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)

To examine endogenous factors affecting the development of the massive bronchoconstriction in the postmortem guinea pig lung, 58 anesthetized open-chest animals were divided into three groups: 1) exsanguination only (n = 13), 2) pulmonary perfusion with 5% dextran and 1% bovine serum albumin (BSA) in Tyrode's solution (Ca2+ perfusate) (n = 21), and 3) pulmonary perfusion with 5% dextran and 1% BSA in saline (Ca2+-free perfusate) (n = 24). These groups were further divided into several subgroups according to treatments: 1) substance P depletion by chronic administration of capsaicin, 2) acute capsaicin treatment to release substance P, 3) dazoxiben treatment to block endogenous synthesis of thromboxane A2, 4) diethylcarbamazine treatment to eliminate leukotriene (LT) synthesis, and 5) FPL 55712 treatment to antagonize actions of LT. Vital capacity from the deflation pressure-volume (PV) curve of the lung was used as the indicator of bronchoconstriction. Most PV curves were performed for 30 min following exsanguination or artificial perfusion. Ca2+-free perfusate enhanced the airway spasm at 5-10 min, but the spasm disappeared gradually after 10 min. Substance P depletion significantly decreased (P less than 0.01) the bronchial constriction at 20-30 min, whereas substance P release induced severe airway spasm (P less than 0.01) during the entire study. In addition, FPL 55712 reduced the bronchospasm (P less than 0.05) in Ca2+ perfusate at 30 min. Thus Ca2+ and several endogenous mediators may be involved with the airway spasm of the postmortem guinea pig lung.
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PMID:Factors affecting massive postmortem bronchoconstriction in guinea pig lungs. 620 78

Cerebrovascular changes after intrathecal (ith) administration of gammaglobulins against substance P (SP) or calcitonin gene-related peptide (CGRP) were investigated before and following a simulated subarachnoid haemorrhage (SAH) in the squirrel monkey. The SAH was produced by injection of homologous blood into the interpeduncular fossa and the cisterna magna. The gammaglobulins were given both prior to the blood injections and daily in 5 days post-SAH. The effect of the gammaglobulins was examined by angiography pre-SAH and at 10 min and at 6 days post-SAH, i.e. the time points for maximal acute and late spasm in the present model. Cerebral blood flow (CBF) was measured under general anesthesia at day 6 post-SAH with an autoradiographic technique. Five of nine animals treated with CGRP antigammaglobulin died from respiratory failure. Four animals received SP antigammaglobulin and two control animals received normal globulin. SP antigammaglobulin per se had no effect on baseline arterial diameter, while CGRP antigammaglobulin significantly reduced the diameter of the arteries. SP antigammaglobulin prevented the occurrence of acute spasm and significantly reduced the degree of late spasm. Moreover, the reduction in CBF noted in the control SAH animals was significantly reduced. In contrast, CGRP antigammaglobulin treatment had no effect on the degree of spasm and did not cause any change in CBF as compared to controls. The finding that CGRP but not SP antigammaglobulin significantly reduces the arterial diameter in conjunction with our previous demonstration that a post-, but not preganglionic trigeminal lesion reduces the baseline arterial diameter, indicates that CGRP could be the transmitter involved in a peripheral axon reflex. The function of SP might be as a neurotransmitter conveying information to the brainstem. The transmitter role is supported by the effect of SP antigammaglobulin impairing SP containing neurons and, in that way, mimicking a bilateral trigeminal rhizotomy.
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PMID:Cerebrovascular changes following administration of gammaglobulins against substance P or calcitonin gene related peptide in monkey with subarachnoid haemorrhage. 750 91

Tonic contraction of rat urinary bladder was elicited in vitro and in vivo by substance P, two selective NK1 receptor agonists, septide ([pGlu6,Pro9]substance P-(6-11)) and [Sar9,Met(O2)11]substance P, and an NK2 agonist, [Lys5,MeLeu9,Nle10]neurokinin A-(4-10), but not by senktide (succinyl[Asp6,MePhe8]substance P-(6-11)), an NK3 agonist. Substance P only stimulated the NK1 receptors of smooth muscle. The non-peptide selective NK1 receptor antagonists, RP 67580 and CP-96,345, both inhibited substance P-induced contraction (pKB values 6.7 and 5.7; ED50 = 1.4 and 5.0 mg/kg i.v., respectively) and septide-induced contraction (pKB values 7.5 and 6.5; ED50 = 0.076 and 0.250 mg/kg i.v., respectively). Both antagonists, at lower doses, also inhibited substance P- and septide-induced plasma extravasation. That both antagonists blocked the effects of septide much more than the effects of substance P suggests the existence of an NK1 receptor subtype or isoform. Selective NK1 receptor antagonists, by blocking both spasm and plasma extravasation in the urinary bladder, would be useful for treating substance P-related motor disorders and cystitis.
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PMID:Antagonism of substance P and related peptides by RP 67580 and CP-96,345, at tachykinin NK1 receptor sites, in the rat urinary bladder. 751 Nov 8

