Olinical Investigator
Clin Investig (1992) 70:549-555
Original Article
© Springer-Verlag 1992
Effects of atrial natriuretie factor on anterior pituitary hormone secretion in normal man M. Kentsch 1, R. Lawrenz ~, P. Ball ~, R. Gerzer 2, and G. Miiller-Esch 1 Klinik f/Jr Innere Medizin, Medizinische Universit/it zu Lfibeck 2 Abteilung f/Jr Klinische Pharmakologie, Medizinische Klinik, Klinikum Innenstadt der Universit/it, Mtinchen
Summary. The effects of intravenous human atrial natriuretic factor ANF(99-126) administration on anterior pituitary hormone secretion have not been extensively investigated in humans. We repeatedly studied 10 healthy volunteers (5 female, 5 male, aged 28_+2 years) on 2 occasions, 3 days apart. In randomized, single blind order, subjects received pretreatment with either placebo or intravenous ANF(99-126) (bolus 100 gg/kg, 30-min infusion of 0.1 gg/kg.min). Subsequently, on both occasions subjects received a combined intravenous bolus injection of pituitary releasing hormones (200 lag thyrotropin releasing hormone, 100 lag gonadotropin releasing hormone, 50 lag growth hormone releasing hormone and 100 lag human adrenocorticotropin releasing hormone; Bissendorf, Hannover, FRG). Plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), thyrotropin (TSH), prolactin, ANF and cyclic guanosine monophosphate (GMP) were determined by radioimmunoassay. ANF(99-126) treatment induced a significant reduction in basal ACTH plasma concentrations and tended to decrease basal plasma cortisol. The TSH response to combined releasing hormone administration was significantly diminished after ANF(99126) pretreatment. In women, the releasing hormone induced prolactin increase was reduced after ANF(99-126) pretreatment. With the present study design, ANF(99-126) did not alter the basal or releasing hormone stimulated plasma concentrations of cortisol, LH, FSH and GH. Releasing hormone administration did not affect ANF and cyclic GMP plasma levels. In humans, effects of Abbreviations. ANF(99-126)= human atrial natriuretic factor; A C T H = adrenocorticotropic hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; G H = growth hormone; TSH=thyrotropin; PRL=prolactin; cyclic G M P = cyclic guanosine monophosphate; TRH = thyrotropin releasing hormone; G n R H = gonadotropin releasing hormone; G H R H = growth hormone releasing hormone; CRH = adrenocorticotropin releasing hormone
natriuretic peptides on anterior pituitary hormone secretion may have to be considered with investigational or therapeutic administration of ANF analogues or agents interfering with the ANF metabolism.
Key words: Atrial natriuretic peptides - Anterior pituitary hormones - Prolactin, somatotropin, thyrotropin, pituitary gonadotropins - Adrenocorticotropic hormone, hydrocortisone - Pituitary function test - Pituitary hormone-releasing hormones - Human study
The atrial natriuretic factor (ANF) is a 28 amino acid peptide hormone which has been isolated from the cardiac atria [17]. Histochemical studies have revealed the presence of ANF immunoreactivity in various parts of the brain including structures involved in the regulation of anterior pituitary hormone secretion like the hypothalamus, the periventricular hypothalamic nuclei and the median eminence [38]. In vitro ANF is released from rat hypothalamic fragments [35]. Plasma concentrations of ANF in rat hypophyseal portal blood are about four times greater than in the peripheral blood [22]. Consistent with the hypothesis that ANF might modulate pituitary hormone release, both established types of ANF receptors have been identified in the anterior pituitary [19]. Corresponding to activation of the guanylate cyclase coupled ANF RI (or B) receptor, anterior pituitary cells dose-dependently produce guanosine monophosphate (GMP) subsequent to ANF stimulation [1]. Activation of the ANF R2 (or C) receptor, which appears to be coupled to the adenylate cyclase system, induces a significant inhibition of adenylate cyclase activity in anterior pituitary preparations [2]. Results of previous investigations on the possible regulatory role of ANF in pituitary hormone
