Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peripheral control of local mechanisms of erection and detumescence has now been more clearly elucidated. This knowledge has been acquired as a result of the recent development of pharmacological research designed to study the regulation of erectile smooth muscle tone. Smooth muscle fibres of the corpora cavernosa and arteries supplying the penis relax in response to a reduction of intracellular calcium. This relaxation allows both an increase of the blood flow to the penis and opening of sinusoid spaces. Cyclic nucleotides, cAMP and cGMP, are intracellular messengers of the mediators acting on smooth muscle fibres and regulating these intracellular calcium movements. Gap-junctions, greatly facilitating rapid ion exchanges between smooth muscle fibres, make erectile tissue a real functional syncytium. Nonadrenergic, noncholinergic neurotransmitters, mainly nitric oxide (NO), are synthesized by parasympathetic neurons present in cavernous nerves and act directly on smooth muscle fibres. NO increases the intracellular cGMP concentration. Other proerectile mediators, such as acetylcholine, CGRP or substance P, act via endothelial cells by promoting the synthesis and release of NO by these cells. In contrast, neurotransmitters of the sympathetic nervous system, norepinephrine and neuropeptide Y, and endothelin, secreted by endothelial tissues, induce contraction of cavernous smooth muscle fibres, thereby opposing erection. Oxygenation of the cavernous tissue is also an important factor in the regulation of local mechanisms of erection. Poor oxygenation prevents the synthesis of cGMP and predisposes to cavernous fibrosis due to increased synthesis of collagen via TGF beta. A better understanding of the peripheral pharmacology of erection opens the way to new pathophysiological and therapeutic prospects in the broad symptomatic context of erectile dysfunction.
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PMID:[The peripheral pharmacology of erection]. 911 35

Ocoteine, isolated from Cassytha filiformis, was found to be an alpha 1-adrenoceptor blocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine-induced vasoconstriction (pA2 = 7.67 +/- 0.09). Removal of endothelium from the aorta did not affect its antagonistic potency (pA2 = 7.97 +/- 0.07). [3H]-Inositol monophosphate formation caused by noradrenaline (3 microM) was suppressed by ocoteine (10 microM) and prazosin (3 microM). Ocoteine did not affect the contraction induced by U-46619, prostaglandin F2 alpha or angiotensin II, but inhibited slightly those by high K+ and endothelin I. Neither the cyclic AMP nor cyclic GMP content of rat thoracic aorta was changed by ocoteine (10 microM). Comparing the EC50 values, the potency of ocoteine against 5-hydroxytryptamine (5-HT) was about 60 times less than that against phenylephrine. Ocoteine (10 microM) also slightly antagonized the clonidine-induced inhibition of the twitch response evoked by field stimulation in rat vas deferens. In guinea pig trachea, the contraction caused by carbachol, histamine, neurokinin A or leukotriene C4 and beta 2-adrenoceptor-mediated relaxing responses induced by isoprenaline were not affected by ocoteine (10 microM). The voltage clamp study in rat ventricular single myocytes revealed that ocoteine (3, 10 microM) inhibited steady state outward currents, but not transient outward currents or slow inward Ca2+ currents. It is concluded that ocoteine is a selective alpha 1-adrenoceptor antagonist in isolated rat thoracic aorta. At high concentrations, it also blocks 5-HT receptors and Na+ and steady state outward currents in rat ventricular myocytes.
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PMID:Pharmacological evaluation of ocoteine, isolated from Cassytha filiformis, as an alpha 1-adrenoceptor antagonist in rat thoracic aorta. 912 15

In this work, we have studied the effects and the possible cellular mechanism of Substance P (SP) on corticosteroid secretion by the adrenal gland of the urodele crested newt, Triturus carnifex. Adrenals were in vitro superfused with SP, prostaglandin E2 (PGE2), nitric oxide (NO) donor, cyclic GMP (cGMP) analogue, and inhibitors of phospholipase A1, phospholipase A2 (PLA2), phospholipase C, adenylate cyclase (AC), cyclooxygenase (COX), NO synthase (NOS), and soluble guanylate cyclase (sGC). PGE2, corticosterone, and aldosterone release and NOS activity were determined. SP, PGE2, NO donor, and cGMP analogue increased corticosterone and aldosterone; SP and PGE2 increased NOS, and SP increased PGE2. PLA2, AC, COX, NOS, and sGC inhibitors counteracted SP and PGE2 effects, except for PLA2, which did not affect PGE2. These results suggest that SP exhibits a stimulatory role on the corticosteroidogenesis of T. carnifex adrenal gland. In particular SP enhances PLA2 activity, increasing PGE2; this prostaglandin affects AC, which, in turn, enhances NO, and the latter therefore affects sGC, with the consequent corticosteroidogenesis increase.
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PMID:Cellular mechanism of substance P in the regulation of corticosteroid secretion by newt adrenal gland. 914 46

