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

The response of G-protein-coupled receptors is modulated by homologous desensitization. Because endothelin A receptor (ETA) plays a part in vasoconstriction, the extent of desensitization and resensitization of endothelin responsiveness was studied. A cDNA clone encoding human ETA receptor was isolated based on similarities to bovine endothelin A receptor. Xenopus laevis oocytes injected with cloned mRNA transcripts were used as a model system for analyzing desensitization. Human neurokinin A (NKA) receptor was used for comparison with ETA receptor in desensitization experiments. Xenopus laevis oocytes injected with the two receptor mRNAs show homologous desensitization but variable rates of recovery. Human NKA receptors desensitize within 5 min and resensitize after 20-30 min. Human ETA receptors also desensitize within 5 min but have a prolonged resensitization period lasting 1.5-2 h. Such a prolonged recovery period is unique to this class of receptors and may serve to regulate some of the deleterious effects mediated by the ETA receptor. The mechanism of differential desensitization is being investigated using genetically engineered mutants of human ETA receptor.
 ...
PMID:Desensitization of human endothelin A receptor. 750 17

The changes induced in the mean arterial blood pressure of anaesthetised rats following the administration of armed spider (Phoneutria nigriventer) venom have been investigated. The intravenous injection of Phoneutria nigriventer venom (0.1 mg/kg) evoked a brief and reversible decrease in the mean arterial blood pressure whereas a higher dose of venom (0.3 mg/kg) caused a biphasic response characterized by a short-lasting hypotension followed by a sustained and prolonged hypertension (40-50 min). These changes were accompanied by tachycardia, salivation, fasciculations, defecation and respiratory disturbances. Pretreatment of the animals with atropine (10 mg/kg), propranolol (100 mg/kg), phenoxybenzamine (100 mg/kg) and indomethacin (4 mg/kg) did not significantly affect the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. Similarly, the bradykinin B2 receptor antagonist Hoe 140 (D-Arg-[Hyp3,Thi5,DTic7,Oic8]-bradykinin) (0.6 mg/kg), the PAF receptor antagonist WEB 2086 (3-(4-(2-chlorophenyl)-9-methyl-6H-thieno-(3,2f) (1,2,4)-triazolo-(4,3-a) (1,4)-diazepine-2-yl)-(4-morpholinyl)-1-propanone) (20 mg/kg), the tachykinin NK1 receptor antagonist SR 140333 ((S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenyl acetyl) piperidin-3-yl] ethyl)-4-phenyl-1-azoniabicyclo[2.2.2] octane, chloride) (0.5 mg/kg), the tachykinin NK2 receptor antagonist SR 48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophen yl) butyl]benzamide) (0.5 mg/kg) and the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (10 mg/kg) had no significant effect on the mean arterial blood pressure changes induced by Phoneutria nigriventer venom. The increase in the blood pressure induced by Phoneutria nigriventer venom was also not significantly affected by either the angiotensin II receptor antagonist losartan (10 mg/kg) or the endothelin ETA receptor antagonist FR 139317 ((R)2-[(R)-2-[[1-(hexahydro-1H-azepinyl]carbonyl]amino-4-methyl- pentanoyl]amino-3-[3-(1-methyl-1H-indoyl)]propionyl] amino-3-(2-pyridyl) propionic acid) (30 mg/kg). The ATP-dependent K+ channel antagonist glibenclamide (50 mg/kg) reduced by 40% the hypotension induced by Phoneutria nigriventer venom without affecting the hypertensive response. Pretreatment of the animals with L-type Ca2+ channel antagonists such as verapamil (10-100 micrograms/kg/min), diltiazem (40-120 micrograms/kg/min) and nifedipine (0.3-10 mg/kg) markedly attenuated the hypertension induced by Phoneutria nigriventer venom. Verapamil (30 micrograms/kg/min) and diltiazem (120 micrograms/kg/min) also promptly reversed the established hypertension induced by Phoneutria nigriventer venom when infused 8 min after venom injection. Our results indicate that the brief decrease of blood pressure induced by Phoneutria nigriventer venom is partially due to ATP-dependent K+ channel activation. The prolonged hypertension seems to result from direct Ca2+ entry into vascular and/or cardiac muscles.
 ...
PMID:The effect of Phoneutria nigriventer (armed spider) venom on arterial blood pressure of anaesthetised rats. 886 97

Endothelin 1 (ET1) desensitizes endothelin A receptor for 90-110 min while neurokinin A (NKA) desensitizes neurokinin A receptor for 25-35 min in Xenopus laevis oocytes. In the present study, endothelin A receptor and neurokinin A receptor were coexpressed in Xenopus laevis oocytes in an effort to characterize heterologous desensitization of the receptors that activate phospholipase C-beta. ET1 desensitizes both the endothelin A receptor and the neurokinin A receptor for 90-110 min, whereas stimulation with NKA desensitizes the same two receptors for only 25-35 min. Homologous and heterologous desensitization experiments were also carried out with endothelin 3 (ET3), a ligand that exhibits lower affinity to the endothelin A receptor and a quicker dissociation rate than ET1. ET3 was unable to desensitize endothelin A receptor and the neurokinin A receptor; this is in contrast to ET1 that desensitizes both receptors. These results suggests that the receptors that undergo homologous desensitization are able to heterologously desensitize other receptors that activate PLC-beta. Furthermore, the agonist-specific dissociation constant dictates the extent of desensitization and time of recovery of the receptor-mediated response.
 ...
PMID:Heterologous desensitization of the human endothelin A and neurokinin A receptors in Xenopus laevis oocytes. 901 65