550 secretion are in part contradictory but suggest influences of A N F on the release of adrenocorticotropin [3, 7, 20], luteinizing hormone [32, 36], follicle-stimulating hormone [13], prolactin [31] and growth hormone [25]. Anatomically, the releasing factor synthesizing neurons in the hypothalamus spread their terminations into the median eminence, which continues inferiorly to form the pituitary stalk. The circumventricular organs, the median eminence and the pituitary gland are located outside the blood-brain barrier [4]. Thus, endogenous plasma A N F and intravenously administered exogenous ANF may reach parts of the hypothalamic regulatory system as well as the pituitary itself. Although ANF(99-126) itself may not gain importance as a therapeutic agent, experimental and clinical studies are underway to evaluate the possible therapeutical use of A N F analogues [18] and of ANF degradation inhibiting agents [14]. Therefore, the effects of pharmacologic plasma A N F levels on the hypothalamic-pituitary axis in humans will have to be established. In humans, studies on the modulation of pituitary function by intravenously given ANF are limited to effects of A N F on basal concentrations of several pituitary hormones [9, 28], on the thyrotropin releasing hormone induced prolactin response [10], and on hormonal changes after insulin-induced hypoglycaemia [16]. In the present study, we therefore investigated the effects of intravenous ANF administration on basal and releasing factor induced pituitary hormone secretion in healthy humans. Methods
Ten healthy volunteers (5 females in the first week of their cycle, 5 males, aged 28 +_2 years) were studied after giving written informed consent. The study was approved by the ethical committee of the University of Luebeck, FRG. None of the volunteers had a history of endocrine, cardiovascular, pulmonary or any other severe disorder. All subjects were within 10% of ideal body weight and were not taking any medication. Subjects were on free sodium intake and had refrained from smoking and alcohol-containing beverages 1 week before the study and during the complete study period. The subjects were studied on two separate occasions 3 days apart. In randomized, single blind order, subjects received an initial treatment with either intravenous ANF(99-126) or placebo, followed on both occasions by a combined intrave-
nous administration of thyrotropin releasing hormone (TRH), gonadotropin releasing hormone (GnRH), growth hormone releasing hormone (GHRH) and corticotropin releasing hormone (CRH). Synthetic human ANF(99-126) (purity > 98%) was supplied by Pharma Bissendorf Peptide (Hannover, FRG) in ampules containing 50 ~tg lyophilized acetate. Immediately before administration, 50 ~tg of ANF(99-126) was diluted in 1 ml of 0.9% sodium chloride solution. Synthetic ANF(99-126) was administered as a bolus injection of 100 Bg, followed by a 30-min infusion of 0.1 gg/kg'min. For continuous infusion, the total dose of 3 ~tg/kg ANF(99-126) was finally diluted in 10 ml of 0.9% sodium chloride solution and administered by an infusion pump at a rate of 20 ml/h. Placebo was prepared accordingly. Pituitary releasing hormones were obtained from Pharma Bissendorf Peptide in ampules containing a combination of 200 ~tg TRH, 100 I-tg GnRH, 50 gg G H R H and 100 ~tg human CRH. The combination of pituitary releasing hormones was diluted in 1 ml of 0.9% sodium chloride solution and administered as an intravenous bolus injection. After an overnight fast and bed rest, the study was performed in supine position. Two peripheral venous lines were inserted, one for drug administration and the other for blood sampling. Heart rate and blood pressure were measured noninvasively. After a resting period of 30 min, two baseline blood samples were drawn consecutively at a 15-rain interval, subsequently followed by the ANF(99-126) or placebo bolus injections and a 30-rain infusion of the respective agent. Blood samples were drawn 5 and 15 min after the beginning and at the end of the infusion period. The combination of pituitary releasing hormones was then administered as an intravenous bolus injection. Further blood samples were drawn 15, 30, 45, 60 and 90 min as well as 24 h after administration of the releasing hormones. Peripheral blood samples were immediately centrifuged, separated and stored at - 2 0 ° C for assaying of ANF, cyclic GMP, adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), thyrotropin (TSH) and prolactin. The two blood samples collected during the ANF or placebo infusion period were only analysed for plasma concentrations of ANF and cyclic GMP. Plasma concentrations were determined by radioimmunoassay for ACTH (Byk-Sangtec, Dietzen-
551 bach, F G R ; normal range, 8 a.m.
