrine factors and stress. This abnormality could be another manifestation of J Psychosom Res 2002; 53: 865–871. chronically increased sympathetic tone in early 8 Goldstein DS. Plasma catecholamines and essential hypertension. An analytical review. Hypertension 1983; hypertension, which may lead to a desensitization 5: 86–99. of central alpha-adrenergic receptors. 9 DeQuattro V, Feng M. The sympathetic nervous system: the muse of primary hypertension. J Hum Hypertens 2002; 16(Suppl 1): S64–S69. 10 Al-Damluji S, Francis D. Activation of central alpha What is known on this topic 1-adrenoceptors in humans stimulates secretion of K Increased peripheral sympathetic activity is suggested to prolactin and TSH, as well as ACTH. Am J Physiol play a key role especially in the early phases of hypertension in young subjects.3,8 1993; 264(2 Part 1): E208–E214. K Increased norepinephrine levels in cerebrospinal fluid and 11 Kiem DT, Barna I, Koenig JI, Makara GB. Adrenocorti- increased norepinephrine turnover were found in cotropin, prolactin and beta-endorphin stimulatory hypothalamic centres of hypertensive subjects.9 action of alpha-2-adrenoceptor antagonists. Neuro- K Central catecholaminergic pathways transmit neural endocrinology 1995; 61: 152–158. stimuli to neuroendocrine hypothalamic centres that 12 Vigas M, Kvetnansky R, Jurcovicova J, Jezova D, Tatar regulate endocrine activity of pituitary cells.10,11 P. Comparison of catecholamine and adenopituitary hormone responses to various stress stimuli in man. In: What this study adds Usdin E, Kvetnansky R and Axelrod J (eds). Stress: The K Norepinephrine is elevated in young, lean, hypertensive patients. Role of Catecholamines and Other Neurotransmitters. K The response of pituitary hormones, growth hormone, Gordon and Breach Science Publishers: New York, adrenocorticotropic hormone ACTH (and resulting cortisol) 1984, 865–882. and prolactin to insulin-induced is 13 Pacak K, Palkovits M. Stressor specificity of central decreased in young, lean, non-treated male patients with neuroendocrine responses: implications for stress- hypertension when compared to matched normotensive related disorders. Endocr Rev 2001; 22: 502–548. controls. 14 European Society of Hypertension – European Society K Increased sympathetic tone in early hypertension may lead of Cardiology Guidelines Committee. European to a desensitization of central alpha-adrenergic receptors Society of Hypertension – European Society of Cardio- and decreased response of pituitary hormones to metabolic stress stimulus. logy guidelines for the management of arterial hyper- tension. J Hypertens 2003; 21: 1011–1053. 15 American Diabetes Association. Diagnosis and classi- fication of diabetes mellitus. Diabetes Care 2004; 27: S5–S10. Acknowledgements 16 Peuler JD, Johnson GA. Simultaneous single isotope This study was supported by the grants of Slovak radioenzymatic assay of plasma norepinephrine, epi- State Program SP 51/02280800/0280/802 and of nephrine and dopamine. Life Sci 1977; 21: 625–636. Slovak Scientific Grants Agency VEGA 2/3150/24. 17 Carrasco GA, Van De Kar LD. Neuroendocrine pharma- cology of stress. Eur J Pharmacol 2003; 463: 235–272. 18 De Kloet RE. Hormones, brain and stress. Endocr Regul 2003; 37: 51–68. 19 Jezova D, Makatsori A, Duncko R, Moncek F, Jakubek References M. High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychosocial 1 Julius S. Borderline hypertension. Clin Exp Hypertens stress. Prog Neuropsychopharmacol Biol Psychiatry 1999; 21: 741–747. 