Cerebral vasospasm following subarachnoid hemorrhage was induced in the squirrel monkey in order to evaluate the involvement of cerebrovascular sensory nerves in the development of the vasospasm. A unilateral surgical section of the trigeminal nerve at post- but not at pre-Gasserian level caused constriction of the major ipsilateral cerebral arteries. A pre- or postganglionic trigeminal lesion induced an increased glucose uptake globally without influencing the cerebral blood flow. Following a subarachnoid hemorrhage, the decrease in cerebral blood flow was similar of that seen in control animals, while post-ganglionically lesioned animals had an additional increase in glucose uptake. Intrathecal injection of gamma-globulin against substance P prevented the occurrence of vasospasm and the decrease in cerebral blood flow, while calcitonin gene-related peptide (CGRP) anti-gamma-globulin injection significantly reduced the resting vessel diameter and did not influence spasm development. It is concluded that a nervous reflex mechanism could underlie cerebral vasospasm. The cerebrovascular sensory nerves have both a peripheral and a central function. A peripheral or axon reflex mechanism exerts a tonic effect on the cerebral arteries. Central neurotransmission seems to be involved in the regulation of cerebral metabolism and possibly in the coordination of cerebral blood flow and glucose metabolism. CGRP could be the transmitter involved in a peripheral axon reflex and substance P might be the neurotransmitter conveying information to the brainstem vascular centers.
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PMID:Cerebrovascular sensory innervation involved in the development of cerebral vasospasm following a subarachnoid hemorrhage. 753 Jul 34

INTRODUCTION--Cerebral blood vessels are innervated by sympathetic nerve fibres storing neuropeptide Y (NPY), parasympathetic nerves storing acetylcholine, vasoactive intestinal peptide (VIP) and sensory afferent fibres containing calcitonin gene-related peptide (CGRP), substance P (SP) and neurokinin A. In experimental studies on subarachnoid haemorrhage (SAH) there are indications that perivascular peptides are involved. In the present study we have in man measured the levels of NPY, VIP, SP and CGRP in brain vessels of patients that have suffered a fatal SAH and compared this with the levels encountered in subjects that died of an extracerebral cause. MATERIAL AND METHODS--Vessels from patients who have died from SAH or nonSAH were obtained during autopsy performed within 24 hrs after death. The peptides were extracted and fractionated with reversed phase liquid chromatography (HPLC). The levels of NPY, VIP, SP, and CGRP were measured with radioimmunoassay. Vasomotor responses of human cerebral arteries were performed using a sensitive in vitro system. RESULTS--Human cerebral vessels contained NPY, VIP, CGRP and SP which eluted at the same positions as the authentic peptides. The level of CGRP was significantly lower (p < 0.01) in arteries removed from SAH patients as compared to control subjects. The level of SP was not changed, if anything it tended to be increased after SAH. The levels of NPY and VIP were not significantly altered after SAH. In isolated brain vessels alpha-CGRP was a potent vasodilator of arteries precontracted with whole blood, prostaglandin F2 alpha or endothelin. It had a poor effect on vessels precontracted with 60 mM potassium. CONCLUSION--The evidence suggest that the trigemino-cerebrovascular system, storing CGRP and SP, is to a differential degree involved in the pathophysiology of SAH in man and supports the hypothesis of an exhaustion of CGRP as one important factor in the development of late spasm occurring after SAH.
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PMID:Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage. 753 26

Experimental SAH in the squirrel monkey induces an angiographically demonstrable late spasm of about 23% at six days post subarachnoid haemorrhage (SAH). The late spasm is associated with a generalized reduction in cerebral blood flow (CBF) of about 30%. Intracisternal administration of the substance P (SP) antagonist spantide two hours and three days post SAH significantly reduces the degree of late spasm and also decreases the degree of CBF reduction. The findings suggest that SP is involved in the development of both angiographical spasm and CBF changes post SAH.
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PMID:Effect of spantide, a substance-P antagonist, on cerebral vasospasm in primates. 768 6