A transient increase in aromatase activity is known to occur in the hypothalamus of rodents in pre- and postnatal periods. The mechanisms regulating such a developmental increase of brain aromatase was studied in fetal mouse diencephalic cells, by measuring aromatase mRNA levels by a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. When slices of diencephalon were cultured on embryonic day (E) 12, E13 and E15, the level of aromatase mRNA continued to increase for the first 2 to 3 days. A time-dependent increase of mRNA was also shown for 3 days in E13 neuronal cells dissociated with papain and cultured in chemically defined medium. However, no significant increase was observed in E10 or E11 brain cells cultured by either method. Aromatase mRNA was detected in neither cerebral cortex neurons nor astrocytes. An alpha1-selective adrenergic agonist, phenylephrine, increased aromatase in the E13 diencephalic neurons in culture, whereas prazosin, an alpha1-antagonist, suppressed the mRNA level. Ligands for alpha2- or beta-adrenergic receptors did not alter the mRNA level. Substance P, cholecystokinin, neurotensin, and brain natriuretic peptide as well as phorbol 12-myristate 13-acetate and dibutyryl-cyclic GMP all increased the mRNA level. We concluded that: (a) the developmental increase of aromatase mRNA in diencephalic neurons is an autonomous event and is perhaps genetically regulated after E12; (b) aromatase mRNA is expressed in a cell type- and region-specific manner; and (c) protein kinases C and G activated via receptors of the specific neurotransmitters may be involved in modulation of the developmental expression of aromatase mRNA.
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PMID:Autonomous expression of aromatase during development of mouse brain is modulated by neurotransmitters. 936 5

The relationship between relaxation produced by acetylcholine (ACh) or substance P (SP) and tissue cyclic GMP content was investigated in the isolated guinea-pig aorta. ACh and SP relaxed aortic rings precontracted with noradrenaline (NA) or high-K solution ([K+]o = 38.8 mM), in an endothelium-dependent manner. The amplitude of relaxation was larger for SP than for ACh. Nitroarginine inhibited ACh-induced but not SP-induced relaxation in NA-contraction, while this chemical inhibited both ACh- and SP-induced relaxations in high-K contraction. The tissue cyclic GMP content was not changed by nitroarginine or by removal of endothelial cells, but was elevated by stimulation with NA, ACh or SP by a factor of about 3, 5 or 11 times, respectively. These actions of ACh or SP were endothelium-dependent, and were inhibited by nitroarginine and remained unaltered by high-K solution. Thus, ACh and SP relax muscles indirectly by releasing endothelial factors, and the former by releasing mainly an endothelium-derived relaxing factor (EDRF), and the latter by releasing EDRF and other unidentified factors. As the relaxing actions of the latter factors are inhibited by high-K solution with no relation to the production of cyclic GMP, an involvement of hyperpolarizing factor, possibly EDHF, is suggested.
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PMID:Comparison of the relaxing actions of acetylcholine and substance P in smooth muscle of the guinea-pig aorta. 940 18

Nitric oxide (NO) contributes to hypoxia-induced pial artery dilation, at least in part, through the formation of cGMP and the subsequent release of methionine enkephalin and leucine enkephalin in the newborn pig. In separate studies, these opioids also were observed to elicit NO-dependent pial artery dilation, whereas light/dye endothelial injury reduced hypoxic pial dilation. The current study was designed to investigate the role of the endothelial isoform of NO synthase in hypoxic pial dilation, associated opioid release, and opioid dilation in piglets equipped with a closed cranial window. N-iminoethyl-L-ornithine (L-NIO) (10(-6) mol/L), an antagonist that may have greater endothelial NO synthase inhibitory selectivity, had no effect on dilation elicited by hypoxia (PO2 approximately 35 mm Hg) (24 +/- 2 versus 24 +/- 2% in the absence and presence of L-NIO, respectively, n = 8). Hypoxic dilation was accompanied by increased CSF cGMP, which also was unchanged in the presence of L-NIO (394 +/- 19 and 776 +/- 63 versus 323 +/- 13 and 739 +/- 25 fmol/mL for control and hypoxia in the absence and presence of L-NIO, respectively, n = 6). Additionally, hypoxic pial dilation was associated with increased CSF methionine enkephalin, which also was unchanged in the presence of L-NIO (992 +/- 73 and 2469 +/- 197 versus 984 +/- 18 and 2275 +/- 185 pg/mL, respectively, n = 6). In contrast, methionine enkephalin-induced dilation was blocked by L-NIO (6 +/- 1, 10 +/- 1, and 16 +/- 1 versus 1 +/- 1, 1 +/- 1, and 2 +/- 1% for 10(-10), 10(-8), 10(-6) mol/L methionine enkephalin, respectively, before and after L-NIO, n = 8). Substance P-induced pial dilation was blunted by L-NIO, whereas responses to sodium nitroprusside and N-methyl-D-aspartate were unchanged. These data indicate that endothelial NO synthase contributes to opioid-induced pial artery dilation but not hypoxia-induced dilation. Additionally, these data suggest that neuronally derived NO contributes to hypoxic pial dilation.
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PMID:Role of endothelial nitric oxide synthase in hypoxia-induced pial artery dilation. 959 45

