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1.
Jerman JC Brough SJ Prinjha R Harries MH Davis JB Smart D 《British journal of pharmacology》2000,130(4):916-922
The vanilloid receptor (VR1) is a ligand-gated ion channel, which plays an important role in nociceptive processing. Therefore, a pharmacological characterization of the recently cloned rat VR1 (rVR1) was undertaken. HEK293 cells stable expressing rVR1 (rVR1-HEK293) were loaded with Fluo-3AM and then incubated at 25 degrees C for 30 min with or without various antagonists or signal transduction modifying agents. Then intracellular calcium concentrations ([Ca(2+)](i)) were monitored using FLIPR, before and after the addition of various agonists. The rank order of potency of agonists (resiniferatoxin (RTX)>capsaicin>olvanil>PPAHV) was as expected, and all were full agonists. The potencies of capsaicin and olvanil, but not RTX or PPAHV, were enhanced at pH 6.4 (pEC(50) values of 7.47+/-0.06, 7.16+/-0.06, 8.19+/-0.06 and 6.02+/-0.03 respectively at pH 7.4 vs 7.71+/-0.05, 7.58+/-0.14, 8.10+/-0.05 and 6.04+/-0.08 at pH 6.4). Capsazepine, isovelleral and ruthenium red all inhibited the capsaicin (100 nM)-induced Ca(2+) response in rVR1-HEK293 cells, with pK(B) values of 7.52+/-0.08, 6.92+/-0.11 and 8.09+/-0.12 respectively (n=6 each). The response to RTX and olvanil were also inhibited by these compounds. None displayed any agonist-like activity. The removal of extracellular Ca(2+) abolished, whilst inhibition of protein kinase C with chelerythrine chloride (10 microM) partially (approximately 20%) inhibited, the capsaicin (10 microM)-induced Ca(2+) response. However, tetrodotoxin (3 microM), nimodipine (10 microM), omega-GVIA conotoxin (1 microM), thapsigargin (1 microM), U73122 (3 microM) or H-89 (3 microM) had no effect on the capsaicin (100 nM)-induced response. In conclusion, the recombinant rVR1 stably expressed in HEK293 cells acts as a ligand-gated Ca(2+) channel with the appropriate agonist and antagonist pharmacology, and therefore is a suitable model for studying the effects of drugs at this receptor. 相似文献
2.
Z. Y. Du G. J. Dusting O. L. Woodman 《Clinical and experimental pharmacology & physiology》1991,18(5):371-374
1. The effect of N-nitro-L-arginine (NOLA) on mean arterial pressure (AP), hindlimb vascular resistance (HVR) and heart rate (HR) was examined in conscious rabbits. 2. NOLA (15 mg kg, i.v.) increased AP (delta AP = 14 +/- 3 mmHg) and HVR (delta HVR = 0.8 +/- 0.3 U) and decreased HR (delta HR = -66 +/- 8 beats/min). AP remained elevated for at least 2 h following NOLA infusion but had returned to control levels after 24 h. In contrast, the hindlimb vaso-constriction and bradycardia were sustained for at least 48 h but had returned to control levels after 72 h. 3. In the presence of total autonomic blockade (hexamethonium 30 mg/kg; propranolol 1 mg/kg and atropine 0.1 mg/kg) NOLA continued to have a pressor (delta AP = 33 +/- 9 mm Hg) and hindlimb vasoconstrictor action (delta HVR = 0.4 +/- 0.1 U) but did not affect HR (delta HR = -1 +/- 3 beats/min). 4. NOLA has a prolonged pressor and vasoconstrictor action which is independent of any action in the central nervous system and which results in a marked reflex bradycardia. These results suggest that the peripheral biosynthesis of nitric oxide is important in regulation vascular tone and arterial pressure. 相似文献
3.