1. The aim of this study was to investigate the effect of various antagonists, selective for the tachykinin NK1 or NK2 receptor, on the atropine-resistant ascending excitatory reflex (AER) to the circular muscle of the guinea-pig ileum elicited by radial stretch (balloon distension) or electrical field stimulation. 2. Submaximal and maximal atropine- (1 microM) resistant AER elicited by balloon distension averaged about 40-50% and 70-90% of maximal circular spasm to 80 mM KCl, respectively. The NK1 receptor antagonist, (+/)-CP 96,345 (1 microM) inhibited both maximal and submaximal AER. FK 888 (1-3 microM) inhibited submaximal AER only. RP 67,580 (1 microM) was ineffective. The NK2 receptor antagonist, GR 94,800, inhibited both maximal and submaximal AER at all concentrations tested (0.1-3.0 microM), while SR 48,968 was effective only at 1.0 microM. The NK2 receptor antagonists, MEN 10,376 and MEN 10,573 inhibited both submaximal and maximal AER at 10 and 1.0 microM, respectively. 3. In other experiments, an NK1 receptor antagonist, (+/-)-CP 96,345 or FK 888 (1.0 microM in each case) was administered first and the effect of GR 94,800 (1.0 microM) on the residual AER response was determined; or GR 94,800 was administered first and the effect of (+/-)-CP 96,345 or FK 888 was determined. The results of these experiments indicated an additive effect produced by the combined treatment with NK1 and NK2 receptor antagonists. 4. Electrical field stimulation (10 Hz for 0.5 s, 10-20 V, 0.15-0.3 ms pulse width) with electrodes placed at 1.4-1.8 cm anal to the recording site, produced ascending contractions which were almost abolished by 10 MicroM hexamethonium (electrically-evoked AER). In the presence of apamin (0.1 MicroM) and N0-nitro-L-arginine (30 MicroM) these contractions were reproducible over 10 consecutive stimulation cycles.GR 94,800 (1 MicroM) and FK 888 (1 MicroM) both produced a partial inhibition of the electrically-evoked AER and their combined administration produced an inhibitory effect which was larger than that induced by each antagonist alone.5. FK 888 (1-3 MicroM), GR 94,800 (1-3 MicroM), MEN 10,573 (1 MicroM) and MEN 10,376 (10 MicroM) did not significantly affect the atropine-sensitive twitch contractions produced by electrical field stimulation of the guinea-pig ileum longitudinal muscle-myenteric plexus preparation, which were abolished by 10-30 MicroM procaine, 1 MicroM tetrodotoxin or 1 MicroM atropine. (+/-)-CP 96,345 (1 MicroM) and SR 48,968 (1 ILM)produced 12% and 27% inhibition of cholinergic twitches in the longitudinal muscle of the ileum,respectively.6. We conclude that both NK1 and NK2 receptors mediate the atropine-resistant AER to the circular muscle of the ileum. NK2 receptor activation plays a more important role than NK1 receptor activation in the AER evoked by radial stretch. Since a consistent fraction of the distension- and electrically evoked atropine-resistant AER persists in the presence of combined NK1 and NK2 receptor blockade,the existence of a third excitatory transmitter to the circular muscle of the ileum, in addition to acetylcholine and tachykinins, is suggested.
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PMID:Tachykinin NK1 and NK2 receptor antagonists and atropine-resistant ascending excitatory reflex to the circular muscle of the guinea-pig ileum. 803 37

Occlusion of aortocoronary venous grafts can be due to thrombosis, atherosclerosis, or vasospasm. Investigations have focused on properties of the graft itself, and little is known about the vascular reactivity and function of the native arteries proximal and distal to the vein graft, although spasm of the native artery distal to the graft site has been observed in patients. We hypothesized that the function of the endothelium of the native arteries may be altered after surgery. Autogenous venous grafts were placed in femoral arteries of rabbits to study the reactivity of the native arteries after grafting. Four weeks after graft implantation, the vein graft, ipsilateral vein, and native artery proximal and distal to the graft were removed for in vitro studies. Morphological evaluation by scanning electron microscopy and fluorescence microscopy after labeling with acetylated low density lipoprotein labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate indicated the presence of an intact, metabolically active endothelial layer. There was no alteration in the contractile responses to phenylephrine of the arteries, vein grafts, or veins. Precontracted vein grafts, veins, and arterial segments proximal to the grafts relaxed when exposed to endothelium-dependent vasodilators (acetylcholine, arachidonic acid, and substance P), but the native arteries distal to the grafts did not. In bioassay cascade experiments, the distal artery did not release any measurable relaxing factor when exposed to acetylcholine. We conclude that the endothelium of the distal artery did not function normally. The extent and reversibility of altered endothelial function remain to be determined. This observation may help to explain the occurrence of myocardial infarction after aortocoronary bypass grafting in some patients.
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PMID:Alteration of reactivity of native arteries induced by venous graft placement. 841 86

