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PubMed1993

Neuronal inositol 1,4,5-trisphosphate receptor localized to the plasma membrane of olfactory cilia.

Both the cyclic adenosine 3',5'-monophosphate and the phosphoinositide second messenger systems are involved in olfactory signal transduction. The inositol 1,4,5-trisphosphate receptor is one of the principal intracellular calcium channels responsible for mobilizing stored calcium. The precise location of the 1,4,5-trisphosphate receptor (endoplasmic reticulum vs surface) and its role in the events of olfactory signal transduction need to be defined. By light microscopic and confocal immunohistochemistry we show expression of the olfactory-enriched G-protein, G(olf), associated with cyclic AMP responses, and of the inositol 1,4,5-trisphosphate receptor in the dendritic projections and cilia of essentially all olfactory receptor neurons, indicating that individual neurons express components of both second messenger systems. By immunoelectron microscopy, we demonstrate that the inositol 1,4,5-trisphosphate receptor is localized to the surface membrane of rat olfactory cilia. This is the first morphological demonstration of the surface membrane localization of inositol 1,4,5-trisphosphate receptor in olfactory cilia. Our findings, taken in conjunction with electrophysiological data from other workers, are supportive of the inositol 1,4,5-trisphosphate receptor playing a novel role in regulating calcium flux at the ciliary surface membrane.

Animals↗
PubMed1996

Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice.

The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanation for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice.

Adenylyl Cyclase Inhibitors↗
PubMed1988

Attenuation of hen granulosa cell steroidogenesis by a phorbol ester and 1-oleoyl-2-acetylglycerol.

A series of studies was conducted to evaluate the effects of phorbol esters and a diacylglycerol analog on basal and hormone-stimulated steroidogenesis in granulosa cells from the largest preovulatory follicle of the domestic hen. Agents that previously have been shown to activate protein kinase C, such as the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), and the synthetic diacylglycerol analog, 1-oleoyl-2-acetylglycerol (OAG), suppressed luteinizing hormone (LH)-induced progesterone (PMA at levels of 10 and 100 ng/tube; OAG at levels of 10 and 25 micrograms/tube), and androgen (10 and 100 ng PMA; 25 micrograms OAG) production, but had no effect on basal levels of either steroid. Furthermore, PMA decreased the ability of vasoactive intestinal peptide to induce steroidogenesis, suggesting that protein kinase C activation may generally modulate the activity of hormones that act via the adenylyl cyclase/cyclic 3',5'-adenosine monophosphate (cAMP) second messenger system. In further support of this proposal was the finding that PMA and OAG decreased the production of cAMP in response to LH, and attenuated the steroidogenic response in granulosa cells exposed to 10 mM 8-bromo-cAMP. By contrast, the induction of calcium mobilization using a calcium ionophore (A23187; 0.5-2.0 microM) stimulated progesterone and androgen production without increasing intracellular levels of cAMP, and this stimulatory effect on steroidogenesis was not inhibited by the presence of 100 ng PMA/tube. From these data, we suggest that the activation of protein kinase C in granulosa cells of the hen may provide a physiological mechanism by which receptor-mediated steroidogenesis, involving the adenylyl cyclase second messenger system, is modulated.

Androgens↗
PubMed1994

Lithium potentiates phosphoinositide-linked 5-HT receptor stimulation in vivo.

The therapeutic effect of lithium in manic-depressive illness may involve alterations in the activity of the phosphoinositide second messenger system. Lithium administration to rats potentiates responses to cholinergic agonists, as evidenced by the production of seizures in lithium-treated rats after normally nonconvulsant doses of cholinergic agonists. We now report that lithium also potentiates the response to a serotonin (5-HT) agonist, DOI, that activates 5-HT2/5-HT1C receptors coupled to phosphoinositide hydrolysis. EEG recordings showed that administration of DOI (8 mg kg-1) to lithium-treated, but not to lithium-naive, rats caused seizures which were blocked by ritanserin pretreatment. These results demonstrate that lithium pretreatment causes a normally subconvulsive dose of serotonergic, in addition to cholinergic, agonists to induce seizures. Since DOI, like cholinergic agonists, activates receptors coupled with phosphoinositide hydrolysis and lithium potentiates responses to each, this second messenger system is likely to be involved in this effect of lithium.

Amphetamines↗
PubMedDate not supplied

Chemical control of growth and morphological characteristics of anaplastic glioma cells.