Tachykinin immunoreactivity is found in a ventromedial spinal plexus in the lamprey. Neurons in this plexus project bilaterally and are thus in a position to modulate locomotor networks on both sides of the spinal cord. We have examined the effects of the tachykinin substance P on NMDA-evoked locomotor activity. Brief (10 min) application of tachykinin neuropeptides results in a prolonged concentration-dependent (>24 hr) modulation of locomotor activity, shown by the increased burst frequency and more regular burst activity. These effects are blocked by the tachykinin antagonist spantide II. There are at least two phases to the burst frequency modulation. An initial phase (approximately 2 hr) is associated with the protein kinase C-dependent potentiation of cellular responses to NMDA. The long-lasting phase (>2 hr) appears to be protein synthesis-dependent, with protein synthesis inhibitors causing the increased burst frequency to recover after washing for 2-3 hr. The modulation of the burst regularity is caused by a separate effect of tachykinins, because unlike the burst frequency modulation it does not require the modulation of NMDA receptors for its induction and is blocked by H8, an inhibitor of cAMP- and cGMP-dependent protein kinases. The effects of substance P were mimicked by the dopamine D2 receptor antagonist eticlopride. The effects of eticlopride were blocked by the tachykinin antagonist spantide II, suggesting that eticlopride may endogenously release tachykinins. Because locomotor activity in vitro corresponds to that during swimming in intact animals, we suggest that endogenously released tachykinins will result in prolonged modulation of locomotor behavior.
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PMID:Substance P modulates NMDA responses and causes long-term protein synthesis-dependent modulation of the lamprey locomotor network. 961 53

Since ancient times, bile secretion has been considered vital for maintaining health. One of the main functions of bile secretion is gastric acid neutralization with biliary bicarbonate during a meal or Pavlovian response. Although the liver has many extrinsic and intrinsic nerve innervations, the functional role of these nerves in biliary physiology is poorly understood. To understand the role of neural regulation in bile secretion, our recent studies on the effect of bombesin, a neuropeptide, on bile secretion and its underlying mechanisms will be reviewed. Using isolated perfused rat livers (IPRL) from both normal and 2 week bile duct ligated rats, as well as hepatocyte couplets and isolated bile duct units (IBDU) from normal rat livers, bombesin was shown to stimulate biliary bicarbonate and fluid secretion from bile ducts. Detailed pH studies indicated that bombesin stimulated the activity of Cl-/HCO3- exchanger, which was counterbalanced by a secondary activation of electrogenic Na+/HCO3- symport. Quantitative videomicroscopic studies showed that bombesin-stimulated fluid secretion in IBDU was dependent on Cl- and HCO3- in the media, anion exchanger(s), Cl- and K+ channels, and carbonic anhydrase, but not on the microtubular system. Furthermore, this bombesin response is inhibited by somatostatin but not substance P. Finally, studies of secondary messengers in isolated cholangiocytes and IBDU indicated that bombesin had no effect on intracellular cAMP, cGMP, or Ca++ levels in cholangiocytes. These results provide evidence that neuropeptides such as bombesin can directly stimulate fluid and bicarbonate secretion from cholangiocytes by activating luminal Cl-/HCO3- exchange, but by different mechanisms from those established for secretin. These findings, in turn, suggest that neuropeptides may play an important regulatory role in biliary transport and secretion. Thus, this neuropeptidergic regulation of bile secretion may provide a plausible mechanism for the bicarbonate-rich choleresis seen with meals or Pavlovian response.
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PMID:Role of the neuropeptide, bombesin, in bile secretion. 962 61

