Growth Hormone-Releasing Hormone and Gonadotropin-Releasing Hormone Stimulate Nitric Oxide Production in 17β-Estradiol-Primed Rat Anterior Pituitary Cells
Abstract:It was reported that neuronal nitric oxide synthase (nNOS) was expressed only in gonadotrophs and folliculo-stellate cells in the anterior lobe of the pituitary gland. However, recent studies have demonstrated the occurrence of nNOS in the somatotrophs and lactotrophs. In the present study, we investigated effects of growth hormone-releasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), and 17beta-estradiol on nitric oxide (NO) release in cultured rat anterior pituitary cells in vitro. The NO2- level … Show more
“…The effectors of vascular flow change may be pericytes, which display long contractile cytoplasmic processes embracing the endothelial tube of portal capillary vessels (30). These express receptors for diffusible vascular signaling factors (31), such as nitric oxide (32), which is synthesized by GH cells (33,34).…”
Growth hormone (GH) exerts its actions via coordinated pulsatile secretion from a GH cell network into the bloodstream. Practically nothing is known about how the network receives its inputs in vivo and releases hormones into pituitary capillaries to shape GH pulses. Here we have developed in vivo approaches to measure local blood flow, oxygen partial pressure, and cell activity at single-cell resolution in mouse pituitary glands in situ. When secretagogue (GHRH) distribution was modeled with fluorescent markers injected into either the bloodstream or the nearby intercapillary space, a restricted distribution gradient evolved within the pituitary parenchyma. Injection of GHRH led to stimulation of both GH cell network activities and GH secretion, which was temporally associated with increases in blood flow rates and oxygen supply by capillaries, as well as oxygen consumption. Moreover, we observed a time-limiting step for hormone output at the perivascular level; macromolecules injected into the extracellular parenchyma moved rapidly to the perivascular space, but were then cleared more slowly in a size-dependent manner into capillary blood. Our findings suggest that GH pulse generation is not simply a GH cell network response, but is shaped by a tissue microenvironment context involving a functional association between the GH cell network activity and fluid microcirculation.blood flow | hormone pulsatility | oxygen pressure | tissue microenvironment | extracellular space
“…The effectors of vascular flow change may be pericytes, which display long contractile cytoplasmic processes embracing the endothelial tube of portal capillary vessels (30). These express receptors for diffusible vascular signaling factors (31), such as nitric oxide (32), which is synthesized by GH cells (33,34).…”
Growth hormone (GH) exerts its actions via coordinated pulsatile secretion from a GH cell network into the bloodstream. Practically nothing is known about how the network receives its inputs in vivo and releases hormones into pituitary capillaries to shape GH pulses. Here we have developed in vivo approaches to measure local blood flow, oxygen partial pressure, and cell activity at single-cell resolution in mouse pituitary glands in situ. When secretagogue (GHRH) distribution was modeled with fluorescent markers injected into either the bloodstream or the nearby intercapillary space, a restricted distribution gradient evolved within the pituitary parenchyma. Injection of GHRH led to stimulation of both GH cell network activities and GH secretion, which was temporally associated with increases in blood flow rates and oxygen supply by capillaries, as well as oxygen consumption. Moreover, we observed a time-limiting step for hormone output at the perivascular level; macromolecules injected into the extracellular parenchyma moved rapidly to the perivascular space, but were then cleared more slowly in a size-dependent manner into capillary blood. Our findings suggest that GH pulse generation is not simply a GH cell network response, but is shaped by a tissue microenvironment context involving a functional association between the GH cell network activity and fluid microcirculation.blood flow | hormone pulsatility | oxygen pressure | tissue microenvironment | extracellular space