Nerve growth factor (NGF) and glia maturation factor (GMF) reverse some of the transformed characteristics of T9 glioma cells (Marushige et al., Cancer Res 47: 4109-4115, 1987). As an attempt to define the mechanisms of such actions, various chemical agents which modulate second messenger systems were examined for their effects on growth and morphological characteristics of these cells. Administration of bromo-cAMP, forskolin and methylisobutylxanthine retarded cell growth and induced formation of long, branching processes which were similar to those induced by GMF. Perturbation of Ca2(+)-mediated processes by a Ca2+ ionophore, ionomycin, and by calmodulin antagonists, chlorpromazine and W-7, on the other hand, arrested cell growth, and caused clustering of cells, spreading of the cytoplasm and development of lamellipodium-like protrusions which were reminiscent of the effects of NGF. Administration of bromo-cAMP in combination with chlorpromazine, W-7 or ionomycin prevented spreading of the cytoplasm and produced compact cell bodies with well-developed processes. The results of this study demonstrate that modulation of specific second messenger systems by chemical agents are capable of simulating selective morphological changes inducible by NGF and GMF.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Angiotensin AT1B receptor mediates calcium signaling in vascular smooth muscle cells of AT1A receptor-deficient mice.

Our studies on angiotensin II receptor subtype 1A (AT1A) knockout mice define how endogenous receptors other than AT1A receptors stimulate changes in cytosolic calcium concentration ([Ca2+]i) in cultured aortic vascular smooth muscle cells (VSMCs). Wild-type cells have a 1.7 ratio of AT1A/AT1B receptor mRNA as determined by semiquantitative reverse transcriptase-polymerase chain reaction. Mutant cells express AT1B receptor mRNA but not that for the AT1A receptor. In wild-type cells with AT1A present, Ang II (10(-7) mol/L) produces a characteristic rapid peak increase in [Ca2+]i of 150 to 180 nmol/L, followed by a plateau phase characterized by a sustained 70 to 80 nmol/L increase in [Ca2+]i. An unexpected finding was that the magnitude and time-dependent pattern of [Ca2+]i changes produced by Ang II were similar in cells that lacked AT1A receptors but possessed AT1B receptors. The response in mutant cells indicates effective coupling of an Ang II receptor to one or more second messenger systems. The similarity of response patterns between cells with and without AT1A receptors suggests that non-AT1A receptors are functionally linked to similar signal transduction pathways in mutant cells. The fact that mutant and wild-type cells exhibit similar patterns of calcium mobilization and entry supports the notion that AT1A and non-AT1A receptors share common signal transduction pathways. The AT2 receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT2 receptors and/or an absence of their linkage to [Ca2+]i pathways. The nonpeptide AT1 receptor blocker losartan antagonizes Ang II-induced [Ca2+]i increases in both cell groups, supporting mediation by native AT1B receptors and effective coupling of this subtype to second messenger systems leading to calcium entry and mobilization. Our results demonstrate that Ang II causes calcium signaling in AT1A-deficient VSMCs that is mediated by an endogenous losartan-sensitive AT1B receptor.

Angiotensin II↗
PubMed1989

Decreased parietal cell secretory capacity following vagotomy and pyloroplasty.

Although vagotomy reduces acid secretion in vivo, the effects of vagotomy at the level of the parietal cell are not known. In the present study we examined the in vitro secretory characteristics of parietal cells in rabbits 8 weeks following vagotomy compared to unoperated and sham-operated controls. Acid secretion was assessed by the uptake of [14C]aminopyrine (AP) in isolated gastric glands. Also, gastric fundus histology, mucosal thickness, parietal cell density, and gastric gland somatostatin content were examined. Basal AP uptake was decreased following vagotomy (8 +/- 0.4 pmole/mg dry wt) compared to controls (21 +/- 2) (P less than 0.001). Increase in AP uptake by the cholinergic agonist carbachol was unaffected after vagotomy (P greater than 0.5) suggesting intact muscarinic receptors and calcium second messenger system. Increase in AP uptake was significantly reduced following vagotomy by the cyclic AMP-mediated agonist histamine (P less than 0.05) and the cyclic AMP mimetic 8-bromo cyclic AMP (P less than 0.001) suggesting an alteration in the ability of the parietal cell to utilize cAMP following vagotomy. There were no discernible differences in histology, mucosal thickness, or parietal cell number in vagotomized animals compared to controls (P greater than 0.5). There was a significant increase in gastric gland somatostatin content following vagotomy (37 +/- 10 fmole/mg dry wt) compared to control (14 +/- 1.5) (P = 0.025). These results suggest that there is a decrease in the capacity of parietal cells to secrete acid following vagotomy. In addition, the decrease in cAMP utilization following vagotomy suggests that the cAMP second messenger system is dependent, at least in part, on an intact vagus nerve.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Paradoxical inhibition by aspirin of naloxone-induced adrenocorticotropin secretion in myotonic dystrophy.

