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)

1. Single pulse electrical field stimulation (EFS) produces a biphasic response of muscle strips of the rat isolated urinary bladder consisting of an early and a late contraction which were atropine-resistant and atropine-sensitive, respectively. Repeated application of desensitizing doses of the P2 purinoceptor agonist, alpha, beta-methylene ATP (mATP) inhibited the early response while leaving unaffected the late component. 2. Omega conotoxin (CTX, 0.1 microM) inhibited both the early and the late response either in control conditions or after enhancement by physostigmine (0.1 microM). The effect of CTX was, in both cases, more pronounced on the late than the early response to EFS. CTX (0.1 microM) failed to affect contraction produced by ATP or acetylcholine at concentrations (0.3 mM and 0.5 microM) which produced a response similar to that to EFS. 3. The effect of physostigmine was more intense for the late than the early response and was abolished by atropine. In the presence of CTX, physostigmine enhanced both the early and the late components of the mechanical response to EFS. 4. Nifedipine (0.1-1 microM) reduced to a similar extent both the early and late responses. Bay K 8644 (1 microM) produced a marked enhancement of the response to EFS, which, however, did not have a distinct late peak. In the presence of Bay K 8644, either atropine (3 microM) or tetrodotoxin (1 microM) had minor inhibitory effects indicating the myogenic origin of the response. 5. Neurokinin A (0.1-1 nM) enhanced both the early and late responses to EFS without affecting the contraction produced by exogenous acetylcholine or ATP. A consistent potentiation was evident also in the presence of CTX and for the early response, in the presence of atropine. Clonidine (3 microM) inhibited the response to EFS either in the absence or the presence of physostigmine. The inhibitory effect of clonidine, shown previously to depend upon activation of prejunctional alpha 2-adrenoceptors, was still observed in presence of CTX or atropine. 6. It is concluded that CTX-sensitive voltage dependent calcium channels play a more important role in determining the cholinergic rather than the non-cholinergic, putatively purinergic, component of the biphasic response of the rat bladder to single pulse EFS. The action of CTX is likely to be exerted on N-type rather than L-type (dihydropyridine-sensitive) calcium channels. Prejunctional modulation (enhancement by neurokinin A, inhibition by clonidine) occurs even in the presence of CTX-sensitive channels blockade.
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PMID:Omega conotoxin and prejunctional modulation of the biphasic response of the rat isolated urinary bladder to single pulse electrical field stimulation. 172 Oct 69

Clonidine, noradrenaline and adrenaline (in the presence of propranolol), but not phenylephrine and methoxamine, stimulated an increase in the oxygen consumption of these slices that was blocked by yohimbine but not by prazosin. The stimulation was inhibited by ouabain and required the presence of Ca2+ in the incubation medium. The calcium ionophore A 23187 stimulated oxygen consumption in the tissue slices and enhanced the respiratory effect of clonidine. Atropine and (D-Pro2, D-Trp7.9)-substance P failed to block the respiratory response to clonidine in concentrations that inhibited the respiratory effects of carbachol and substance P, respectively. Release of acetylcholine from the unstimulated gland slices was reduced by clonidine or Ca2+ omission. Yohimbine prevented the clonidine effect and stimulated acetylcholine resting release. Nifedipine did not affect either the release of acetylcholine or the clonidine-induced reduction of acetylcholine release but blocked the oxygen uptake due to clonidine or to release acetylcholine.
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PMID:Differentiation of alpha adrenoceptors mediating increase of oxygen consumption in rat submandibular salivary gland slices. 217 72

The dependence-inducing effects of clonidine were investigated on the guinea-pig isolated ileum. Clonidine produced relaxation of the ileum with a threshold concentration between 0.01 and 0.1 mumol 1(-1). Washout of clonidine did not induce a withdrawal contraction. Following 2 min contact of the ileum with clonidine, 1 mumol 1(-1), addition of phentolamine, 5 mumol 1(-1), induced a contracture. The phentolamine-precipitated withdrawal contracture did not increase in height with a longer period of contact (32 min) of the ileum with clonidine. The phentolamine-precipitated withdrawal contracture following 2 min contact of ileum with clonidine was abolished by atropine, 5 mumol 1(-1), and substance P (SP) antagonists, (D-Pro2,D-Phe7, D-Trp9)-SP and spantide, 10 mumol 1)-1). [Met5]enkephalin, 1 mumol 1(-1), abolished the withdrawal response to clonidine and clonidine, 1 mumol 1(-1), abolished the withdrawal response to [Met5]enkephalin. Following 2 min contact of the ileum with noradrenaline, 5 mumol 1(-1), washout or addition of phentolamine or yohimbine, 5 mumol 1(-1), also induced a withdrawal response. The noradrenaline washout withdrawal response was abolished by atropine, 5 mumol 1(-1), and spantide, 10 mumol 1(-1). Since clonidine dependence may be induced as rapidly as opiate dependence in the ileum and the pharmacology of the withdrawal responses is similar, it is suggested that they both induce the same post-receptor neuronal feedback disturbance in which substance P neurones play a major role.
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PMID:The properties of the clonidine withdrawal response of guinea-pig isolated ileum. 241 24