Clin Investig (1992) 70:549-555
Original Article
© Springer-Verlag 1992
Effects of atrial natriuretie factor on anterior pituitary hormone secretion in normal man M. Kentsch 1, R. Lawrenz ~, P. Ball ~, R. Gerzer 2, and G. Miiller-Esch 1 Klinik f/Jr Innere Medizin, Medizinische Universit/it zu Lfibeck 2 Abteilung f/Jr Klinische Pharmakologie, Medizinische Klinik, Klinikum Innenstadt der Universit/it, Mtinchen
Summary. The effects of intravenous human atrial natriuretic factor ANF(99-126) administration on anterior pituitary hormone secretion have not been extensively investigated in humans. We repeatedly studied 10 healthy volunteers (5 female, 5 male, aged 28_+2 years) on 2 occasions, 3 days apart. In randomized, single blind order, subjects received pretreatment with either placebo or intravenous ANF(99-126) (bolus 100 gg/kg, 30-min infusion of 0.1 gg/kg.min). Subsequently, on both occasions subjects received a combined intravenous bolus injection of pituitary releasing hormones (200 lag thyrotropin releasing hormone, 100 lag gonadotropin releasing hormone, 50 lag growth hormone releasing hormone and 100 lag human adrenocorticotropin releasing hormone; Bissendorf, Hannover, FRG). Plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), thyrotropin (TSH), prolactin, ANF and cyclic guanosine monophosphate (GMP) were determined by radioimmunoassay. ANF(99-126) treatment induced a significant reduction in basal ACTH plasma concentrations and tended to decrease basal plasma cortisol. The TSH response to combined releasing hormone administration was significantly diminished after ANF(99126) pretreatment. In women, the releasing hormone induced prolactin increase was reduced after ANF(99-126) pretreatment. With the present study design, ANF(99-126) did not alter the basal or releasing hormone stimulated plasma concentrations of cortisol, LH, FSH and GH. Releasing hormone administration did not affect ANF and cyclic GMP plasma levels. In humans, effects of Abbreviations. ANF(99-126)= human atrial natriuretic factor; A C T H = adrenocorticotropic hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; G H = growth hormone; TSH=thyrotropin; PRL=prolactin; cyclic G M P = cyclic guanosine monophosphate; TRH = thyrotropin releasing hormone; G n R H = gonadotropin releasing hormone; G H R H = growth hormone releasing hormone; CRH = adrenocorticotropin releasing hormone
natriuretic peptides on anterior pituitary hormone secretion may have to be considered with investigational or therapeutic administration of ANF analogues or agents interfering with the ANF metabolism.
Key words: Atrial natriuretic peptides - Anterior pituitary hormones - Prolactin, somatotropin, thyrotropin, pituitary gonadotropins - Adrenocorticotropic hormone, hydrocortisone - Pituitary function test - Pituitary hormone-releasing hormones - Human study
The atrial natriuretic factor (ANF) is a 28 amino acid peptide hormone which has been isolated from the cardiac atria [17]. Histochemical studies have revealed the presence of ANF immunoreactivity in various parts of the brain including structures involved in the regulation of anterior pituitary hormone secretion like the hypothalamus, the periventricular hypothalamic nuclei and the median eminence [38]. In vitro ANF is released from rat hypothalamic fragments [35]. Plasma concentrations of ANF in rat hypophyseal portal blood are about four times greater than in the peripheral blood [22]. Consistent with the hypothesis that ANF might modulate pituitary hormone release, both established types of ANF receptors have been identified in the anterior pituitary [19]. Corresponding to activation of the guanylate cyclase coupled ANF RI (or B) receptor, anterior pituitary cells dose-dependently produce guanosine monophosphate (GMP) subsequent to ANF stimulation [1]. Activation of the ANF R2 (or C) receptor, which appears to be coupled to the adenylate cyclase system, induces a significant inhibition of adenylate cyclase activity in anterior pituitary preparations [2]. Results of previous investigations on the possible regulatory role of ANF in pituitary hormone
