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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An account is given of the authors' work with isolated adrenal chromaffin cells to study the synthesis, storage and release of catecholamines and of a number of neuropeptides endogenous to the adrenal medulla. A review of other studies in the literature with the isolated chromaffin cell system is included. It is seen that the isolated chromaffin cells are a convenient in vitro system well-suited to studies of basic release mechanisms. The isolated adrenal chromaffin cells maintain high levels of catecholamines and opiates and release them by exocytosis. The cells have both nicotinic and muscarinic receptors but only the nicotinic are involved in the agonist-evoked release of catecholamines (EC50 nicotine 5 X 10(-6) M: ACh 5 X 10(-5) M). The cells can synthesize AChE and selectively release the 10S molecular form by a mechanism different from exocytosis. Substance P (SP) modulates the secretion of catecholamines and ATP evoked by ACh or nicotine but not that evoked by K+ or veratridine. SP appears to interact with the nicotinic receptor-ionophore complex to regulate Na+ entry. SP receptors on the chromaffin cells show similar structural requirements to SP receptors in other SP responsive tissues. Binding studies on isolated chromaffin cell membranes with [4-3H-Phe]SP have shown specific binding in the nM range. In addition, at high concentrations of ACh, SP protects against nicotinic receptor desensitization. Since SP is contained in the splanchnic nerve terminals that innervate the medulla, the demonstration of SP action and SP receptors on the chromaffin cells suggests a physiological role for SP in the regulation of secretion from the adrenal medulla. Somatostatin (SS) and a number of SS analogues also inhibit release, but are approximately 15-fold less potent than SP. Leu- and Met-enkephalin, which are co-stored with adrenaline in the bovine adrenal medullary cells produce a non-specific inhibition of the nicotine-evoked release of CA, but enhance the basal release of endogenous catecholamines by a mechanism that is Ca2+-dependent, stereospecific and reversible by naloxone and naltrexone. The implication of these peptide-amine interactions for physiological processes regulating homeostasis in the adrenal are discussed.
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PMID:Use of isolated chromaffin cells to study basic release mechanisms. 618 74

The mechanism underlying the positive inotropic and chronotropic effects of capsaicin were investigated using the spontaneously beating guinea-pig atrium in vitro. Capsaicin induced a long-lasting stimulatory effect (threshold dose 10(-9) M). Tetrodotoxin, phentolamine, 6-OHDA, mepyramine plus cimetidine, methysergide-, indomethacin-, somatostatin- or morphine pretreatment and local treatment with capsaicin on the vagal nerves did not reduce the capsaicin response, while it was abolished up to 1 month after systemic capsaicin pretreatment. The capsaicin response was subject to a rapid tachyphylaxis. During capsaicin tachyphylaxis, the positive inotropic and chronotropic effects of noradrenaline, serotonin and histamine were unchanged. Various neuropeptides were investigated with regard to cardiac activity. Physalaemin, eledoisin and somatostatin had negative inotropic and chronotropic effects. Substance P, bombesin, kassinin, CCK-8 or PHI (up to 10(-6)M of each) did not cause any detectable response on the guinea-pig auricle, while the substance P antagonist [D-Arg, D-Pro, D-Trp, Leu]SP induced a long-lasting stimulation of heart activity, VIP also stimulated the heart. Various adenyl compounds were also tested. Adenosine, AMP, ADP, ATP and beta-, gamma-methylene ATP had negative chronotropic and inotropic effects, while alpha-, beta-methylene ATP induced a stimulatory response. During alpha-, beta-methylene ATP tachyphylaxis, the auricles still responded to capsaicin. The inhibitory effects of adenosine and ATP analogues were antagonized by theophylline and 8-p-sulfophenyl theophylline. Capsaicin induced a small release of labelled nucleotides from 3(H)-adenine-prelabelled atria from control, but not from capsaicin-pretreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Capsaicin-induced stimulation of the guinea-pig atrium. Involvement of a novel sensory transmitter or a direct action on myocytes? 620 51