采用兔离体隐动脉血管环张力实验及电场刺激诱发交感嘌呤能血管收缩实验,观察5-单硝酸异山梨酯(isosorbide-5-mononitrate,ISMN)对交感嘌呤能缩血管反应的作用,并分析其作用机制。结果表明,电场刺激(电压15 V,波宽1 ms,时程1 s)诱发兔离体隐动脉(去内皮)产生血管收缩反应。该收缩反应呈频率(2~16 Hz)依赖性,可被0.1 μmol·L-1河豚毒素(tetrodotoxin)完全抑制。α1受体阻断药哌唑嗪(1 μmol·L-1)对2~8 Hz电刺激诱发的血管收缩反应无影响。P2X1受体激动药α,β-亚甲基ATP(3 μmol·L-1)脱敏P2X1受体,同时联合应用哌唑嗪(1 μmol·L-1)完全抑制电刺激诱发的血管收缩反应。采用一个标本一个浓度给药时,ISMN(0.1 mmol·L-1)显著抑制8 Hz电刺激诱发的血管收缩反应,在0.3及1.0 mmol·L-1时ISMN显著抑制各频率电刺激诱发的血管收缩反应; 1.0 mmol·L-1 ISMN对电刺激诱发的血管收缩反应的抑制率分别为46%(2 Hz)、 47%(4 Hz)、 34%(8 Hz)和22%(16 Hz)。ISMN(0.3及1.0 mmol·L-1)对外源性去甲肾上腺素(0.01~100 μmol·L-1)或腺苷三磷酸(1 mmol·L-1)诱发的血管收缩反应无影响。以上结果提示,ISMN显著抑制电场刺激诱发的交感嘌呤能血管收缩反应,其作用机制可能是ISMN作用于交感神经末梢突触前膜抑制嘌呤能神经递质产生的血管收缩反应。 相似文献
4.
Evans RG Goddard D Eppel GA O'Connor PM 《Clinical and experimental pharmacology & physiology》2011,38(4):247-254
1. Oxygen tension (PO(2)) in renal cortical tissue can remain relatively constant when renal blood flow changes in the physiological range, even when changes in renal oxygen delivery (DO(2)) and oxygen consumption (VO(2)) are mismatched. In the current study, we examined whether this also occurs in the renal medulla and skeletal muscle, or if it is an unusual property of the renal cortex. We also examined the potential for dysfunction of the mechanisms underlying this phenomenon to contribute to kidney hypoxia in disease states associated with increased renal VO(2) . 2. In both the kidney and hindlimb of pentobarbitone anaesthetized rabbits, whole organ blood flow was reduced by intra-arterial infusion of angiotensin-II and increased by acetylcholine infusion. In the kidney, this was carried out before and during renal arterial infusion of the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), or its vehicle. 3. Angiotensin-II reduced renal (-34%) and hindlimb (-25%) DO(2) , whereas acetylcholine increased renal (+38%) and hindlimb (+66%) DO(2) . However, neither renal nor hindlimb VO(2) were altered. Tissue PO(2) varied with local perfusion in the renal medulla and biceps femoris, but not the renal cortex. DNP increased renal VO(2) (+38%) and reduced cortical tissue PO(2) (-44%), but both still remained stable during subsequent infusion of angiotensin-II and acetylcholine. 4. We conclude that maintenance of tissue PO(2) in the face of mismatched changes in local perfusion and VO(2) is an unusual property of the renal cortex. The underlying mechanisms remain unknown, but our current findings suggest they are not compromised when resting renal VO(2) is increased. 相似文献
5.
Presynaptic cannabinoid CB(1) receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats
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1. Our study was undertaken to investigate whether bacterial endotoxin/lipopolysaccharide (LPS) affects the neurogenic vasopressor response in rats in vivo by presynaptic mechanisms and, if so, to characterize the type of presynaptic receptor(s) operating in the initial phase of septic shock. 2. In pithed and vagotomized rats treated with pancuronium, electrical stimulation (ES) (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibers or intravenous bolus injection of noradrenaline (NA) (1-3 nmol x kg(-1)) increased the diastolic blood pressure (DBP) by about 30 mmHg. Administration of LPS (0.4 and 4 mg x kg(-1)) under continuous infusion of vasopressin inhibited the neurogenic vasopressor response by 25 and 50%, respectively. LPS did not affect the increase in DBP induced by exogenous NA. 3. The LPS-induced inhibition of the neurogenic vasopressor response was counteracted by the cannabinoid CB(1) receptor antagonist SR 141716A (0.1 micromol x kg(-1)), but not by the CB(2) receptor antagonist SR 144528 (3 micromol x kg(-1)), the vanilloid VR1 receptor antagonist capsazepine (1 micromol x kg(-1)) or the histamine H(3) receptor antagonist clobenpropit (0.1 micromol x kg(-1)). The four antagonists by themselves did not affect the increase in DBP induced by ES or by injection of NA in rats not exposed to LPS. 4. We conclude that in the initial phase of septic shock, the activation of presynaptic CB(1) receptors by endogenously formed cannabinoids contributes to the inhibition of the neurogenic vasopressor response. 相似文献
6.
