In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth h... more In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagoguereceptor 1a (GHS-R 1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R 1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.4560.07 mm 2 in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P,0.05) and JMV-1843 (P,0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P,0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P,0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus.
Beta-endorphin concentrations have been evaluated in the hypothalamus, pituitary lobes and plasma... more Beta-endorphin concentrations have been evaluated in the hypothalamus, pituitary lobes and plasma after 1-and 3-week treatment with 2-Br-alpha-ergocriptine or lisuride, two potent dopaminergic drugs. Hypothalamic beta-endorphin concentrations were significantly decreased after the administration of the dopaminergic agents for 1 or 3 weeks. Similarly, beta-endorphin concentrations decreased in the neurointermediate lobe and plasma. After gel chromatography, it appeared that in the anterior pituitary, beta-lipotropin concentrations were unchanged or lightly increased concomitantly with a decrease of beta-endorphin. Our data indicate that, both in the hypothalamus and the neurointermediate pituitary lobe, beta-endorphin is under an inhibitory dopaminergic tone. The latter may also play a role in inhibiting beta-endorphin cleavage from beta-lipotropin in the anterior pituitary.
Journal of Pediatric Endocrinology and Metabolism, 1995
Newly synthesized peptides are described which release growth hormone in the infant rat and their... more Newly synthesized peptides are described which release growth hormone in the infant rat and their biological activity is compared with known GHRPs. Some of these peptides are the most potent GHRPs reported to date.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
Recently, we demonstrated that TLQP-21 triggers lipolysis and induces resistance to obesity by re... more Recently, we demonstrated that TLQP-21 triggers lipolysis and induces resistance to obesity by reducing fat accumulation [1]. TLQP-21 is a 21 amino acid peptide cleavage product of the neuroprotein VGF and was first identified in rat brain. Although TLQP-21 biological activity and its molecular signaling is under active investigation, a receptor for TLQP-21 has not yet been characterized. We now demonstrate that TLQP-21 stimulates intracellular calcium mobilization in CHO cells. Furthermore, using Atomic Force Microscopy (AFM), we also provide evidence of TLQP-21 binding-site characteristics in CHO cells. AFM was used in force mapping mode equipped with a cantilever suitably functionalized with TLQP-21. Attraction of this functionalized probe to the cell surface was specific and consistent with the biological activity of TLQP-21; by contrast, there was no attraction of a probe functionalized with biologically inactive analogues. We detected interaction of the peptide with the binding-site by scanning the cell surface with the cantilever tip. The attractive force between TLQP-21 and its binding site was measured, statistically analyzed and quantified at approximately 40 pN on average, indicating a single class of binding sites. Furthermore we observed that the distribution of these binding sites on the surface was relatively uniform.
In a previous work, we reported that passive immunization with anti-growth hormone-releasing horm... more In a previous work, we reported that passive immunization with anti-growth hormone-releasing hormone (GHRH) antibodies (GHRH-Ab) in neonatal rats caused disruption of somatotropic function that was still present 60 d posttreatment. We studied the reversibility of this condition by growth hormone (GH) replacement therapy. Neonatal rats received GHRH-Ab (50 ~U r d t , s.c.) or normal rabbit serum every second day from birth up to postnatal d 10 and received hGH (0.4 &g body weight, s.c., b i d .) or vehicle in a 2 x 2 factorial design. Animals were studied on d 11 of age. In GHRH-Abtreated rats, GH therapy 1) counteracted the reduced body weight and low plasma IGF-I levels; 2) failed to modify the reduced pituitary weight and GH content; 3) further reduced the low plasma GH levels; 4) partially restored the defective GH responsiveness to GHRH; 5) failed to modify the reduced hypothalamic somatostatin and increased GHRH gene expression in the hypothalamus; and 6) reverted the decreased pituitary somatostatin binding. Morphologic and morphometric evaluation of the pituitary gland from GHRH-Ab+GH pups showed that the number of GH-labeled structures was lower than in normal rat serum-GH-treated pups, whereas the total GH immunoreact~ty per unit surface, an index of intracellular hormone concentration, was slightly higher than in vehicle-GH or GHRH-Ab pups. As determined by electron microscopy, somatotropes from GHRH-Ab+GH pups had morphologic features of high cellular activity. It appears that in GHRH-deprived pups GH replacement therapy can normalize most but not all altered indices of the somatotropic function. The effects of GH are mainly directed at the pituitaly, whereas the sensitivity of the hypothalamus to GH replacement is lower. (Pediatr Res 36: 315-322, 1994) Abbreviations GH, growth hormone GHRH, growth hormone-releasing hormone GHRH-Ab, anti-GHRH-antibodies NRS, normal rabbit serum dCTP, deoxycytidine triphosphate PRL, prolactin SS, somatostatin Recent studies by us (1,2) and by other groups (3,4) have shown that rat pups treated with GHRH-Ab may represent a suitable animal model for the study of the human growth disorders caused b y a primary hypothalamic dysfunction. Neonatal administration of GHRH-Ab permanently inhibits the growth rate and alters several indices of the hypophyseal somatotropic function (I).