The colocalization of acetylcholine (ACh) and neuropeptides (e.g., substance P and enkephalins) in the splanchnic nerve terminals suggests that these compounds might interact to modulate adrenal catecholamine release. Use has been made of primary monolayer and suspension cultures of bovine adrenal chromaffin cells to investigate postsynaptic receptor interactions between acetylcholine and a number of neuropeptides endogenous to the adrenal medulla and splanchnic nerve. The cells have both nicotinic and muscarinic acetylcholine receptors, but only the nicotinic receptors stimulate catecholamine release. Substance P, somatostatin, and the enkephalins all produced an inhibition of the ACh-evoked secretion of catecholamines, but their potency ranged over 100-fold. Substance P was the most potent with a mean inhibitory concentration (IC50) of 10(-6) M and Leu-enkephalin the least potent with an IC50 greater than 10(-4) M. These pharmacological effects were monitored conveniently by measuring the release of [3H]norepinephrine preloaded into the cells or alternatively, "on-line" by measuring ATP released into an incubation medium containing luciferin and firefly tail extract (luciferase). Of interest, the endogenous enkephalin heptapeptide (Met-enkephalin Arg6-Phe7) and "big" Met-enkephalin (BAM- 22P ) were some 100-fold more effective than Leu- or Met-enkephalin at inhibiting the nicotinic secretin of catecholamines, suggesting that a unique opiate receptor may be involved. Substance P had two distinct actions on the nicotinic response: (1) substance P inhibited acetylcholine-induced release of catecholamines; and (2) substance P protected against acetylcholine-induced desensitization of catecholamine release. With regard to (1), substance P inhibited the secretion of catecholamines and ATP evoked by acetylcholine or nicotine but not that evoked by K+ or veratridine, nor did substance P by itself affect secretion. Substance P appeared to interact with a regulatory site on the acetylcholine receptor - ionophore complex. Substance P receptors on chromaffin cells have similar structural requirements for activation as do substance P receptors in other substance P responsive tissues. With regard to (2), substance P (greater than 5 X 10(-6) M) completely protected against desensitization of catecholamine release produced by acetylcholine (greater than 10(-4) M) or nicotine (greater than 2.5 X 10(-6) M) with no effect on K+-induced desensitization.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptors and receptor modulation in cultured chromaffin cells. 620 33

A brief review is first presented of findings during the past few years by the authors and by others on the nonprostaglandin endothelium-dependent relaxation of isolated arteries by a large number of vasoactive agents. Among these agents are acetylcholine (ACh); the calcium ionophore A23187; ATP and ADP; substance P; bradykinin (canine, human, and porcine arteries); histamine, acting via an H1-receptor (rat arteries); thrombin (canine arteries); serotonin (canine coronary artery); and norepinephrine, acting via an alpha2-receptor (canine coronary artery). The endothelium-derived relaxing factor (EDRF) released by ACh and other agents has not yet been identified. Our original hypothesis that arachidonic acid is the precursor of EDRF is not supported by the finding that other unsaturated fatty acids in addition to arachidonic acid, and even stearic acid, elicited nonprostaglandin endothelium-dependent relaxations. Methylene blue and hemoglobin (but not methemoglobin) rapidly inhibited relaxation of rabbit aorta by ACh or A23187, suggesting that our proposal that EDRF is a labile free radical may be correct. The endothelium-dependent relaxation by each of these agents was shown to be preceded by an endothelium-dependent increase in cyclic GMP in the smooth muscle--a finding consistent with the hypothesis that EDRF stimulates guanylate cyclase in the muscle, leading to an increase in cyclic GMP that somehow activates relaxation. Some questions relating to the potential physiological important of endothelium-dependent relaxations are discussed.
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PMID:Endothelial cells as mediators of vasodilation of arteries. 620 42

Calmodulin present in rat parotid homogenates activated cyclic AMP phosphodiesterase activity by 8 to 10 fold. The activation was Ca2+-dependent and reversed by trifluoperazine. Half-maximal inhibition required 12 microM trifluoperazine. Incubation of parotid slices with up to 40 microM trifluoperazine had no effect on the basal rate of amylase and K+ release or on cellular ATP content. Isoproterenol stimulated glucose utilization and substance P stimulated amylase secretion were also unaffected by 40 microM trifluoperazine. 20 or 40 microM Trifluoperazine however inhibited amylase secretion induced by isoproterenol, dibutyryl cyclic AMP, carbamoylcholine or phenylephrine. The possible involvement of calmodulin in regulating enzyme secretion following stimulation of the parotid gland with the various types of agonists is discussed.
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PMID:Does calmodulin mediate stimulus-secretion coupling in the parotid gland? Studies using trifluoperazine. 620 27