Endothelin-1 (ET-1) is a potent endothelium-derived vasoactive peptide and may be involved in the microvascular actions of insulin for the normal delivery of nutrients to muscle, although higher levels may be antagonistic. Our aim was to observe the interaction between ET-1 and insulin. Initially, we attempted to distinguish the vascular from the metabolic effects of ET-1 in the constant-flow pump-perfused rat hindlimb by using various doses of ET-1 and measuring changes in perfusion pressure (PP), oxygen consumption (VO(2)), glucose uptake (GU) and lactate release (LR). Sodium nitroprusside (SNP) was used to block vasoconstriction and to thus assess the relationship between vascular and metabolic effects. Insulin was included in later experiments to determine the interaction between insulin and ET-1 on the above parameters. ET-1 caused a dose-dependent increase in PP. Effects on VO(2) were biphasic, with low doses increasing VO(2), and higher doses leading to a net inhibition. GU and LR were increased at lower doses (ET-1 < or =1 nM), but this effect was lost at higher doses (> or =10 nM ET-1). SNP (50 microM) fully blocked the increase in pressure and metabolism due to low-dose ET-1 and partly blocked both pressure and metabolic responses by the high dose. ET-1 vasodilatory activity was minimal at high or low dose. Insulin (15 nM) alone caused GU, which was not affected by ET-1. Of the other parameters measured, insulin behaved essentially the same as SNP, inhibiting the pressure and oxygen effects. Overall, these results show that ET-1 has a biphasic dose-dependent vasoconstrictor effect on hindlimb blood vessels, able to modulate flow to cause both the stimulation and inhibition of metabolism, although these effects are blocked by insulin, which is able to vasodilate against both low and high doses of ET-1. 相似文献
7.
The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion. 总被引:4,自引:4,他引:0
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1. The effects were investigated of the ETA receptor antagonist, FR 139317, on endothelin-1 (ET-1)-induced coronary vasoconstriction in the isolated perfused heart of the rabbit. In addition, this study examined whether FR 139317 reduced infarct size in a rabbit model of coronary artery occlusion and reperfusion. 2. In the rabbit isolated perfused heart, ET-1 (1-100 pmol) elicited a dose-dependent increase in coronary perfusion pressure (CPP). For example, 30 pmol ET-1 caused CPP to rise by 22 +/- 8 mmHg and 100 pmol ET-1 by 47 +/- 10 mmHg (n = 8). Infusion of FR 139317 (1 microM) significantly attenuated the increase in CPP caused by ET-1 (30 pmol: 3 +/- 1 mmHg, 100 pmol: 8 +/- 2 mmHg; n = 8). 3. In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 45 or 60 min of coronary artery occlusion followed by 2 h of reperfusion was 47 +/- 6% (n = 6) and 55 +/- 7% (n = 5), respectively. A continuous infusion of FR 139317 (0.2 mg kg-1 min-1 preceded by a loading dose of 1.0 mg kg-1, i.v.; n = 5-6) had no effect on the extent of the myocardial infarct size (45 min: 47 +/- 6%; 60 min: 49 +/- 7%).(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
8.