550 secretion are in part contradictory but suggest influences of A N F on the release of adrenocorticotropin [3, 7, 20], luteinizing hormone [32, 36], follicle-stimulating hormone [13], prolactin [31] and growth hormone [25]. Anatomically, the releasing factor synthesizing neurons in the hypothalamus spread their terminations into the median eminence, which continues inferiorly to form the pituitary stalk. The circumventricular organs, the median eminence and the pituitary gland are located outside the blood-brain barrier [4]. Thus, endogenous plasma A N F and intravenously administered exogenous ANF may reach parts of the hypothalamic regulatory system as well as the pituitary itself. Although ANF(99-126) itself may not gain importance as a therapeutic agent, experimental and clinical studies are underway to evaluate the possible therapeutical use of A N F analogues [18] and of ANF degradation inhibiting agents [14]. Therefore, the effects of pharmacologic plasma A N F levels on the hypothalamic-pituitary axis in humans will have to be established. In humans, studies on the modulation of pituitary function by intravenously given ANF are limited to effects of A N F on basal concentrations of several pituitary hormones [9, 28], on the thyrotropin releasing hormone induced prolactin response [10], and on hormonal changes after insulin-induced hypoglycaemia [16]. In the present study, we therefore investigated the effects of intravenous ANF administration on basal and releasing factor induced pituitary hormone secretion in healthy humans. Methods
Ten healthy volunteers (5 females in the first week of their cycle, 5 males, aged 28 +_2 years) were studied after giving written informed consent. The study was approved by the ethical committee of the University of Luebeck, FRG. None of the volunteers had a history of endocrine, cardiovascular, pulmonary or any other severe disorder. All subjects were within 10% of ideal body weight and were not taking any medication. Subjects were on free sodium intake and had refrained from smoking and alcohol-containing beverages 1 week before the study and during the complete study period. The subjects were studied on two separate occasions 3 days apart. In randomized, single blind order, subjects received an initial treatment with either intravenous ANF(99-126) or placebo, followed on both occasions by a combined intrave-
nous administration of thyrotropin releasing hormone (TRH), gonadotropin releasing hormone (GnRH), growth hormone releasing hormone (GHRH) and corticotropin releasing hormone (CRH). Synthetic human ANF(99-126) (purity > 98%) was supplied by Pharma Bissendorf Peptide (Hannover, FRG) in ampules containing 50 ~tg lyophilized acetate. Immediately before administration, 50 ~tg of ANF(99-126) was diluted in 1 ml of 0.9% sodium chloride solution. Synthetic ANF(99-126) was administered as a bolus injection of 100 Bg, followed by a 30-min infusion of 0.1 gg/kg'min. For continuous infusion, the total dose of 3 ~tg/kg ANF(99-126) was finally diluted in 10 ml of 0.9% sodium chloride solution and administered by an infusion pump at a rate of 20 ml/h. Placebo was prepared accordingly. Pituitary releasing hormones were obtained from Pharma Bissendorf Peptide in ampules containing a combination of 200 ~tg TRH, 100 I-tg GnRH, 50 gg G H R H and 100 ~tg human CRH. The combination of pituitary releasing hormones was diluted in 1 ml of 0.9% sodium chloride solution and administered as an intravenous bolus injection. After an overnight fast and bed rest, the study was performed in supine position. Two peripheral venous lines were inserted, one for drug administration and the other for blood sampling. Heart rate and blood pressure were measured noninvasively. After a resting period of 30 min, two baseline blood samples were drawn consecutively at a 15-rain interval, subsequently followed by the ANF(99-126) or placebo bolus injections and a 30-rain infusion of the respective agent. Blood samples were drawn 5 and 15 min after the beginning and at the end of the infusion period. The combination of pituitary releasing hormones was then administered as an intravenous bolus injection. Further blood samples were drawn 15, 30, 45, 60 and 90 min as well as 24 h after administration of the releasing hormones. Peripheral blood samples were immediately centrifuged, separated and stored at - 2 0 ° C for assaying of ANF, cyclic GMP, adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), thyrotropin (TSH) and prolactin. The two blood samples collected during the ANF or placebo infusion period were only analysed for plasma concentrations of ANF and cyclic GMP. Plasma concentrations were determined by radioimmunoassay for ACTH (Byk-Sangtec, Dietzen-
551 bach, F G R ; normal range, 8 a.m.