The effects of nitric oxide (NO) on the spontaneous release of 5-hydroxytryptamine (5-HT) were studied in the in vitro vascularly perfused guinea-pig small intestine. The NO donor SIN-1 concentration-dependently decreased 5-HT release with an EC50 of 1.34 microM, whereas the NO synthase inhibitor N(G)-nitro-L-arginine (100 microM) was without effect. The inhibition by SIN-1 of 5-HT release was enhanced by superoxide dismutase (150 U/ml) and antagonized by the selective inhibitor of soluble guanylyl cyclase, ODQ (1 microM). Tetrodotoxin (1 microM) prevented the inhibition by SIN-1 of 5-HT release, which suggests that the effect of SIN-1 is indirectly mediated via release of an inhibitory neurotransmitter. Substance P could be excluded as inhibitory transmitter because the effect of SIN-1 remained unchanged in the presence of the NK1 receptor antagonist CP 99994 (100 nM). The cyclic GMP analogue, 8-bromo cyclic GMP (300 microM), also decreased basal release of 5-HT, but this decrease was not tetrodotoxin-sensitive. It is concluded that NO inhibits the release of 5-HT from enterochromaffin cells via release of an enteric neurotransmitter. Acetylcholine (via nicotinic receptors) and substance P (via NK1 receptors) are not involved in the NO-mediated inhibition. The inhibition of 5-HT outflow by NO is due to the activation of soluble guanylyl cyclase. 8-Bromo cyclic GMP inhibited 5-HT release by a direct effect on the enterochromaffin cells.
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PMID:Inhibition by nitric oxide and cyclic GMP of 5-hydroxytryptamine release from the vascularly perfused guinea-pig small intestine. 967 48

Since nitric oxide has been found to control the function of many organs of the body by the non-adrenergic, non-cholinergic branch of the autonomic nervous system, we hypothesized that it might play a role in salivary secretion. Therefore, we investigated the distribution of nitric oxide synthase (NOS) throughout the submaxillary gland and also studied the ability of inhibitors of NOS to interfere with salivation induced by a cholinergic agonist, metacholine, and by a polypeptide, substance P. The secretory responses were determined in rats anesthetized with chlorolose following intravenous injection of the various pharmacological agents. There was no basal flow of saliva and dose-response curves were obtained by sequential intravenous injection of increasing doses of the drugs. Then, in the same animal, the same dose-response curves were performed in the presence of NOS inhibitors. L-Nitro-arginine-methyl-ester (L-NAME; 20 mg/kg) produced an over 50% inhibition of the dose-related salivation induced by metacholine. Similar results were produced with L-NG-monomethyl-L-arginine (L-NMMA; 5 mg/kg). The salivation induced by much lower molar doses of substance P was dramatically greater than that obtained with metacholine. The response to substance P was almost completely inhibited by L-NMMA at the lowest dose (0.3 mg/kg), but at higher doses (1 mg/kg), the inhibition was only around 60% and at the highest dose (3 mg/kg) only about 20%. In control rats, there were roughly equal amounts of calcium-dependent and calcium-independent NOS in the gland at this time. At the end of the experiment, the effect of the inhibitor of NOS, L-NMMA, on the NOS activity in the submandibular gland was determined. At this time, the Ca2+-dependent NOS was decreased and the Ca2+-independent NO was increased. The prior injection of L-NMMA reduced calcium-dependent NOS activity by approximately 70% but calcium-independent activity by only 30%. These results indicate that, at least at the end of the experiment, the blockade of NOS imposed by NMMA was incomplete. This could account in part for the failure of the inhibitors to block completely the stimulatory effect of the two secretagogues. Analysis of the distribution of NOS in the salivary gland revealed that it was not present in the acinar cells, but in neural terminals within the gland and also in the ductile system which contained neural (n) NOS in the apical membrane of the excretory and striated ducts, the cytoplasm of granular convoluted tubules and, to a lesser extent, in the cytoplasm of excretory and striated ducts. Macrophage (inducible) NOS was also found not only in the macrophages, but also in the tubules and ducts. Since drugs were used that would act on the receptors in the gland, the role of NO in our conditions is probably mediated by nNOS and iNOS in the ductile and tubular structures. Since iNOS would already be active, it is unlikely to play a role in this acute secretory activity. Rather the nNOS in these non-neural cells is probably activated by muscarinic or K1 receptors by metacholine and substance P, respectively, leading to an increase in intracellular free calcium that activates NOS leading to the generation of cGMP that opens ion channels to initiate the secretory process.
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PMID:Role of nitric oxide in salivary secretion. 973 Jun 90


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