... Irit Gil-Ad a , 2 , Vittorio Locatelli a , Daniela Cocchi a , Robert Carminati a , Carlo Arez... more ... Irit Gil-Ad a , 2 , Vittorio Locatelli a , Daniela Cocchi a , Robert Carminati a , Carlo Arezzini a andEugenio E. Müller ring operator. a Department of Pharmacology, University of Milan, Italy. ... 12. GD NISWENDER, AR MIDGLEY, Jr., SE MONROE, and LEREICHERT, Proc. Soc. Exp. ...
Capsaicin has been administered intraventricularly to adult rats and subcutaneously to neonatal r... more Capsaicin has been administered intraventricularly to adult rats and subcutaneously to neonatal rats. Adult rats were killed three, five, seven and fifteen days after capsaicin administration, while rats treated neonatally were killed when six months old. In the adult rats capsaicin induced a decrease in hypothalamic B-endorphin concentrations three, five and seven days after treatment, while they returned to normal values by day fifteen. A decrease in B-endorphin hypothalamic concentrations was also present in rats treated neonatally, while substance P, somatostatin and met-enkephalin concentrations were never affected by capsaicin treatment.
Ghrelin has been proposed as a natural ligand of the GH secretagogue receptor(s) (GHS-R), which w... more Ghrelin has been proposed as a natural ligand of the GH secretagogue receptor(s) (GHS-R), which was an orphan receptor activated by synthetic peptidyl (hexarelin) and non-peptidyl (MK-0677) GHS to strongly release GH in animals and humans. Herein we studied: 1) the binding of 125I-labeled human ghrelin to membranes from human hypothalamus and pituitary gland; 2) the ability of human ghrelin (either octanoylated or desoctanoylated), as well as of some GHS and neuropeptides to compete with the radioligand. The saturation binding analysis showed, in both tissues, the existence of a single class of high-affinity binding sites with limited binding capacity. The Bmax (maximal number of binding sites) values of ghrelin receptors in the hypothalamus were significantly greater (p<0.001) than those detected in the pituitary, whereas the Kd (dissociation constant) values in the two tissues were similar. 125I-ghrelin bound to hypothalamic membranes was displaced by ghrelin, hexarelin, MK-067...
In the past few years, search of compounds alternative to either GH or GHRH, endowed with oral bi... more In the past few years, search of compounds alternative to either GH or GHRH, endowed with oral bioavailability and high effectiveness, has resulted in the development of a new family of molecules named growth hormone-releasing peptides (GHRPs). This family now comprises a number of different short peptidyl and non-peptidyl agonists, some of which have been already proven to be effective in humans, and for this reason these compounds are more generally referred to as the growth hormone secretagogues (GHSs). At present, no cardiac effects of the non-peptidyl compounds have been reported and therefore in this chapter we will focus on the cardiovascular actions of GHRPs.
With some of the greatest advances from developmental endocrinology to clinical research being ac... more With some of the greatest advances from developmental endocrinology to clinical research being achieved as a direct result of close collaboration between basic and clinical investigators, 'Hormone Research in Paediatrics' facilitates the interchange of ideas by placing findings at all levels and from all branches side by side in a single source. Original research papers provide a background of experimental data on the pathology, cytology, histology, biochemistry, pharmacology and regulation of hormones. This information is complemented by authoritative ...