“…Based on the route of administration, this antagonist could alter different hypothalamic systems given that dopamine is involved in the regulation of various endocrine loops including the GnRH and somatostatin producing neurons of the hypothalamus (McMahon et al 1998;West et al 1997;Hileman and Jackson 1999;Tortonese 1999). Thus, considering that GnRH or GHRH which is influenced by somatostatin activates nNOS in pituitary cells (Chen et al 1999;Ferrini et al 2001;Tsumori et al 2002), we cannot totally exclude the possibility that the haloperidol effects which we have observed on pituitary nNOS-positive cells reflect the indirect effects of hypothalamic systems.…”
Nitric oxide is an unconventional transmitter since it is not transported and released by exocytosis. In the pituitary gland, nitric oxide is locally synthesised by gonadotroph and folliculo-stellate cells. Dopamine, the principal central inhibitory signal in prolactin release, may exert its inhibitory effects by stimulation of nitric oxide production. However, the effects of dopaminergic modulation on nitric oxide-producing pituitary cells have not been analysed. Therefore, we examined the effects of intraventricular administration of the dopamine antagonist haloperidol (40 microg) on the pituitary expression of neuronal nitric oxide synthase (nNOS) in male adult rats. In untreated and control animals, nNOS-positive cells were very similar. Two types of nNOS-positive cells appeared in the pars distalis: round or polygonal cells and stellate cells. Although some isolated cells were found, the nNOS-positive cells commonly appeared grouped in clusters close to blood vessels. nNOS immunoreactivity appeared as a uniform staining throughout the cytoplasm, including cell prolongations. The number and size of nNOS-expressing cells in the pituitary gland decreased significantly after treatment with haloperidol (p<0.01). To evaluate the potential direct effect of dopamine on pituitary cells, pituitary monolayer cultures were treated with dopamine during a time-course of 12 h. Our in vitro studies revealed that dopamine increases the percentage of nNOS-positive cells and augments cellular area (p<0.05). These results demonstrate that: (1) treatment of rats in vivo with a dopamine antagonist significantly decreases expression of nNOS in the pituitary and (2) in vitro dopamine exerts a direct effect on pituitary cultures by increasing nNOS-positive cells. Thus, these findings suggest that dopamine may function as a physiological stimulator of nNOS expression in the rat pituitary gland.
“…Statistical analysis was performed by a of cell types. In the pituitary, different endocrine cells express neuronal NO synthase (nNOS; Hokfelt et al 1994, Andric et al 2001, Tsumori et al 2002, and vascular endothelial cells express endothelial NO synthase (eNOS; Garcia-Cardena et al 1996). Both nNOS and eNOS produce NO using L-arginine as substrate.…”
Section: Regulation Of Blood Flowmentioning
confidence: 99%
“…Both nNOS and eNOS produce NO using L-arginine as substrate. Various peptides, including hypothalamic neuropeptides and pituitary hormones, can modulate NOS activity and vascular tone (Boger 1999, Tsumori et al 2002. NO, in turn, can modulate secretory activity and hormone output (Gonzalez-Hernandez & Gonzalez 2000).…”
Section: Regulation Of Blood Flowmentioning
confidence: 99%
“…3). It should be noted, however, that the ability of GHRH to activate nNOS and increase NO production, as opposed to a compensatory increase in blood flow in direct response to tissue hypoxia, may account for the observed increases in blood flow (Boger 1999, Tsumori et al 2002. Potential regulatory mechanisms that may exist in the pituitary to modify blood flow following GHRH stimulation have been proposed .…”
Section: Blood Flow Measurement and Oxygen Consumptionmentioning
Hormones are dynamically collected by fenestrated capillaries to generate pulses, which are then decoded by target tissues to mount a biological response. To generate hormone pulses, endocrine systems have evolved mechanisms to tightly regulate blood perfusion and oxygenation, coordinate endocrine cell responses to secretory stimuli, and regulate hormone uptake from the perivascular space into the bloodstream. Based on recent findings, we review here the mechanisms that exist in endocrine systems to regulate blood flow, and facilitate coordinated cell activity and output under both normal physiological and pathological conditions in the pituitary gland and pancreas.
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