The ACTH response to endogenous or exogenous CRH is increased in patients with myotonic dystrophy (DM), possibly because of abnormal function of cAMP-dependent protein kinases in this condition. Arachidonic acid (AA) metabolites are believed to interact with the cAMP-dependent second messenger system activated by CRH; therefore, drugs that interfere with AA metabolism may alter ACTH secretion in DM. In this study, seven DM patients were given naloxone, which stimulates endogenous CRH release, and aspirin, which inhibits the synthesis of prostaglandins from AA via the cyclooxygenase metabolic pathway. Pretreatment with aspirin reduced the mean integrated ACTH response to naloxone by 33% (P < 0.05). However, the corresponding 18% reduction in cortisol levels was not statistically significant (P > 0.10). These findings are in contrast to those of a previous study using an identical protocol, in which aspirin increased the ACTH response to naloxone in six normal volunteers. This difference between DM and control subjects is consistent with the hypothesis that the interaction between AA metabolites and the cAMP-dependent protein kinase-A second messenger system is abnormal in the corticotrophs of persons with DM.

Adrenocorticotropic Hormone↗
PubMed2001

Increased platelet membrane phosphatidylinositol-4,5-bisphosphate in drug-free depressed bipolar patients.

Prior investigations in bipolar disorder patients have suggested abnormalities in the cellular phosphoinositide second messenger system. This study was conducted to examine the levels of platelet membrane phosphoinositides in drug-free bipolar patients in the depressed state (n=9) and healthy controls (n=19). Bipolar patients had significantly increased levels of platelet membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)) compared to healthy individuals (0.67+/-0.14 and 0.44+/-0.17%, respectively, t-test=3.71, d.f.=26, P=0.001). No significant differences in the levels of phosphatidylinositol-4-phosphate (PIP) (0.65+/-0.17 and 0.58+/-0.20%, respectively, t-test=1.02; d.f.=26; P=0.32) or phosphatidylinositol (PI) (5.92+/-1.23 and 5.56+/-1.45%, respectively, t-test=0.68; d.f.=26; P=0.51) were found. These findings provide the first demonstration of increased PIP(2) platelet levels in bipolar patients in the depressed state, and provide additional evidence that the phosphoinositide second messenger system may be a site of abnormality in bipolar disorder.

Adult↗
PubMed1975

Regulation of cyclic AMP content in normal and malignant brain cells.

Pharmacologic characterization of the neurotransmitter-sensitive cyclic AMP-second messenger systems of brain has proven to be a complex and difficult endeavor. At least two types of receptor appear to be involved in the mediation of the effects of NE on cyclic AMP content. One of these receptor systems appears to mediate the potentiation by NE of the effect of adenosine of cyclic AMP accumulation. The cellular heterogeneity of brain has retarded the determination of the mechanism underlying the synergistic interaction of catecholamines and adenosine. An attempt to use clonal cell lines to examine the action of NE and adenosine on cyclic AMP content has resulted in the demonstration that adenosine acts in a hormone-like fashion to stimulate adenylate cyclase activity. However, the studies did not shed light on the mechanism of synergism. An increasing number of reports are appearing which support the idea that the responsiveness of cells to neuronally released NE may involve adaptive changes in the responsiveness of the cyclic AMP-second messenger system which compensate for chronic over- or underproduction of the first messenger, NE. Evidence was presented that such a regulatory process may be operative in rat cerebral cortex. Our studies of catecholamine-induced loss of responsiveness in human astrocytoma cells have led us to the conclusion that the loss in the capacity of the cells to accumulate cyclic AMP is a result of a loss in the capacity to synthesize cyclic AMP. However, it is probable that different cells make use of different mechanisms (e.g., changes in phosphodiesterase activity) to regulate their ability to respond to hormones or neurotransmitters. The physiologic importance of this level of regulation of responsiveness to hormones is not known at this time.