Cardiac and regional haemodynamics, inducible nitric oxide synthase (NOS) activity, and the effects of NOS inhibitors in conscious, endotoxaemic rats. 总被引:7,自引:4,他引:3
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S. M. Gardiner P. A. Kemp J. E. March T. Bennett 《British journal of pharmacology》1995,116(3):2005-2016
1. A reproducible model of the hyperdynamic circulatory sequelae of endotoxaemia in conscious, chronically-instrumented Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 micro g kg(-1) h(-1)) for 32 h. Over the first 2 h of LPS infusion, there was a transient hypotension and tachycardia, accompanied by a marked increase in renal flow and vascular conductance, although there were reductions in cardiac and stroke index. Between 4-8 after the start of LPS infusion, there was slight hypotension and tachycardia, and a transient rise in mesenteric flow and conductance, but reductions in the hindquarters vascular bed; the hyperaemic vasodilatation in the renal vascular bed was maintained. At this stage, all cardiac haemodynamic variables were not different from baseline. At this stage, cardiac and stroke index were substantially elevated, in association with marked increases in peak aortic flow, dF/dtmax and total peripheral conductance; these changes were well-maintained over the following 8 h of LPS infusion. 2. By 2 h after the start of LPS infusion, only lung inducible nitric oxide synthase (iNOS) activity was increased, but at 6 h there were significant increases in iNOS activity in lung, liver, spleen, heart and aorta. (43.3 +/- 7.8, 28.8 +/- 3.3, 50.8 +/- 7.2, 3.04 +/- 0.29, 3.76 +/- 0.94 pmol min(-1) mg(-1) protein, respectively). However, by 24 h after the start of LPS infusion, iNOS activity was not elevated significantly in any tissue examined, and kidney iNOS activity did not change significantly during LPS infusion. Plasma nitrite/nitrate levels were increased after 2 h infusion of LPS (from 6.07 +/- 1.23 to 29.44 +/- 7.08 micromol l(-1)), and further by 6 h (228.10 +/- 29.20 micromol l(-1)), but were less 24 h after onset of LPS infusion (74.96 +/- 11.34 micromol l(-1)). Hence, the progressive hypotension, increasing cardiac function and developing hyperaemic vasodilatation in renal and hindquarters vascular beds between 8-24 h after the onset of LPS infusion, occurred when tissue iNOS activity and plasma nitrite/nitrate levels were falling. 3. Pretreatment with NG-monomethyl-L-arginine (L-NMMA, 30 mg kg(-1) bolus, 30 mg kg(-1) h(-1) infusion) 1 h before LPS infusion did not prevent the early hypotension, but abolished the initial renal vasodilatation and the later (6-8 h) fall in mean arterial pressure (MAP), and the additional renal vasodilatation. 相似文献
9.
Nina Skottová Rostislav Vecera Karel Urbánek Petr Vána Daniela Walterová Ladislav Cvak 《Pharmacological research》2003,47(1):17-26
To study the influence of polymerised polyphenolics (PP), a fraction of silymarin (SM), on lipids and oxidant status, rats were fed high-cholesterol (1%), high-fat (10%) diets containing either lard fat (LFD) rich in saturated/monounsaturated fatty acids, or currant oil (COD) rich in polyunsaturated fatty acids. PP and SM were administered as dietary supplements (0.1-0.5-1.0%) for 3 weeks. PP (1%) decreased cholesterol (C) in VLDL (from 0.72+/-0.08 mmol l(-1) in LFD control to 0.35+/-0.07 mmol l(-1), P<0.01, and from 0.33+/-0.05 mmol l(-1) in COD control to 0.09+/-0.02 mmol l(-1), P<0.001), and increased HDL-C/VLDL-C ratio, however, without effect on the total plasma C and LDL-C. Liver C content (LFD 19.32+/-1.50 micromol g(-1), COD 18.64+/-2.13 micromol g(-1), N.S.) decreased after PP (1%) to 12.24+/-0.76 micromol g(-1), P<0.01, and 8.78+/-0.95 micromol g(-1), P<0.001, respectively. Triacylglycerols (TAG) in plasma and VLDL decreased after PP in the LFD group only, which displayed higher TAG levels than the COD group. Likewise, LFD caused a higher liver TAG content than did COD (31.16+/-3.00 micromol g(-1) versus 17.31+/-1.48 micromol g(-1), P<0.01), and PP (1%) decreased liver TAG only in rats fed LFD (19.55+/-2.43 micromol g(-1), P<0.02). Blood glutathione (GSH) increased after PP (1%) in the LFD group from 0.97+/-0.11 to 1.54+/-0.19 mmol l(-1) (P<0.05) and in the COD group from 0.58+/-0.15 to 1.23+/-0.10 mmol l(-1) (P<0.01), while liver GSH and plasma TBARS did not change. On principle, effects of PP were dose-dependent and parallel to SM. These results suggest that the polyphenolic fraction of SM positively modifies lipoprotein profile, counteracts the development of fatty liver and ameliorates an antioxidant status in circulation. 相似文献
10.