Capsaicin (8-methyl-N-vannillyl-6-nonenamide), via binding to the vanilloid receptor subtype 1 (VR1), stimulates a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin-sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a "sensory-effector" function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to the VR1. A subset of capsaicin-sensitive sensory nerves contains calcitonin gene-related peptide (CGRP) and substance P (SP). These sensory neuropeptides are potent vasodilators and natriuretic/diuretic factors. Neonatal degeneration of capsaicin-sensitive sensory nerves has revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms are reviewed, which include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neuro-hormonal systems to maintain normal blood pressure when challenged with salt loading. Mechanisms underlying pneumotoxicity and pulmonary hypertension as revealed by degeneration of capsaicin-sensitive nerves are also discussed. Finally, the therapeutic utilities of capsaicin, endogenous anandamide, and CGRP agonists are assessed.
 ...
PMID:Capsaicin sensitive-sensory nerves and blood pressure regulation. 1532 Jun 97

Mammalian transient receptor potential (TRP) channels consist of six related protein sub-families that are involved in a variety of pathophysiological function, and disease development. The TRPV1 channel, a member of the TRPV sub-family, is identified by expression cloning using the "hot" pepper-derived vanilloid compound capsaicin as a ligand. Therefore, TRPV1 is also referred as the vanilloid receptor (VR1) or the capsaicin receptor. VR1 is mainly expressed in a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin-sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a "sensory-effector" function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to VR1. The most studied sensory neuropeptides are calcitonin gene-related peptide (CGRP) and substance P (SP), which are potent vasodilators and natriuretic/diuretic factors. Recent evidence using the model of neonatal degeneration of capsaicin-sensitive sensory nerves revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neurohormonal systems to maintain normal blood pressure when challenged with salt loading. The therapeutic utilities of vanilloid compounds, endogenous agonists, and sensory neuropeptides are also discussed.
 ...
PMID:The vanilloid receptor and hypertension. 1571 23

Activation of renal mechanosensory nerves is enhanced by a high-sodium diet and suppressed by a low-sodium diet. Angiotensin (Ang) II and endothelin (ET)-1 each contributes to the impaired responsiveness of renal mechanosensory nerves in a low-sodium diet. We examined whether stimulation of ETA receptors (Rs) contributes to Ang II-induced suppression of the responsiveness of renal mechanosensory nerves. In anesthetized rats fed a low-sodium diet, renal pelvic administration of the Ang type I receptor (AT1-R) antagonist losartan enhanced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mm Hg from 7+/-2% to 15+/-2% and the prostaglandin (PG) E(2)-mediated substance P release from 0+/-1 to 8+/-1 pg/min. Adding the ETA-R antagonist BQ123 to the renal pelvic perfusate containing losartan did not produce any further enhancement of the ARNA response or PGE(2)-mediated release of substance P (17+/-3% and 8+/-1 pg/min). Likewise, renal pelvic administration of BQ123 and BQ123+losartan resulted in similar enhancements of the ARNA responses to increased renal pelvic pressure and PGE(2)-mediated substance P release. In high-sodium-diet rats, pelvic administration of Ang II reduced the ARNA response to increased renal pelvic pressure from 27+/-4% to 8+/-3% and the PGE(2)-mediated substance P release from 9+/-0 to 1+/-1 pg/min. Adding BQ123 to the renal pelvic perfusate containing Ang II restored the increases in ARNA and the PGE(2)-mediated substance P release toward control (27+/-6% and 7+/-1 pg/min). In conclusion, stimulation of ETA-R plays an important contributory role to the Ang II-mediated suppression of the activation of renal mechanosensory nerves in conditions of low-sodium diet.
 ...
PMID:Activation of endothelin-a receptors contributes to angiotensin-induced suppression of renal sensory nerve activation. 1706 May 3

Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which in turn decreases ERSNA via activation of the renorenal reflexes in the overall goal of maintaining low ERSNA. We now examined whether the ERSNA-induced increases in ARNA are modulated by dietary sodium and the role of endothelin (ET). The ARNA response to reflex increases in ERSNA was enhanced in high (HNa)- vs. low-sodium (LNa) diet rats, 7,560 +/- 1,470 vs. 900 +/- 390%.s. The norepinephrine (NE) concentration required to increase PGE(2) and substance P release from isolated renal pelvises was 10 pM in HNa and 6,250 pM in LNa diet rats. In HNa diet pelvises 10 pM NE increased PGE(2) release from 67 +/- 6 to 150 +/- 13 pg/min and substance P release from 6.7 +/- 0.8 to 12.3 +/- 1.8 pg/min. In LNa diet pelvises 6,250 pM NE increased PGE(2) release from 64 +/- 5 to 129 +/- 22 pg/min and substance P release from 4.5 +/- 0.4 to 6.6 +/- 0.7 pg/min. In the renal pelvic wall, ETB-R are present on unmyelinated Schwann cells close to the afferent nerves and ETA-R on smooth muscle cells. ETA-receptor (R) protein expression in the renal pelvic wall is increased in LNa diet. In HNa diet, renal pelvic administration of the ETB-R antagonist BQ788 reduced ERSNA-induced increases in ARNA and NE-induced release of PGE(2) and substance P. In LNa diet, the ETA-R antagonist BQ123 enhanced ERSNA-induced increases in ARNA and NE-induced release of substance P without altering PGE(2) release. In conclusion, activation of ETB-R and ETA-R contributes to the enhanced and suppressed interaction between ERSNA and ARNA in conditions of HNa and LNa diet, respectively, suggesting a role for ET in the renal control of ERSNA that is dependent on dietary sodium.
 ...
PMID:Dietary sodium modulates the interaction between efferent renal sympathetic nerve activity and afferent renal nerve activity: role of endothelin. 1947 89