Adenosine↗
PubMed2001

Angiotensin signaling and receptor types in teleost fish.

Despite advances characterizing mammalian angiotensin receptors, the phylogeny of fish angiotensin receptors remains unclear. Three aspects of receptor function: (1) the nature of the ligand; (2) the second messenger system activated by it; and (3) the pharmacological profile of specific antagonists, are examined to provide insight into the fish receptor. (1) The octapeptide sequences of fish and mammalian angiotensin II (ANG II) are nearly homologous, differing only at the first and fifth residues. Both peptides are almost equally efficacious and equipotent in heterologous systems and both contain key agonist switches Tyr(4) and Phe(8) necessary to activate mammalian AT(1)-type receptors. (2) ANG II increases inositol trisphosphate production, and elevates intracellular calcium in fish tissues consistent with activation of the AT(1) receptor. (3) However, the specific mammalian sartan-type AT(1) antagonists, e.g. losartan, produce inconsistent results in fish often acting as partial agonists, or inhibiting only at elevated concentrations. Because sartans and ANG II act at distinct sites on the AT(1) receptor, we propose that the teleost receptor is an AT(1)-type receptor that is fairly well conserved with respect to both the ANG binding site and coupling to the second messenger system, whereas the sartan binding site has been poorly conserved. The evidence for non-AT(1) type ANG II receptors in teleosts is limited. Mammalian AT(2) receptor antagonists are generally ineffective but may block at elevated, non-specific doses. Truncated ANG II fragments, ANG III and ANG IV, are often less potent than ANG II, however, their receptors have not been examined. Preliminary studies in trout indicate that angiotensin 1-7 may have a mild vasodilatory effect; additional work is needed to determine if non-AT(1)-type receptors are involved.

Amino Acid Sequence↗
PubMed1991

Gonadotrophin-releasing hormone: physiological significance and relevance to cancer.

Gonadotrophin releasing hormone (GnRH) is a decapeptide released by the hypothalamus. The binding of the peptide to pituitary receptors leads to the activation of second messenger systems. The physiological outcome of the exposure of pituitary cells to GnRH is the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH). Continued exposure of these receptors to high concentrations of the peptide desensitises the receptor, thus inhibiting the release of gonadotrophins. This paradoxical effect has proved to be beneficial in the clinic where long-acting and enzyme-resistant analogues are used to inhibit the pituitary-gonadal axis, for example in the treatment of advanced prostatic cancer. In addition GnRH-analogues may affect tumour cells directly as observed in vitro. These direct effects have been described as inhibitory but recent data suggests that low concentrations of GnRH-analogues may stimulate short term growth of prostatic cancer cells in vitro. GnRH shares many other common characteristics with peptide growth factors, including common second messenger systems and receptor desensitisation on prolonged exposure to the ligand. It is possible that the direct inhibitory effects of GnRH-analogues are mediated through the desensitisation of tumour GnRH receptors, as suggested by recent observations. The nature and mechanism of the direct anti-tumour effect is important to understand and to promote the therapeutic efficacy of GnRH-analogues in the clinic.

Amino Acid Sequence↗
PubMed2004

Effects of the new ethacrynic acid derivative SA9000 on intraocular pressure in cats and monkeys.

To evaluate the pharmacological characteristics of the new ethacrynic acid (ECA) derivative SA9000, we examined its ocular hypotensive effects in cats and cynomolgus monkeys, its corneal toxicity in rabbits, and its binding affinities for forty-three receptors, ion channels, and second messenger systems. A 20 microl injection into the anterior chamber of eye (intracameral injection) of 0.1 mM SA9000 significantly reduced intraocular pressure (IOP) 3.8 mmHg in cats. A 10 microl intracameral injection of 1 mM SA9000 significantly reduced IOP 7 mmHg in living monkeys without evidence of in vivo (or in vitro) toxicity. The ocular hypotensive effect of SA9000 in monkeys was greater than that of ECA. The morphology of corneal endothelial and epithelial cells in rabbit eyes after intracameral injection of SA9000 was observed using electron microphotography. SA9000 at 2 mM did not induce any abnormalities, indicating that it has no corneal toxicity at a concentration higher than the minimum needed for an ocular hypotensive effect (1 mM). SA9000 at 0.01 mM showed negligible binding affinity for, or inhibition of, forty-three different receptors, ion channel proteins, and second messenger systems. These findings indicate that SA9000 has the potential to be both effective and safe as an ocular hypotensive drug, although the mechanism of action remains unclear.