In resistance arteries pressure-induced (myogenic) tone (MT) and flow (shear stress)-induced dilation (FD) are potent determinant of vascular resistance. We investigated the role of angiotensin II and endothelin-1 in FD and MT in resistance arteries and their potential change in hypertension. Flow - diameter - pressure relationship was established in situ, under anaesthesia, in two daughter branches of a mesenteric resistance artery (180 microM, n=7 per group) from spontaneously hypertensive (SHR) or normotensive (WKY) rats. One artery was ligated distally, so that it was submitted to pressure only, while the other was submitted to pressure and flow. Drugs were added to the preparation and external diameter, pressure and flow measured continuously. External diameter (with flow) ranged from 150+/-3 to 191+/-7 microM in WKY (n=28) rats and from 168+/-6 to 186+/-6 microM in SHR (n=28). Flow induced a dilation of the non-ligated arteries which was lower in SHR (13+/-5 - 31+/-4 microM vs WKY: 5+/-5 - 44+/-4 microM). In the ligated artery, the diameter did not significantly change, due to MT. In the vessels submitted to flow angiotensin converting enzyme inhibition (perindopril, 10 micromol L(-1)) increased the diameter in SHR (+11+/-2 microM) significantly more than in WKY (+2+/-1 microM). Angiotensin type 1 receptor (AT(1)R) blockade (losartan, 10 micromol L(-1)) increased the diameter in the vessels with flow in SHR only (+6+/-1 microM). Angiotensin type 2 receptor (AT(2)R) blockade (PD 123319, 1 micromol L(-1)) decreased arterial diameter in WKY only (9+/-2). Endothelin-1 type A receptor (ET(A)R) blockade (LU135252, 0.1 micromol L(-1)) increased the diameter only in SHR in the artery submitted to flow (by 6+/-1 microM). Thus FD was counteracted by a flow-dependent AT(1) and ET(A) receptors-activation in SHR whereas in WKY FD AT(2)-dependent dilation is involved. 相似文献
11.
H S Lin A B Barua J A Olson K S Low S Y Chan M L Shoon P C Ho 《Journal of pharmaceutical sciences》2001,90(12):2023-2031
All-trans-retinoyl-beta-D-glucuronide (RAG) is an endogenous active metabolite of all-trans-retinoic acid (ATRA). In the present study, the pharmacokinetics of RAG was examined after the administration of a single intravenous does (5, 10, or 15 micromol/kg) and of multiple daily intravenous doses (5 micromol/kg) to rats for 8 days. The plasma concentrations of RAG and ATRA were measured by a reverse-phase HPLC method. A rapid distribution phase of approximately 1 h was observed in all of the rats after single or multiple doses. Thereafter, RAG was eliminated through a first-order process, in accord with a typical two-compartment first order pharmacokinetic profile. After single intravenous doses, the AUC of RAG increased proportionally with the dose and the clearance remained unchanged within the tested doses. There was no statistical significant difference in distribution rate constants from central compartment to peripheral compartment (K(12)) and from peripheral compartment to central compartment (K(21)) between different doses. However, as the dose increased from 5 micromol/kg to 10 micromol/kg, the volume of distribution at the steady state (V(ss)) and the volume of peripheral compartment (V(p)) decreased significantly (p < 0.05) from 1.290 +/- 0.269, 0.928 +/- 0.232. L/kg to 0.961 +/- 0.149, 0.647 +/- 0.107 L/kg, respectively. V(ss) and V(p) at a dose of 15 micromol/kg (0.924 +/- 0.187, 0.698 +/- 0.165 L/kg) were not significantly different from that at 10 micromol/kg. Thus, RAG might saturate the tissue-binding sites at higher doses. ATRA was detected as a metabolite of RAG at low levels (usually < 0.05 microM) only in the first 2 h after intravenous administration. RAG clearly was not extensively hydrolyzed to ATRA in our study. After multiple daily intravenous administration of RAG, the clearance (Cl) and the elimination rate constant (K(10)) remained unchanged (p > 0.05), indicating that long-term daily administration of RAG did not induce its accelerated metabolism. However, K(12), V(p), and V(ss) declined significantly (p < 0.05) from 1.67 +/- 0.54 h(-1), 0.928 +/- 0.232 L/kg, and 1.290 +/- 0.269 L/kg to 0.96 +/- 0.48 h(-1), 0.494 +/- 0.147 L/kg, and 0.818 +/- 0.187 L/kg, respectively. Therefore, long-term daily dosing of RAG seemed to decrease its distribution profile. Although the AUC of RAG did not change significantly after multiple dosing, the AUC of ATRA after RAG dosing significantly declined (p < 0.05) from 0.032 +/- 0.019 microM x h to 0.010 +/- 0.006 microM x h. The decline in the AUC of ATRA might reflect an increase in its uptake by tissue and/or in its metabolism. Because enhanced clearance is not associated with RAG after multiple administrations, RAG could be considered as an alternate to ATRA in appropriate clinical applications. 相似文献
12.