From the data presented it appears that ergot drugs are both a useful tool for use in the study o... more From the data presented it appears that ergot drugs are both a useful tool for use in the study of neuroendocrine control of pituitary hormone secretion and a valid pharmacologic weapon for treatment of hyperprolactinemic states, GH and, probably, ACTH and MSH hypersecretion. In fact, they are capable of a long-lasting disruption of PRL secretion from a normal or tumoral pituitary gland, are unable to affect directly the somatotrophs of an intact AP, but inhibit GH and, possibly, ACTH secretion from a hyperplastic or tumoral gland. Ergolines also exert clear-cut PRL-lowering effects and are capable of suppressing GH secretion in acromegaly. The intimate mechanism(s) and hence site(s) of action of some of these compounds await clarification.
The effect of hexarelin, a potent synthetic growth hormone (GH)-secretagogue, and of human GH wer... more The effect of hexarelin, a potent synthetic growth hormone (GH)-secretagogue, and of human GH were studied on the mechanical and metabolic changes elicited by the calcium-paradox phenomenon in isolated rat hearts submitted to 5 min Ca(2+)-depletion followed by reperfusion with reintegrated Ca(2+)medium. Hexarelin, (80 microg kg(-1)s.c.) administered to normal male young rats for 3 and 7-day, time-dependently antagonized the sudden increase in resting tension of the isolated perfused hearts upon Ca(2+)-repletion. The beneficial effect of hexarelin was particularly evident in the 7-day treatment. In this instance, ventricular contraction peaked at 30 +/- 2 mmHg (controls, 76 +/- 7 mmHg) and the recovery of left ventricular developed pressure (LVDP) was two times higher (P&amp;amp;lt;0.001) than that recorded in controls (LVDP, 29 +/- 2 mmHg). Moreover, the release of creatine kinase into the heart effluent during Ca(2+)-repletion was reduced by 40% (P&amp;amp;lt;0.001) as compared to controls. The protecting activity of hexarelin against the damage induced by calcium-paradox in the heart was apparently divorced from any stimulation of the GH/insulin-like growth factor (IGF) axis, since plasma and heart concentrations of IGF-1 were similar to those measured in control rats. In contrast to hexarelin, administration of GH (400 microg kg(-1) s.c.) for 7 days did not affect the mechanical and metabolic manifestations of calcium-paradox in the perfused rat hearts. Hexarelin (8 microg ml(-1)) perfused for 60 min through the hearts in recirculating conditions did not modify heart contractility and failed to prevent ventricular hypercontractility developed on Ca(2+)-readmission. In conclusion, the mode of action of hexarelin in protecting the rat heart from calcium-paradox events is presently unknown; it would seem, however, that only prolonged exposure to hexarelin makes myocardial cells competent to maintain cytoplasmatic electrolyte balance and to control of Ca(2+)gain, two functions that are impaired during the &amp;amp;#39;calcium-paradox&amp;amp;#39; phenomenon.
12-day-old female and male pups were killed 10 min after the injection of either saline or thyrot... more 12-day-old female and male pups were killed 10 min after the injection of either saline or thyrotropin releasing hormone (TRH), and plasma growth hormone (GH) and prolactin (PRL) levels were measured by radioimmunoassay (RIA). At all doses used (0.15, 0.3, 0.6 and 1.5 mug/100 g b.w.i.p.), TRH induced a significant, although not dose-related, increase in plasma GH levels, but was effective in releasing PRL only at the greatest dose level (1.5 mug/100 g b.w.). The GH-releasing effect of TRH was even more evident in 12-day-old pups subjected to central sympathectomy of 6-hydroxydopamine (6-OHDA, 60 mug/10 mul intraventricular route) 1 week before; in these animals, TRH was ineffective in releasing PRL even at the greatest dose level (1.5 mug/100 g b.w.). In pups pretreated with 6-OHDA, the GH-lowering effect of insulin hypoglycemia or cold exposure was markedly reduced, while the PRL responses were unmodified. Baseline plasma PRL levels were markedly increased following 6-OHDA administration. It is proposed that in the infant rat the greater GH than PRL responsiveness to TRH, which opposed the pattern of response present in the adult animal, may be due to the existence of a &amp;amp;amp;amp;#39;physiologic&amp;amp;amp;amp;#39; functional disconnection between the central nervous system (CNS) and the anterior pituitary (AP). Results obtained following central sympathectomy by 6-OHDA, which further disrupted CNS-AP links, substantiate this view.