Animals↗
PubMed1992

Role of Ras in signal transduction from the nerve growth factor receptor: relationship to protein kinase C, calcium and cyclic AMP.

A dominant inhibitory ras mutant (Ha-ras Asn-17) has been used to investigate the role of Ras in nerve growth factor (NGF)-mediated signal transduction in PC12 cells. Expression of Ha-Ras Asn-17 blocks neuronal differentiation of these cells in response to NGF treatment. The Ha-Ras Asn-17 block was bypassed by treatment with NGF plus dibutyryl cAMP or NGF plus the Ca2+ ionophore ionomycin, but not by NGF plus 12-O-tetradecanoyl phorbol acetate (TPA). Direct stimulation of the cAMP or Ca2+ pathways thus appeared to act synergistically with a Ras-independent NGF signaling pathway. This Ras-independent pathway was also distinct from protein kinase C, since its activity was not affected by protein kinase C down-regulation. It thus appears that NGF stimulation generates a Ras-independent intracellular signal that contributes to neuronal differentiation independently of the cAMP, Ca2+ or protein kinase C second messenger systems. Since TPA did not bypass the Ha-Ras Asn-17 block to differentiation, protein kinase C also did not appear to be sufficient for Ras-dependent pathways mediating NGF-induced differentiation. Down-regulation experiments further indicated that protein kinase C was not required for NGF induction of early response genes via either Ras-dependent or Ras-independent pathways. Moreover, the formation of inositol phosphates and mobilization of intracellular calcium in response to NGF was not inhibited in PC12 cells expressing the Ha-Ras Asn-17 protein. Therefore, although calcium was able to bypass the Ha-Ras Asn-17 block to PC12 differentiation, Ras activity was not required for activation of phospholipase C in response to NGF. It thus appears that both Ras-dependent and Ras-independent signaling pathways contribute to NGF-induced PC12 cell differentiation independently of the cAMP, calcium and protein kinase C second messenger systems.

Animals↗
PubMed1996

Halothane reduces myofilament Ca2+ sensitivity during muscarinic receptor stimulation of airway smooth muscle.

This study used a beta-escin-permeabilized canine tracheal smooth muscle preparation to test the hypothesis that the volatile anesthetic halothane decreases myofilament Ca2+ sensitivity by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity and not by inhibiting Ca(2+)-calmodulin activation of the contractile proteins. Acetylcholine (ACh) caused a GTP-dependent increase in force at constant submaximal cytosolic Ca2+ concentration. ACh, guanosine-5'-O-(3-thiotriphosphate), and the protein kinase C agonist 12,13-phorbol dibutyrate each significantly decreased the concentration of free Ca2+ producing a half-maximal response from 0.77 +/- 0.09 microM (Ca2+ alone) to 0.16 +/- 0.01, 0.19 +/- 0.02, and 0.37 +/- 0.03 microM, respectively, demonstrating an increase in myofilament Ca2+ sensitivity. Halothane (0.92 +/- 0.12 mM) had no effect on the free Ca2+ concentration-response curves generated by Ca2+ alone. However, in the presence of 3 microM ACh plus 10 microM GTP to maximally activate muscarinic receptors, halothane significantly increased the EC50 for free Ca2+ from 0.17 +/- 0.01 microM to 0.38 +/- 0.03 microM. These findings suggest that halothane decreases myofilament Ca2+ sensitivity in beta-escin-permeabilized canine tracheal smooth muscle by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity.

Acetylcholine↗
PubMed1989

Postreceptor mechanisms of small-bowel water and electrolyte transport.