Innervation of circular muscle of the canine stomach studied in vitro was investigated by subjecting muscle strips to electrical field stimulation. Strips were cut from the lesser curvature of the gastric corpus and stimulated with 10-s trains of 0.5-ms pulses at 0.5-20 Hz, 40 V. Most responses were classified into one of three types. In general, field stimulation tended to elicit sequences of varying magnitudes of transient on-contraction, on-relaxation, off-relaxation, off-contraction. Responses were abolished by tetrodotoxin. On-contraction was almost abolished by atropine plus desensitization by 5-hydroxytryptamine (5-HT) or substance P. On-relaxation and off-relaxation were not affected by adrenergic blockade, methysergide, apamin, or 4-aminopyridine. ATP usually caused contraction and slightly diminished relaxation to field stimulation. Vasoactive intestinal polypeptide (VIP) had little effect on tone and response to field stimulation. Relaxation disappeared after scorpion venom treatment. This probably resulted from depletion of the transmitter which mediates relaxation. Off-contraction was reduced by atropine, desensitization by 5-HT or substance P, cromoglycate, indomethacin or ATP, but was not affected by adrenergic blockade, hexamethonium, methysergide, mepyramine, or VIP. The findings suggest that innervation of gastric corpus circular muscle included excitatory cholinergic and both excitatory and inhibitory noncholinergic, nonadrenergic innervation. However, the responses of circular muscle to field stimulation in vitro were drastically different from those obtained previously in vivo, suggesting damage or altered inputs to circular muscle when strips of circular muscle are studied.
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PMID:Multiple responses to electrical field stimulation in circular muscle of canine gastric corpus. 620 2

A comparison was made between the effects of several neuropeptides and ATP as possible mediators of the non-adrenergic, non-cholinergic excitatory response in detrusor strips from the guinea-pig urinary bladder. Both substance P and vasoactive intestinal polypeptide produced contractions of the guinea-pig bladder, but the form of the atropine-resistant neurogenic excitation was mimicked more precisely by ATP. Neither methionine enkephalin nor leucine enkephalin had a prominent direct action on the smooth muscle (up to 100 microM) and did not significantly modify the cholinergic or non-cholinergic components of the response elicited by field stimulation. A proteolytic enzyme, chymotrypsin (10 U/ml), antagonised the excitatory effect of substance P, but not that of the non-adrenergic, non-cholinergic excitatory response or ATP. The slow excitation elicited by a high concentration of vasoactive intestinal polypeptide (10 microM), in contrast to responses elicited by ATP or field stimulation, was attenuated by preincubation with the structurally related polypeptide PHI, which was itself inactive (up to 10 microM). The present observations argue against a role for the peptides studied as neuromuscular transmitters in the detrusor but do not preclude such a role for ATP.
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PMID:Neuropeptide action on the guinea-pig bladder; a comparison with the effects of field stimulation and ATP. 620 46

1. The nature of the non-cholinergic, non-adrenergic (non-ch., non-adr.) excitatory and inhibitory transmission in the longitudinal and circular muscle layers of the guinea-pig ileum was investigated, and the effects of various agents on the junction potentials were observed using the micro-electrode method.2. In longitudinal muscle cells, ATP (3 x 10(-5)-10(-4) M) and adenosine (10(-5)-10(-4) M) depolarized the membrane, decreased the input resistance, increased the spike activity and abolished the generation of cholinergic excitatory junction potentials (e.j.p.s).3. In the presence of atropine (10(-6) M) with guanethidine (10(-5) M), field stimulation evoked three different types of the response (non-ch., non-adr. e.j.p.s, i.j.p.s (inhibitory junction potentials) or both) from cells of the longitudinal muscle layers, and only one type of the response (non-ch., non-adr. i.j.p.s) from cells of the circular muscle layer. In the following experiments atropine and guanethidine were present in the bathing fluid for at least 20 min.4. In some longitudinal muscle cells (non-ch., non-adr. i.j.p. type), ATP (5 x 10(-6)-10(-3) M) and adenosine (10(-5)-3 x 10(-5) M) depolarized the membrane, while in other cells (non-ch., non-adr. e.j.p. type), ATP (10(-5)-10(-4) M) and adenosine (10(-5)-3 x 10(-5) M) hyperpolarized the membrane and further increases in the concentration of ATP (10(-3) M) resulted in a depolarization of the membrane.5. Apamin (10(-7)-3 x 10(-6) M) inhibited the generation of non-ch., non-adr. i.j.p.s in both longitudinal and circular muscle cells, while this agent had no effect on the non-ch., non-adr. e.j.p.s. As a consequence, in some cells of the longitudinal muscle layer (non-ch., non-adr. e.j.p. and i.j.p. type) the amplitude of e.j.p.s was enhanced in the presence of apamin. TEA (5 x 10(-3)-1.5 x 10(-2) M) suppressed the after-hyperpolarization of the spike and i.j.p.s recorded from both muscle layers, whereas the duration and amplitudes of cholinergic and non-ch., non-adr. e.j.p.s were enhanced.6. Vasoactive intestinal polypeptide (VIP; 10(-8)-10(-7) M) had no effect on the membrane potential and junction potentials of longitudinal and circular muscle layers.7. Substance P (SP; 10(-8)-10(-7) M) depolarized the membrane of cells of the longitudinal layer (non-ch., non-adr. e.j.p. type), while this agent had no effect on cells of longitudinal (non-ch., non-adr. i.j.p. type) and circular muscle layers. SP suppressed the generation of non-ch., non-adr. e.j.p.s but had no effect on i.j.p.s. Generation of non-ch., non-adr. e.j.p.s was not restored under conditions of repolarization of the membrane to the resting level by application of inward current.8. Bradykinin (BK; 10(-8)-10(-5) M) hyperpolarized the membrane and suppressed the generation of i.j.p.s in the cells of longitudinal (non-ch., non-adr. i.j.p. type) and circular muscle layers. However, when the membrane potential was displaced to the control level by outward current in the presence of BK, field stimulation evoked the i.j.p. In cells of non-ch., non-adr. e.j.p. type of the longitudinal muscle layer, BK depolarized the membrane, increased the spike activity, generated slow waves and blocked the generation of non-ch., non-adr. e.j.p.s. Displacement of the membrane potential to the control level by inward current did not restore the non-ch., non-adr. e.j.p.s.9. These results suggest that in the guinea-pig ileum ATP and adenosine probably do not contribute to the generation of non-ch., non-adr. e.j.p.s and i.j.p.s, as transmitter substances. The actions of other possible candidates such as SP and BK, are discussed.
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PMID:The nature of non-cholinergic, non-adrenergic transmission in longitudinal and circular muscles of the guinea-pig ileum. 629 75