Cisternal injections of blood in the rat and squirrel monkey produce an angiographically demonstrable biphasic vasospasm with a maximal late spasm at two days in the rat and six days post-subarachnoid hemorrhage (SAH) in the monkey. The SAH induces a decrease in cerebral blood flow of about 25% and a corresponding increase in glucose uptake of between 30% and 50%. In about half of the animals low-flow areas were noted in the cortex and the basal ganglia with a corresponding marked increase in glucose uptake. Lesioning of the A2-nucleus, its ascending pathway or the median eminence prevents the occurrence of spasm. Similarly, treatment with a substance P antagonist or gammaglobulin against substance P prevents or significantly reduces the degree of spasm. A unilateral post-ganglionic trigeminal lesion causes an ipsilateral constriction of the cerebral arteries of 27%, while a preganglionic lesion does not affect the baseline diameter. A pre- or post-ganglionic trigeminal lesion induces an increase in glucose uptake globally of about 50% without influencing cerebral blood flow. Following SAH the decrease in blood flow in both groups of lesioned animals is similar to that seen in controls. After SAH there is no further change in glucose uptake in the animals with a preganglionic lesion, while in the post-ganglionically lesioned animals there is an additional increase in glucose uptake of about 50% as compared to controls or the animals with a preganglionic lesion.
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PMID:Trigeminal afferents and brainstem centers involved in the occurrence of cerebral vasospasm. 891 53

The sensory neuron stimulant drug capsaicin stimulates primary afferent nerve endings in the guinea-pig small intestine, which in turn activate myenteric cholinergic neurons by an unknown mechanism. The tachykinins substance P and neurokinin A are present in primary afferent neurons. This study was performed to assess the possible involvement of endogenous tachykinins acting via neurokinin-1, neurokinin-2 and neurokinin-3 receptors in the contractile effect of capsaicin in the isolated guinea-pig ileum and oesophagus by using the receptor-specific antagonists GR 82334 (3 microM) for neurokinin-1 receptors, MEN 10627 (3 microM; ileum) or MEN 11420 (1 microM; oesophagus) for neurokinin-2 receptors and SR 142801 (0.1 microM) for neurokinin-3 receptors. In the ileum, the peak contraction evoked by capsaicin (2 microM) was not reduced when tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors were blocked separately, whereas an inhibition of neurokinin-3 receptors diminished the area under the curve of the capsaicin response. A combined blockade of neurokinin-1 and neurokinin-3 receptors significantly depressed the effect of capsaicin; the amplitude of the contractile response was 53.3+/-3.7% of the maximal longitudinal spasm in control preparations, whereas in the presence of GR 82334 plus SR 142801 it reached only 27.6+/-5% (P<0.001, Kruskal-Wallis test; n=9 and 10, respectively). Also, the area under the curve of the contractile response to capsaicin was more than 85% lower in the group of preparations treated with GR 82334 plus SR 142801 than in the control group (P<0.001). Including a neurokinin-2 blocker in the combination did not produce any further inhibition. A concomitant tachyphylaxis to substance P (natural neurokinin-1 receptor stimulant) and the neurokinin-3 receptor agonist senktide (5 and 1 microM, respectively) also reduced the contractile effect of capsaicin. In the oesophagus, capsaicin (1 microM) induced biphasic contractions which were strongly inhibited by atropine (1 microM) or capsaicin pretreatment (1 microM for 10 min). Here again, a blockade of tachykinin neurokinin-1, neurokinin-2 or neurokinin-3 receptors separately failed to inhibit the response to capsaicin, whereas a combined blockade of any two tachykinin receptors caused a partial inhibition. The reduction of the contractile effect of capsaicin was strongest when all three tachykinin receptors were blocked. In seven control preparations, peaks for the first and second phases of contraction reached 35.3+/-3.7% and 20+/-3.2% of maximal longitudinal spasm; the corresponding values in the presence of a combination of GR 82334, MEN 11420 and SR 142801 were 7.5+/-0.8% and 9.1+/-2.2%, respectively (n=6, P<0.001 and 0.05, respectively). Tetrodotoxin (0.5 microM) practically abolished the contractile effect of capsaicin in both tissues studied. It is concluded that an interplay of neuronal tachykinin neurokinin-1 and neurokinin-3 receptors (ileum) and neurokinin-1, neurokinin-2 and neurokinin-3 receptors (oesophagus) is involved in the contractile action of capsaicin, probably in mediating excitation of myenteric neurons by tachykinins released from primary afferents. In both tissues, there also seems to be a non-tachykininergic component of the capsaicin-induced contraction.
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PMID:Tachykinin receptors are involved in the "local efferent" motor response to capsaicin in the guinea-pig small intestine and oesophagus. 1018 48


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