Anterior pituitaries from female Sprague-Dawley rats (160-200 g b.w) bearing electrolytic lesions... more Anterior pituitaries from female Sprague-Dawley rats (160-200 g b.w) bearing electrolytic lesions of the median eminence were qualitatively and quantitatively investigated by electron microscopy and the findings compared with those from intact animals or sham-operated controls. This study was performed in basal conditions and after stimulation with thyrotropin-releasing hormone. Animals with lesions showed a reduction of both the number of somatotrophic cells and growth hormone granules. After injection of thyrotropin-releasing hormone exocytosis of growth hormone granules from somatotrophs was frequent in rats with lesions of the median eminence but rare in sham-operated animals. The differences were statistically significant.
In ovariectomized rats the intraventricular administration of ethanolamine-O-sulfate (EOS, 300 mi... more In ovariectomized rats the intraventricular administration of ethanolamine-O-sulfate (EOS, 300 micrograms), a specific, competitive and catalytic inhibitor of gamma-aminobutyric acid (GABA) transaminase, induced 3-4 h later a marked reduction in serum prolactin (PRL) concentrations and a 3- to 4-fold rise in the concentration of GABA in pituitary stalk, but not systemic, plasma. The administration of EOS also resulted in an elevation of GABA concentrations in the hypothalamus. These results demonstrate that GABA in pituitary stalk plasma is derived from the central nervous system and that an abrupt increase in the concentration of GABA in hypophysial portal blood is associated with a suppression of PRL secretion.
In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth h... more In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagoguereceptor 1a (GHS-R 1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R 1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.4560.07 mm 2 in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P,0.05) and JMV-1843 (P,0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P,0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P,0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus.
Beta-endorphin concentrations have been evaluated in the hypothalamus, pituitary lobes and plasma... more Beta-endorphin concentrations have been evaluated in the hypothalamus, pituitary lobes and plasma after 1-and 3-week treatment with 2-Br-alpha-ergocriptine or lisuride, two potent dopaminergic drugs. Hypothalamic beta-endorphin concentrations were significantly decreased after the administration of the dopaminergic agents for 1 or 3 weeks. Similarly, beta-endorphin concentrations decreased in the neurointermediate lobe and plasma. After gel chromatography, it appeared that in the anterior pituitary, beta-lipotropin concentrations were unchanged or lightly increased concomitantly with a decrease of beta-endorphin. Our data indicate that, both in the hypothalamus and the neurointermediate pituitary lobe, beta-endorphin is under an inhibitory dopaminergic tone. The latter may also play a role in inhibiting beta-endorphin cleavage from beta-lipotropin in the anterior pituitary.
Journal of Pediatric Endocrinology and Metabolism, 1995
Newly synthesized peptides are described which release growth hormone in the infant rat and their... more Newly synthesized peptides are described which release growth hormone in the infant rat and their biological activity is compared with known GHRPs. Some of these peptides are the most potent GHRPs reported to date.