Neurohumoral agents modulate intestinal transport by interactions with cell membrane receptors. Intracellular second messenger systems implicated in mediation of membrane receptor regulation of cellular events include the phosphoinositide and adenylate cyclase systems. In this study we have investigated the effects of direct postreceptor activation of key components of these systems on intestinal water and electrolyte transport. Rabbit ileal segments (n = 35) were arterially perfused ex vivo with an oxygenated sanguineous solution. The lumen was perfused with an isotonic solution containing 14C-polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- in six experimental groups were calculated for three 20-minute periods: basal, drug infusion, and recovery. The control group had no drug infusion. Two phorbol esters--phorbol 12, 13-diacetate (PDA; 10(-5) mol), and phorbol 12, 13-dibutyrate (PDB; 10(-5) mol)--were used to activate protein kinase C, an important component of the phosphoinositide system. The inactive 4 alpha-phorbol 12, 13-didecanoate (PDD; 10(-5) mol) served as a drug-infused control. Forskolin at two doses (FOR; 10(-5) mol and 10(-6) mol) was used to activate adenylate cyclase. The control and PDD groups had no changes in the flux of water and electrolytes. Both PDA and PDB had proabsorptive effects, with the more lipophilic and potent phorbol ester (PDB) having a more pronounced, significant effect (p less than 0.05). FOR caused significant secretion of H2O, Na+, and Cl- in a dose-dependent fashion (p less than 0.05). These results indicate that direct protein kinase C activation causes a proabsorptive effect and that direct activation of adenylate cyclase causes a secretory effect in the isolated small bowel. The activation status of these second messenger systems has a major influence on the transport state of the intestine.

Animals↗
PubMed1988

Cholinergic stimulation of phosphoinositide hydrolysis in rabbit kidney.

An injection of acetylcholine (ACh) into renal artery is known to cause diuresis. In brain and other organs, cholinergic agents have been shown to produce their actions through the phosphoinositide (PI) second messenger system. To determine if cholinergic agents also produce activation of the PI messenger system in the kidney, we investigated the effects of carbachol (a stable analog of acetylcholine) on PI hydrolysis in the cortex, outer medulla and inner medulla of the rabbit kidney. PI hydrolysis was determined by measuring the formation of inositol phosphates in response to stimulation by carbachol in the presence of 8 mM lithium. Carbachol, 1 mM, was able to stimulate PI hydrolysis in the inner medulla and outer medulla (622 and 388% over control values, respectively), but not the cortex. The response to carbachol in the inner medulla was concentration-dependent (EC50 = 10(-5) M). The response was blocked by 1 microM atropine and not by 1 microM hexamethonium. The nicotinic agonist, 1,1-dimethyl-4-phenylpiperazinium iodide did not stimulate PI hydrolysis. The effect of carbachol was dependent upon the presence of calcium ions. Substitution of alpha-ketoglutarate for glucose inhibited the response to carbachol in the inner medulla, suggesting a specific substrate requirement in PI metabolism. It is concluded that cholinergic agents produce stimulation of PI hydrolysis through muscarinic receptors in the inner medulla. Whether PI second messenger system in the kidney is involved in the diuretic effect of cholinergic agents remains to be determined.

Animals↗
PubMed1990

Growth hormone and prolactin secretion in cultured somatomammotroph cells.

A somatomammotropic cell line (P0) derived from adult rat pituitaries has been maintained in culture for 2 yr. Secretion of GH and PRL by this cell line has been studied in response to hypophysiotropic peptides known to affect the release of both hormones as well as agents that affect second messenger systems in an attempt to characterize the stimulus-secretion mechanisms used by these cells. GH and PRL release during short term (4 h) incubations of P0 cells and primary cultures of dispersed rat pituitary cells was initially measured in response to GRF, TRH, vasoactive intestinal peptide (VIP), and SRIF. In P0 cells, the minimal effective dose of each of the hypophysiotropic peptides was comparable with respect to GH and PRL secretion. The effects of TRH and VIP were similar to those in freshly dispersed cells with respect to PRL release, whereas those of GRF and SRIF were less potent with respect to GH release. The stimulation of GH and PRL release in P0 cells by adenylate cyclase-related agents ((Bu)2 cAMP and forskolin) was comparable to that for GH secretion in mature somatotrophs but much greater than that of PRL release in mature lactotrophs. Stimulation of GH and PRL release in P0 cells by protein kinase C-related agents (diacylglycerol and phorbol ester) was also similar to that observed for GH release from mature pituitary cells, whereas minimal or undetectable effects were observed on PRL release from mature cells. The results indicate that the P0 somatomammotropic cell line possesses receptors, second messenger systems, and secretory characteristics of both somatotrophs and lactotrophs, although where differences exist, there is more resemblance to somatotrophs. They also demonstrate that the responses to each of the agents studied are bihormonal and appear to be regulated by a common mechanism.

Animals↗