Enhancement of the hypotensive and vasodilator effects of endotoxaemia in conscious rats by the endothelin antagonist, SB 209670. 总被引:5,自引:5,他引:0
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S. M. Gardiner P. A. Kemp J. E. March T. Bennett 《British journal of pharmacology》1995,116(2):1718-1719
In conscious, chronically-instrumented rats, the non-selective endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1), caused marked enhancement of the fall in mean arterial blood pressure during infusion of lipopolysaccharide (LPS) for 24 h (LPS alone = -6 +/- 3 mmHg; LPS+SB 209670 = -30 +/- 2 mmHg). This effect was accompanied by a conversion of the mesenteric vasoconstriction to a substantial mesenteric vasodilatation and an augmentation of the hindquarters vasodilatation, seen with LPS alone. Notably, the marked renal hyperaemic vasodilatation during LPS infusion was not affected significantly by SB 209670. These results indicate that endothelin, directly and/or indirectly, plays a pivotal role in the cardiovascular sequelae of endotoxaemia in conscious rats, and prevents marked hypotension, particularly by opposing mesenteric vasodilatation. 相似文献
13.
To test the hypothesis that activation of the transient receptor potential vanilloid type 1 (TRPV1) channels leads to natriuresis and diuresis via an increase in glomerular filtration rate (GFR), recirculating Krebs-Henseleit buffer added with inulin was perfused in the isolated perfused kidney of male Wistar rat at a constant flow, and perfusion pressures (PPs) were pre-adjusted to three different levels ( approximately 100, approximately 150, and approximately 190mmHg) with phenylephrine. Capsaicin (Cap), a selective TRPV1 agonist, was perfused in the presence or absence of capsazepine (Capz), a selective TRPV1 antagonist, CGRP(8-37), a selective calcitonin gene-related peptide (CGRP) receptor antagonist, or spantide II (Spa), a selective substance P (SP) receptor antagonist. At the higher (150 and 190mmHg) but not baseline (100mmHg) PP levels, Cap at 10microM significantly decreased PP and increased GFR, urine flow rate (UFR) and Na+ excretion (UNaV). At the highest (190mmHg) PP level, Cap (2, 10, 30microM) dose-dependently decreased PP and increased GFR, UFR, UNaV, and the release of CGRP and SP. Capz or CGRP(8-37) combined with Spa fully blocked the effect of Cap on PP, GFR, UFR, UNaV, and the release of CGRP and SP. In conclusion, activation of TRPV1 in the isolated kidney decreases renal PP and increases GFR and water/sodium excretion possibly via simultaneous activation of CGRP and SP receptors upon their enhanced release, suggesting that TRPV1 plays a key role in modulating renal hemodynamics and excretory function. 相似文献
14.
Alice M C Martins Fabiola C M Sousa Paulo S F Barbosa Marcos H Toyama Daniela O Toyama Cleidiana C Aprígio Maria G R Queiroz Mirian C Guarnieri Alexandre Havt Dalgimar B de Menezes Manassés C Fonteles Helena S A Monteiro 《Toxicon》2005,46(6):595-599
Acute renal failure is the most common complication in the lethal cases caused by snakebites in Brazil. Among the Brazilian venom snakes, Bothrops erythromelas is responsible for the majority of accidents in Northeastern Brazil. Didelphis marsupialis serum could inhibit myonecrotic, hemorrhagic, edematogenic hyperalgesic and lethal effects of envenomation determined by ophidian bites. In the present study, we evaluated the action of the anti-bothropic factor isolated from D. marsupialis on the renal effects promoted by B. erythromelas venom without systemic interference. Isolated kidneys from Wistar rats were perfused with Krebs-Henseleit solution containing 6% bovine serum albumin. We analyzed renal perfusion pressure (PP), renal vascular resistance (RVR), glomerular filtration rate (GFR), urinary flow (UF), and the percentages of sodium and potassium tubular transport (%TNa+, %TK+). The B. erythromelas venom (10 microg mL(-1)) decreased the PP (ct = 108.71+/-5.09 mmHg; BE = 65.21+/-5.6 mmHg*) and RVR (ct = 5.76+/-0.65 mmHg mL(-1) g(-1) min(-1); BE = 3.10+/-0.45 mmHg mL(-1) g(-1) min(-1)*). On the other hand, the GFR decreased at 60 min (ct60 = 0.76+/-0.07 mL g(-1) min(-1); BE60 = 0.42+/-0.12 mL g(-1) min(-1)*) and increased at 120 min (ct120 = 0.72+/-0.01 mL g(-1) min(-1); BE120 = 1.24+/-0.26 mL g(-1) min(-1)*). The UF increased significantly when compared with the control group (ct = 0.14+/-0.01 mL g(-1) min(-1); BE = 0.47+/-0.08 mL g(-1) min(-1)*). The venom reduced the %TNa(+) (ct90 = 79.18+/-0.88%; BE90 = 58.35+/-4.86%*) and %TK+ (ct90 = 67.20+/-4.04%; BE90 = 57.32+/-5.26%*) The anti-bothropic factor from D. marsupialis (10 microg mL(-1)) incubated with B. erythromelas venom (10 microg mL(-1)) blocked the effects on PP, RVR, %TNa+, and %TK+, but was not able to reverse the effects in UF and GFR promoted by venom alone. However, the highest concentration of D. marsupialis serum (30 microg mL(-1)) reversed all the renal effects induced by the venom. In conclusion, B. erythromelas venom altered all the renal functional parameters evaluated and the anti-bothropic factor from D. marsupialis was able to inhibit the effects induced by the venom in isolated kidney. 相似文献
15.