2004; 28: 1331–1336. 2 Svetkey LP. Management of prehypertension. Hyper- 20 Muller EE, Locatelli V, Cocchi D. Neuroendocrine tension 2005; 45: 1056–1061. control of growth hormone secretion. Physiol Rev 3 Amerena J, Julius S. The role of the autonomic nervous 1999; 79: 511–607. system in hypertension. Hypertens Res 1995; 18: 21 Al-Damluji S. Adrenergic control of the secretion of 99–110. anterior pituitary hormones. Baillieres Clin Endocrinol 4 Rose KM, North K, Arnett DK, Ellison RC, Hunt SC, Metab 1993; 7: 355–392. Lewis CE et al. Blood pressure and pulse responses to 22 Tatar P, Vigas M. Role of alpha 1- and alpha 2- three stressors: associations with sociodemographic adrenergic receptors in the growth hormone and

Journal of Human Hypertension Endocrine response in hypertension Z Radikova et al 516 prolactin response to insulin-induced hypoglycemia drug treatment and withdrawal. J Cardiovasc Pharma- in man. Neuroendocrinology 1984; 39: 275–280. col 1987; 10(Suppl 12): S205–S210. 23 Bolli GB, Fanelli CG. Physiology of glucose counter- 38 Lambert GW, Ferrier C, Kaye DM, Kalff V, Kelly MJ, regulation to hypoglycemia. Endocrinol Metab Clin Cox HS et al. Monoaminergic neuronal activity in North Am 1999; 28: 467–493. subcortical brain regions in essential hypertension. 24 Schwartz NS, Clutter WE, Shah SD, Cryer PE. Blood Pressure 1994; 3: 55–66. Glycemic thresholds for activation of glucose counter- 39 Lambert GW, Ferrier C, Kaye DM, Jennings GL, Kalff V, regulatory systems are higher than the thresholds for Kelly MJ et al. Central nervous system norepinephrine symptoms. J Clin Invest 1987; 79: 777–781. turnover in essential hypertension. Ann NY Acad Sci 25 Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, 1995; 763: 679–694. Kiss I et al. Hierarchy of glycemic thresholds for 40 Tan Y, Gan Q, Knuepfer MM. Central alpha-adrenergic counterregulatory hormone secretion, symptoms and receptors and corticotrophin releasing factor mediate cerebral dysfunction. Am J Physiol Endocrinol Metab hemodynamic responses to acute cold stress. Brain Res 1991; 260: E67–E74. 2003; 968: 122–129. 26 Kinsley BT, Levy CJ, Simonson DC. Prolactin and beta 41 Tsuda K, Tsuda S, Nishio I. Role of alpha-2-adrenergic endorphin responses to hypoglycemia are reduced in receptors and cyclic adenosine monophosphate- well-controlled insulin-dependent diabetes mellitus. dependent protein kinase in the regulation of norepi- Metabolism 1996; 45: 1434–1440. nephrine release in the central nervous system 27 Giustina A, Doga M, Bossoni S, Bodini C, Legati F, of spontaneously hypertensive rats. J Cardiovasc Pizzocolo G et al. Central alpha-2 adrenergic function Pharmacol 2003; 42(Suppl 1): S81–S85. in patients with essential hypertension. Horm Metab 42 Barbieri C, Ferrari C, Caldara R, Curtarelli G. Growth Res 1990; 22: 451–452. hormone secretion in hypertensive patients: evidence 28 Julius S, Nesbitt S. Clinical consequences of the for a derangement in central adrenergic function. Clin autonomic imbalance in hypertension and congestive Sci (London) 1980; 58: 135–138. heart failure. Scand Cardiovasc J Suppl 1998; 47: 43 Alba-Roth J, Losa M, Spiess Y, Schopohl J, Muller OA, 23–30. von Werder K. Interaction of clonidine and GHRH on 29 Schlaich MP, Lambert E, Kaye DM, Krozovski Z, GH secretion in vivo and in vitro. Clin Endocrinol Campbell DJ, Lambert G et