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2013
Recently, we demonstrated that TLQP-21 triggers lipolysis and induces resistance to obesity by re... more Recently, we demonstrated that TLQP-21 triggers lipolysis and induces resistance to obesity by reducing fat accumulation [1]. TLQP-21 is a 21 amino acid peptide cleavage product of the neuroprotein VGF and was first identified in rat brain. Although TLQP-21 biological activity and its molecular signaling is under active investigation, a receptor for TLQP-21 has not yet been characterized. We now demonstrate that TLQP-21 stimulates intracellular calcium mobilization in CHO cells. Furthermore, using Atomic Force Microscopy (AFM), we also provide evidence of TLQP-21 binding-site characteristics in CHO cells. AFM was used in force mapping mode equipped with a cantilever suitably functionalized with TLQP-21. Attraction of this functionalized probe to the cell surface was specific and consistent with the biological activity of TLQP-21; by contrast, there was no attraction of a probe functionalized with biologically inactive analogues. We detected interaction of the peptide with the binding-site by scanning the cell surface with the cantilever tip. The attractive force between TLQP-21 and its binding site was measured, statistically analyzed and quantified at approximately 40 pN on average, indicating a single class of binding sites. Furthermore we observed that the distribution of these binding sites on the surface was relatively uniform.
In a previous work, we reported that passive immunization with anti-growth hormone-releasing horm... more In a previous work, we reported that passive immunization with anti-growth hormone-releasing hormone (GHRH) antibodies (GHRH-Ab) in neonatal rats caused disruption of somatotropic function that was still present 60 d posttreatment. We studied the reversibility of this condition by growth hormone (GH) replacement therapy. Neonatal rats received GHRH-Ab (50 ~U r d t , s.c.) or normal rabbit serum every second day from birth up to postnatal d 10 and received hGH (0.4 &g body weight, s.c., b i d .) or vehicle in a 2 x 2 factorial design. Animals were studied on d 11 of age. In GHRH-Abtreated rats, GH therapy 1) counteracted the reduced body weight and low plasma IGF-I levels; 2) failed to modify the reduced pituitary weight and GH content; 3) further reduced the low plasma GH levels; 4) partially restored the defective GH responsiveness to GHRH; 5) failed to modify the reduced hypothalamic somatostatin and increased GHRH gene expression in the hypothalamus; and 6) reverted the decreased pituitary somatostatin binding. Morphologic and morphometric evaluation of the pituitary gland from GHRH-Ab+GH pups showed that the number of GH-labeled structures was lower than in normal rat serum-GH-treated pups, whereas the total GH immunoreact~ty per unit surface, an index of intracellular hormone concentration, was slightly higher than in vehicle-GH or GHRH-Ab pups. As determined by electron microscopy, somatotropes from GHRH-Ab+GH pups had morphologic features of high cellular activity. It appears that in GHRH-deprived pups GH replacement therapy can normalize most but not all altered indices of the somatotropic function. The effects of GH are mainly directed at the pituitaly, whereas the sensitivity of the hypothalamus to GH replacement is lower. (Pediatr Res 36: 315-322, 1994) Abbreviations GH, growth hormone GHRH, growth hormone-releasing hormone GHRH-Ab, anti-GHRH-antibodies NRS, normal rabbit serum dCTP, deoxycytidine triphosphate PRL, prolactin SS, somatostatin Recent studies by us (1,2) and by other groups (3,4) have shown that rat pups treated with GHRH-Ab may represent a suitable animal model for the study of the human growth disorders caused b y a primary hypothalamic dysfunction. Neonatal administration of GHRH-Ab permanently inhibits the growth rate and alters several indices of the hypophyseal somatotropic function (I).
... Irit Gil-Ad a , 2 , Vittorio Locatelli a , Daniela Cocchi a , Robert Carminati a , Carlo Arez... more ... Irit Gil-Ad a , 2 , Vittorio Locatelli a , Daniela Cocchi a , Robert Carminati a , Carlo Arezzini a andEugenio E. Müller ring operator. a Department of Pharmacology, University of Milan, Italy. ... 12. GD NISWENDER, AR MIDGLEY, Jr., SE MONROE, and LEREICHERT, Proc. Soc. Exp. ...
Capsaicin has been administered intraventricularly to adult rats and subcutaneously to neonatal r... more Capsaicin has been administered intraventricularly to adult rats and subcutaneously to neonatal rats. Adult rats were killed three, five, seven and fifteen days after capsaicin administration, while rats treated neonatally were killed when six months old. In the adult rats capsaicin induced a decrease in hypothalamic B-endorphin concentrations three, five and seven days after treatment, while they returned to normal values by day fifteen. A decrease in B-endorphin hypothalamic concentrations was also present in rats treated neonatally, while substance P, somatostatin and met-enkephalin concentrations were never affected by capsaicin treatment.