SONIA ALLIBARDI GIAMPIERO MERATI SERGIO CHIERCHIA MICHELE SAMAJA 《Pharmacological research》1999,39(6):431-435
Metabolic events during ischaemia are probably important in determining post-ischaemic myocardial recovery. The aim of this study was to assess the effects of the beta-blocker atenolol and the high energy demand in an ischaemia-reperfusion model free of neurohormonal and vascular factors. We exposed Langendorff-perfused isolated rat hearts to low-flow ischaemia (30 min) and reflow (20 min). Three groups of hearts were used: control hearts (n =11), hearts that were perfused with 2.5 micrograms l-1atenolol (n =9), and hearts electrically paced during ischaemia to distinguish the effect of heart rate from that of the drug (n =9). The hearts were freeze-clamped at the end of reflow to determine high-energy phosphates and their metabolites. During ischaemia, the pressure-rate product was 2.3+/-0.2, 5.2+/-1.1, and 3.3+/-0.3 mmHg 10(3)min in the control, atenolol and paced hearts, respectively. In addition, the ATP turnover rate, calculated from venous (lactate), oxygen uptake and flow, was higher in atenolol (11.2+/-1.7 micromol min-1) and paced (8.1+/-0.8 micromol min-1) hearts than in control (6.2+/-0.8 micromol min-1). At the end of reflow, the pressurexrate product recovered 75.1+/-6.4% of baseline in control vs 54.1+/-9.1 and 48.8+/-4.4% in atenolol and paced hearts (P<0.05). In addition, the tissue content of ATP was higher in the control hearts (15.8+/-1. 0 micromol g(dw)(-1)) than in atenolol (10.5+/-2.6 micromol g(dw)(-1)) and paced (10.9+/-1.3 micromol g(dw)(-1)) hearts. Thus, by suppressing the protective effects of down-regulation, both atenolol and pacing apparently depress myocardial recovery in this model. 相似文献
16.
1. The cardiac depressant actions of TNF were investigated in the isolated perfused rat heart under constant flow (10 ml min(-1)) and constant pressure (70 mmHg) conditions, using a recirculating (50 ml) mode of perfusion. 2. Under constant flow conditions TNF (20 ng ml(-1)) caused an early (< 25 min) decrease in left ventricular developed pressure (LVDP), which was maintained for 90 min (LVDP after 90 min: control vs TNF; 110 +/- 4 vs 82 +/- 10 mmHg, P < 0.01). 3. The depression in cardiac function seen with TNF under constant flow conditions, was blocked by the ceramidase inhibitor N-oleoylethanolamine (NOE), 1 microM, (LVDP after 90 min: TNF vs TNF with NOE; 82 +/- 10 vs 11 +/- 5 mmHg, P < 0.05). 4. In hearts perfused at constant pressure, TNF caused a decrease in coronary flow rate (change in flow 20 min after TNF: control vs TNF; -3.0 +/- 0.9 vs -8.7 +/- 1.2 ml min(-1), P < 0.01). This was paralleled by a negative inotropic effect (change in LVDP 20 min after TNF: control vs TNF; -17 +/- 7 vs -46 +/- 6 mmHg, P < 0.01). The decline in function was more rapid and more severe than that seen under conditions of constant flow. 5. These data indicate that cardiac function can be disrupted by TNF on two levels, firstly via a direct, ceramidase dependant negative inotropic effect, and secondly via an indirect coronary vasoconstriction. 相似文献
17.