Arteries relax to the vasodilators acetylcholine, substance P, ATP and bradykinin only if the endothelium is present. One hypothesis is that these substances stimulate the endothelial cells to release a vasodilator substance which in turn relaxes the underlying smooth muscle. We considered that other hormones which have direct actions on smooth muscle cells may also release the dilator substance. If the hormone contracts smooth muscle cells and also activates the release of the dilator from endothelial cells, the algebraic sum of these stimuli would determine the physiological response. Our preliminary experiments in pig and dog isolated coronary arteries showed that noradrenaline (NA) and serotonin (5-hydroxytryptamine, 5-HT) were significantly more powerful vasoconstrictors in the absence of endothelium. We report here the unexpected finding that these constrictor amines release a vasodilator substance from endothelial cells that can act as a physiological antagonist of the well known smooth muscle contractile responses. We suggest that the potential involvement of the vasodilator signal should be considered in the responses to vasoconstrictors in both normal and diseased blood vessels.
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PMID:Endothelium-dependent relaxation of coronary arteries by noradrenaline and serotonin. 662 11

The effects of apamin, a polypeptide isolated from bee venom, on different vasodilator mechanisms in the small and large intestines were studied in atropinized cats. In the large intestine vasodilatation in response to pelvic nerve stimulation was either abolished or markedly diminished by I.A. apamin. However, neither the contraction of colonic muscle which occurred under these conditions nor sympathetic vasoconstriction was significantly influenced by apamin, suggesting that the effect of the peptide was not a non-specific effect on nerves or vascular smooth muscle. In the small intestine it was observed that the nervous vasodilatation induced by transmural electrical field stimulation or mechanical mucosal stimulation was either diminished or abolished by apamin. Intestinal vasodilatation, caused by close I.A. infusions of 5-hydroxytryptamine (5-HT), was abolished by apamin. After giving apamin 5-HT infusions induced a vasoconstriction in five out of six experiments. Vasodilatation induced by vasoactive intestinal polypeptide (VIP) was not significantly affected by apamin. In a series of in vitro experiments on rat portal vein, dose-response curves of several putative intestinal neurotransmitters were determined in the presence and absence of apamin. The following substances were tested: VIP, substance P, bradykinin, 5-HT, ATP and adenosine. Apamin had no effect on the dose-response curves of any of these compounds. The results are discussed in relation to the possibility that apamin may act by blocking the release of a putative peptidergic transmitter from nerve terminals.
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PMID:The effect of apamin on non-adrenergic, non-cholinergic vasodilator mechanisms in the intestines of the cat. 687 56


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