Ghrelin has been proposed as a natural ligand of the GH secretagogue receptor(s) (GHS-R), which w... more Ghrelin has been proposed as a natural ligand of the GH secretagogue receptor(s) (GHS-R), which was an orphan receptor activated by synthetic peptidyl (hexarelin) and non-peptidyl (MK-0677) GHS to strongly release GH in animals and humans. Herein we studied: 1) the binding of 125I-labeled human ghrelin to membranes from human hypothalamus and pituitary gland; 2) the ability of human ghrelin (either octanoylated or desoctanoylated), as well as of some GHS and neuropeptides to compete with the radioligand. The saturation binding analysis showed, in both tissues, the existence of a single class of high-affinity binding sites with limited binding capacity. The Bmax (maximal number of binding sites) values of ghrelin receptors in the hypothalamus were significantly greater (p<0.001) than those detected in the pituitary, whereas the Kd (dissociation constant) values in the two tissues were similar. 125I-ghrelin bound to hypothalamic membranes was displaced by ghrelin, hexarelin, MK-067...
In the past few years, search of compounds alternative to either GH or GHRH, endowed with oral bi... more In the past few years, search of compounds alternative to either GH or GHRH, endowed with oral bioavailability and high effectiveness, has resulted in the development of a new family of molecules named growth hormone-releasing peptides (GHRPs). This family now comprises a number of different short peptidyl and non-peptidyl agonists, some of which have been already proven to be effective in humans, and for this reason these compounds are more generally referred to as the growth hormone secretagogues (GHSs). At present, no cardiac effects of the non-peptidyl compounds have been reported and therefore in this chapter we will focus on the cardiovascular actions of GHRPs.
With some of the greatest advances from developmental endocrinology to clinical research being ac... more With some of the greatest advances from developmental endocrinology to clinical research being achieved as a direct result of close collaboration between basic and clinical investigators, 'Hormone Research in Paediatrics' facilitates the interchange of ideas by placing findings at all levels and from all branches side by side in a single source. Original research papers provide a background of experimental data on the pathology, cytology, histology, biochemistry, pharmacology and regulation of hormones. This information is complemented by authoritative ...
From the data presented it appears that ergot drugs are both a useful tool for use in the study o... more From the data presented it appears that ergot drugs are both a useful tool for use in the study of neuroendocrine control of pituitary hormone secretion and a valid pharmacologic weapon for treatment of hyperprolactinemic states, GH and, probably, ACTH and MSH hypersecretion. In fact, they are capable of a long-lasting disruption of PRL secretion from a normal or tumoral pituitary gland, are unable to affect directly the somatotrophs of an intact AP, but inhibit GH and, possibly, ACTH secretion from a hyperplastic or tumoral gland. Ergolines also exert clear-cut PRL-lowering effects and are capable of suppressing GH secretion in acromegaly. The intimate mechanism(s) and hence site(s) of action of some of these compounds await clarification.