al. Sympathetic augmenta- (Oxford) 1989; 30: 485–491. tion in hypertension: role of nerve firing, norepinephr- 44 Cella SG, Morgese M, Mantegazza P, Muller EE. ine reuptake, and angiotensin neuromodulation. Inhibitory action of the alpha 1-adrenergic receptor Hypertension 2004; 43: 169–175. on growth hormone secretion in the dog. Endocrino- 30 Esler M, Lux A, Jennings G, Hastings J, Socratous F, logy 1984; 114: 2406–2408. Lambert G. Rilmenidine sympatholytic activity pre- 45 Jezova-Repcekova D, Klimes I, Jurcovicova J, serves mental stress, orthostatic sympathetic responses Vigas M. Effect of adrenergic receptor blockade on and adrenaline secretion. J Hypertens 2004; 22: cortisol and GH response to insulin-induced hypo- 1529–1534. glycemia in man. Int J Clin Pharmacol Biopharm 1979; 31 Frey MJ, Lanoce V, Molinoff PB, Wilson JR. Skeletal 17: 64–67. muscle beta-receptors and isoproterenol-stimulated 46 Karhuvaara S, Kallio A, Koulu M, Scheinin H, vasodialtation in canine heart failure. J Appl Physiol Scheinin M. No involvement of alpha 2- adreno- 1989; 67: 2026–2031. ceptors in the regulation of basal prolactin secretion 32 Hayes MJ, Qing F, Rhodes CG, Rahman SU, Ind PW, in healthy men. Psychoneuroendocrinology 1990; 15: Sriskandan S et al. In vivo quantification of human 125–129. pulmonary beta-adrenoreceptors: effect of beta-agonist 47 Krulich L, Jurcovicova J, Le T. Prolactin (PRL) release- therapy. Am J Resp Crit Care Med 1996; 154: inhibiting properties of the alpha 2 adrenergic receptor 1277–1283. antagonist idazoxan: comparison with yohimbine. Life 33 Beau SL, Tolley TK, Saffitz JE. Heterogeneous trans- Sci 1989; 44: 809–818. mural distribution of beta-adrenergic receptor sub- 48 Kapoor R, Chapman IM, Willoughby JO. Alpha 2 and types in failing human hearts. Circulation 1993; 88: beta adrenoceptors in the mediobasal hypothalamus 2501–2509. and alpha 2 adrenoceptors in the preoptic-anterior 34 DeRosa MA, Cryer PE. Hypoglycemia and the sym- hypothalamus stimulate prolactin secretion in the pathoadrenal system: neurogenic symptoms are largely conscious male rat. J Neuroendocrinol 1993; 5: the result of sympathetic neural, rather than adreno- 189–193. medullary, activation. Am J Physiol Endocrinol Metab 49 Jurcovicova J, Le T, Krulich L. The paradox of alpha 2 2004; 287: E32–E41. adrenergic regulation of prolactin (PRL) secretion. I. 35 Eide I, Kolloch R, DeQuattro V, Miano L, Dugger R, Van The PRL-releasing action of the alpha 2 receptor der Meulen J. Raised cerebrospinal fluid norepinephr- agonist. Brain Res Bull 1989; 23: 417–424. ine in some patients with primary hypertension. 50 Jurcovicova J, Le T, Krulich L. The paradox of alpha 2 Hypertension 1979; 1: 255–260. adrenergic regulation of prolactin (PRL) secretion. II. 36 Kawano Y, Fukiyama K, Takeya Y, Abe I, Omae T. The PRL-releasing action of the alpha 2 receptor Catecholamines, angiotensin II and odium concentra- antagonists. Brain Res Bull 1989; 23: 425–432. tions in cerebrospinal fluid in young men with 51 Cuneo RC, Livesey JH, Nicholls MG, Espiner EA, borderline hypertension. Clin Exp Hypertens A 1984; Donald RA. Effects of alpha-2 adrenoreceptor blockade 6: 1131–1145. by yohimbine on the hormonal response to hypogly- 37 Cubeddu LX, Hoffman IS. Cerebrospinal fluid norepi- caemic stress in normal man. Horm Metab Res 1989; nephrine levels in essential hypertension: effects of 21: 33–36.

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