Clonidine has been reported to produce analgesia in man after epidural and intrathecal administration. In the present investigation the alpha 2-adrenoceptor agonists clonidine and guanfacine were tested to evaluate their potential spinal neurotoxic effects. Rats were injected daily for 14 consecutive days via catheters implanted in the intrathecal space. Clonidine was administered at a dose of 1.63 micrograms or 16.3 micrograms, and guanfacine at 16.3 or 75 micrograms. After perfusion with a buffered 3% glutaraldehyde solution, the spinal cords and nerve roots were taken for neuropathological analysis using light and electron microscopy. Compared to animals injected with 0.9% saline, clonidine and guanfacine gave rise to no detectable neurotoxic changes in the doses employed. An additional group of rats had intrathecal injections of a substance P-antagonist (D-Arg1, D-Trp7,9, Leu11)-substance P (spantide) with known neurotoxic effect as a test of the histotechnical methods used. Degenerative lesions, with a preference for the ventral horns, were consistently present in the grey matter of the cord in these animals. We conclude that the absence of detectable changes in rats given clonidine and guanfacine is probably a real expression of the low degree of toxicity for these compounds on rat spinal cord and nerve roots and not an artifact of the sensitivity of the histotechniques applied. The doses of clonidine administered were considerably greater than those reported to produce clinical greater than those reported to produce clinical analgesia.
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PMID:Evaluation of the toxicity of subarachnoid clonidine, guanfacine, and a substance P-antagonist on rat spinal cord and nerve roots: light and electron microscopic observations after chronic intrathecal administration. 243 Apr 89

We have investigated the influence on the excitability of lumbar motoneurons of 5-hydroxytryptamine (5-HT), substance P and thyrotropin releasing hormone (TRH), three substances which coexist in the same bulbospinal descending pathway and end in large part around motoneurons. We have also studied the effect of clonidine, an alpha 2 noradrenergic agonist. This was done in spinalized rats (T5) treated three weeks before with 5-7-dihydroxytryptamine. Under those circumstances 5-HTP (I.P.), 5-HT (intrathecally) TRH (I.P. or I.T.) and substance P (I.T.) all elicited a strong excitation of motoneurons as measured by integrated EMG of the hindlimb muscles. Substance P reduced by almost half the subsequent response to 5-HTP, 1 hour and 24 hours later. TRH given acutely did not modify the response to 5-HTP but given chronically for twenty one days by means of Alzet minipump, markedly increased the response to 5-HTP. Clonidine by itself decreased the excitability of motoneurons and antagonized the excitatory effect of 5-HTP and TRH. In a pilot trial, cyproheptadine, a 5-HT antagonist was shown to decrease the manifestations of spasticity in patients with a partial spinal lesion. Clonidine also appears to be of potential use in the treatment of spasticity.
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PMID:Action of 5-hydroxytryptamine, substance P, thyrotropin-releasing hormone and clonidine on motoneurone excitability. 244 57

The intracellular adenine nucleotide pool of rabbit iris-ciliary body was labelled by uptake of 3H-adenine in vitro. A variety of agents were tested for their ability to stimulate or inhibit the incorporation of radioactivity into cyclic AMP formed from ATP labelled with 3H-adenine. Isoproterenol, vasoactive intestinal peptide, forskolin, and prostaglandin E2 stimulated incorporation of label 3-10-fold in 15-20 min compared with paired tissues not treated with hormone, whereas histamine, serotonin, substance P, and bradykinin were inactive. Clonidine, alpha-methylnorepinephrine, and dopamine decreased the rate of incorporation of label into the cyclic-AMP pool in tissues that showed high spontaneous basal rates. In low-basal tissues these drugs were inactive by themselves but clonidine and alpha-methylnorepinephrine blocked the stimulation effected by isoproterenol. The findings indicate that several receptor-coupled adenylate cyclase systems are present in ICB and that dual adrenergic control of adenylate cyclase through positive and negative coupling of adrenergic receptors probably occurs. The negatively coupled adrenergic receptors appear to be similar to the alpha 2-subclass of adrenergic receptor described in other tissues. These observations suggest a role for the large number of alpha 2-adrenergic-binding sites found in albino rabbit iris-ciliary body by ligand binding assays.
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PMID:Drug responses of adenylate cyclase in iris-ciliary body determined by adenine labelling. 298 54