The effect of hexarelin, a potent synthetic growth hormone (GH)-secretagogue, and of human GH wer... more The effect of hexarelin, a potent synthetic growth hormone (GH)-secretagogue, and of human GH were studied on the mechanical and metabolic changes elicited by the calcium-paradox phenomenon in isolated rat hearts submitted to 5 min Ca(2+)-depletion followed by reperfusion with reintegrated Ca(2+)medium. Hexarelin, (80 microg kg(-1)s.c.) administered to normal male young rats for 3 and 7-day, time-dependently antagonized the sudden increase in resting tension of the isolated perfused hearts upon Ca(2+)-repletion. The beneficial effect of hexarelin was particularly evident in the 7-day treatment. In this instance, ventricular contraction peaked at 30 +/- 2 mmHg (controls, 76 +/- 7 mmHg) and the recovery of left ventricular developed pressure (LVDP) was two times higher (P&amp;amp;lt;0.001) than that recorded in controls (LVDP, 29 +/- 2 mmHg). Moreover, the release of creatine kinase into the heart effluent during Ca(2+)-repletion was reduced by 40% (P&amp;amp;lt;0.001) as compared to controls. The protecting activity of hexarelin against the damage induced by calcium-paradox in the heart was apparently divorced from any stimulation of the GH/insulin-like growth factor (IGF) axis, since plasma and heart concentrations of IGF-1 were similar to those measured in control rats. In contrast to hexarelin, administration of GH (400 microg kg(-1) s.c.) for 7 days did not affect the mechanical and metabolic manifestations of calcium-paradox in the perfused rat hearts. Hexarelin (8 microg ml(-1)) perfused for 60 min through the hearts in recirculating conditions did not modify heart contractility and failed to prevent ventricular hypercontractility developed on Ca(2+)-readmission. In conclusion, the mode of action of hexarelin in protecting the rat heart from calcium-paradox events is presently unknown; it would seem, however, that only prolonged exposure to hexarelin makes myocardial cells competent to maintain cytoplasmatic electrolyte balance and to control of Ca(2+)gain, two functions that are impaired during the &amp;amp;#39;calcium-paradox&amp;amp;#39; phenomenon.
12-day-old female and male pups were killed 10 min after the injection of either saline or thyrot... more 12-day-old female and male pups were killed 10 min after the injection of either saline or thyrotropin releasing hormone (TRH), and plasma growth hormone (GH) and prolactin (PRL) levels were measured by radioimmunoassay (RIA). At all doses used (0.15, 0.3, 0.6 and 1.5 mug/100 g b.w.i.p.), TRH induced a significant, although not dose-related, increase in plasma GH levels, but was effective in releasing PRL only at the greatest dose level (1.5 mug/100 g b.w.). The GH-releasing effect of TRH was even more evident in 12-day-old pups subjected to central sympathectomy of 6-hydroxydopamine (6-OHDA, 60 mug/10 mul intraventricular route) 1 week before; in these animals, TRH was ineffective in releasing PRL even at the greatest dose level (1.5 mug/100 g b.w.). In pups pretreated with 6-OHDA, the GH-lowering effect of insulin hypoglycemia or cold exposure was markedly reduced, while the PRL responses were unmodified. Baseline plasma PRL levels were markedly increased following 6-OHDA administration. It is proposed that in the infant rat the greater GH than PRL responsiveness to TRH, which opposed the pattern of response present in the adult animal, may be due to the existence of a &amp;amp;amp;amp;#39;physiologic&amp;amp;amp;amp;#39; functional disconnection between the central nervous system (CNS) and the anterior pituitary (AP). Results obtained following central sympathectomy by 6-OHDA, which further disrupted CNS-AP links, substantiate this view.
Anterior pituitaries from female Sprague-Dawley rats (160-200 g b.w) bearing electrolytic lesions... more Anterior pituitaries from female Sprague-Dawley rats (160-200 g b.w) bearing electrolytic lesions of the median eminence were qualitatively and quantitatively investigated by electron microscopy and the findings compared with those from intact animals or sham-operated controls. This study was performed in basal conditions and after stimulation with thyrotropin-releasing hormone. Animals with lesions showed a reduction of both the number of somatotrophic cells and growth hormone granules. After injection of thyrotropin-releasing hormone exocytosis of growth hormone granules from somatotrophs was frequent in rats with lesions of the median eminence but rare in sham-operated animals. The differences were statistically significant.
In ovariectomized rats the intraventricular administration of ethanolamine-O-sulfate (EOS, 300 mi... more In ovariectomized rats the intraventricular administration of ethanolamine-O-sulfate (EOS, 300 micrograms), a specific, competitive and catalytic inhibitor of gamma-aminobutyric acid (GABA) transaminase, induced 3-4 h later a marked reduction in serum prolactin (PRL) concentrations and a 3- to 4-fold rise in the concentration of GABA in pituitary stalk, but not systemic, plasma. The administration of EOS also resulted in an elevation of GABA concentrations in the hypothalamus. These results demonstrate that GABA in pituitary stalk plasma is derived from the central nervous system and that an abrupt increase in the concentration of GABA in hypophysial portal blood is associated with a suppression of PRL secretion.
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