Recent studies have demonstrated that the neurons of the lower brainstem that are responsible for maintaining normal levels of arterial pressure reside in a specific area of the rostral ventrolateral medulla. In rat, the critical zone corresponds to a small region containing a subpopulation of the adrenergic C1 group, defined immunocytochemically by the presence of the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase. Neurons of this region (the C1 area), possibly including the adrenergic neurons, directly innervate preganglionic neurons in the spinal cord, and are tonically active and sympathoexcitatory. The excitatory transmitter released into the spinal cord is unknown. The discharge of C1 area neurons is locked to the cardiac cycle and, in turn, leads to firing of sympathetic preganglionic neurons. The C1 area neurons are inhibited by baroceptor input and mediate the vascular component of baroceptor reflexes. They also mediate somato-sympathetic pressor responses from skin and muscle and participate in reflex responses to hypoxia. The neurons are directly innervated by local neurons containing gamma-aminobutyric acid, acetylcholine, enkephalin, and substance P, all of which modulate arterial pressure. The C1 area is the site of the hypotensive actions of clonidine. Clonidine appears to act on imidazole receptors in the C1 area to lower arterial pressure. The natural ligand for these receptors may be a newly defined substance in brain, clonidine-displacing substance. Neurons of the C1 area appear to be the critical neuronal group governing the normal resting and reflex control of arterial pressure. They may play a critical role in the maintenance of elevated arterial pressure in hypertension and as a site of action of antihypertensive drugs.
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PMID:The C1 area of the brainstem in tonic and reflex control of blood pressure. State of the art lecture. 327 78

The effects of clonidine on the submaxillary gland of the rat were studied. Doses ranging between 100 to 3.000 micrograms/kg produced a sustained secretory response which was blocked by 0.1 mg/kg of prazosin but not by 1 mg/kg of yohimbine. Clonidine 10 micrograms/kg markedly inhibited the salivation induced by noradrenaline, methacholine and substance P but not that induced by isoproterenol. The inhibition caused by the alpha 2-agonist was greater for noradrenaline than for either methacholine or substance P. Blockade of alpha 2 adrenoceptors with yohimbine (0.3 - 1 mg/kg) prevented the inhibition by clonidine of noradrenaline, methacholine and substance P induced salivation. On the other hand, prazosin 0.1 mg/kg did not modify the inhibition by clonidine of methacholine induced secretion. The results obtained indicate that clonidine exerts a dual effect on salivary secretion: at high doses it elicits salivation through activation of alpha 1-adrenoceptors; at the dose of 10 micrograms/kg clonidine activates alpha 2-adrenoceptors which inhibit the secretory response evoked through either muscarine, substance P and alpha 1-adrenoceptor agonists.
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PMID:Clonidine inhibits salivary secretion by activation of postsynaptic alpha 2-receptors. 620 41

The spinal nociceptive system is the target of various pain depressing agents. It is capable to function without control from the brain. It is activated by tissue damage which, by excitation of nociceptive afferents, evokes activity in axons ascending to the brain (sensory nociceptive response) and in spinal reflex pathways (motor and autonomic responses). The prototype of an analgesic agent, morphine, suppresses nociceptive responses by binding to opiate receptors; it imitates the effect of the transmitter(s) released from endorphinergic neurones. Pentobarbital and diazepam reduce nociceptive (and non-nociceptive) responses by acting on the GABA receptor complex; both drugs facilitate the effect of the transmitter GABA which mediates presynaptic inhibition in the spinal cord. Pentobarbital may produce its effects by an additional action on postsynaptic neurone membranes. Clonidine depresses nociceptive responses, probably by imitating the action of the inhibitory transmitter, noradrenaline. Substance P acts as a "synaptic modulator"; it may facilitate or inhibit nociceptive responses. Ceruletide and cholecystokinin octapeptide depress nociceptive motor responses but do not affect the nociceptive sensory response. This indicates that motor and sensory responses of the spinal nociceptive system are not rigidly linked together. With the help of appropriate drugs, it is possible to manipulate them separately.
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PMID:Pain-depressing agents and the spinal nociceptive system. 620 17

Several points are particularly relevant to an understanding of the effects of clonidine in the brain: Clonidine appears to act preferentially at alpha-2 adrenergic receptors and, in systemic doses of less than 50-100 microgram/kg, to exert its effects at autoreceptors, which initially decrease noradrenergic neuronal firing rates, NE release, and NE turnover. This action results in functional decreases of the usual effects of these neurons at their post synaptic alpha-1 and beta-adrenergic receptor-mediated projections, which are widely distributed throughout the limbic system, cerebrum, cerebellum, and spinal cord. Higher doses of clonidine appear to produce agonist effects at alpha-1 adrenergic receptors, counteracting the effects of decreases in firing rates and turnover. However, decreased function at beta receptors would continue after these higher doses owing to continued inhibition of neuronal activity and the lack of direct effects of clonidine on beta receptors. Receptors for GABA, endorphins, substance P, and ACh on LC neurons provide an anatomical and physiological basis for interactions among systems utilizing these substances as neurotransmitters in that they act on a common final noradrenergic pathway. These noradrenergic pathways, in turn, also project to and mediate functional changes in areas utilizing other neurotransmitters. Although these changes affect numerous types of behavior and responses that are measurable by psychopharmacologists, it is the neurons of the locus coeruleus and other noradrenergic neurons with similar receptor combination that provide the entry point to this NE system. Studies of the LC, therefore, may help to determine the nature of these specific effects and to characterize the effects of clonidine and other alpha-2 agonists on the brain.
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PMID:The neuroanatomy and pharmacology of the nucleus locus coeruleus. 627 1


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