Regional blood flow responses to acute ANG II infusion: effects of nitric oxide synthase inhibition.
J D Symons T I Musch K S Hageman C L Stebbins 《Journal of cardiovascular pharmacology》1999,34(1):116-123
We hypothesized that nitric oxide (NO) opposes regional vasoconstriction caused by acute angiotensin II (ANG II) infusion in conscious rats. Mean arterial pressure (MAP), blood flow, and vascular conductance (regional blood flow/ MAP; ml/min/100 g/mm Hg) were measured and/or calculated before and at 2 min of ANG II infusion (0.05 or 1 microg/kg/min, i.a.) in the absence and presence of NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME), 0.25 or 1 mg/kg, i.a.]. ANG II reduced stomach and hindlimb conductance only after NOS inhibition. For example, whereas 0.05 microg/kg/min ANG II did not attenuate conductance in the stomach (i.e., 1.04+/-0.08 to 0.93+/-0.12 ml/min/100 g/mm Hg), this variable was reduced (i.e., 0.57+/-0.14 to 0.34-/+0.05 ml/min/100 g/mm Hg; p < 0.05) when ANG II was infused after 0.25 mg/kg L-NAME. In addition, whereas hindlimb conductance was similar before and after administering 1 microg/kg/min ANG II (i.e., 0.13+/-0.01 and 0.09+/-0.02, respectively), this variable was reduced (i.e., 0.07+/-0.01 and 0.02+/-0.00, respectively; p < 0.05) when ANG II was infused after 1 mg/kg L-NAME. These findings indicate that NO opposes ANG II-induced vasoconstriction in the stomach and hindlimb. In contrast, whereas both doses of ANG II decreased (p < 0.05) vascular conductance in the kidneys and small and large intestine regardless of whether NOS inhibition was present, absolute vascular conductance was lower (p < 0.05) after L-NAME. For example, 1 microg/kg ANG II reduced renal conductance from 3.34+/-0.31 to 1.22+/-0.14 (p < 0.05). After 1 mg/kg L-NAME, renal conductance decreased from 1.39+/-0.18 to 0.72+/-0.16 (p < 0.05) during ANG II administration. Therefore the constrictor effects of NOS inhibition and ANG II are additive in these circulations. Taken together, our results indicate that the ability of NO to oppose ANG II-induced constriction is not homogeneous among regional circulations. 相似文献
18.
Daniela N Amora Ticiana M Sousa Alice M C Martins Paulo S F Barbosa Marta R Magalh?es Marcus H Toyama Manassés C Fonteles Dalgimar B de Menezes Helena S A Monteiro 《Toxicon》2006,47(3):260-264
Ophidian accidents caused by the subspecies Crotalus durissus are responsible for high morbity and mortality rates. Acute renal failure is a common complication observed in these accidents. The aim of the present study was to investigate the renal effects promoted by the venom of C. d. collilineatus and its fractions, crotoxin and phospholipase A2. C. d. collilineatus (Cdc; 30 microg mL(-1)), crotoxin (CTX; 10 microg mL(-1)) and phospholipase A2 (PLA2; 10 microg mL(-1)) were tested in isolated rat kidney. The first 30 min of each experiment were used as an internal control and Cdc or its fractions, CTX and PLA2 were added to the system after this period. All experiments lasted 120 min. The venom of Cdc decreased perfusion pressure (PP; control120 = 110.3 +/- 3.69 mmHg; Cdc120 = 96.7+/-8.1 mmHg), renal vascular resistance (RVR; control120 = 6.42+/-0.78 mmHg mL g(-1) min(-1); Cdc120 = 4.8+/-0.56 mmHg/mL g(-1) min(-1)), urinary flow (UF; control120 = 0.19+/-0.03 mL g(-1) min(-1); Cdc120 = 0.12 +/- 0.01 mL g(-1) min(-1)), and glomerular filtration rate (GFR; control120 = 0.79 +/- 0.07 mL g(-1) min(-1); Cdc120 = 0.53 +/- 0.09 mL g(-1) min(-1)), but had no effect on the percent of sodium tubular transport (%TNa+), percent of chloride tubular transport (%TK+) and percent of potassium tubular transport (%TCl-). CTX and PLA2 reduced the GFR, while UF, PP and RVR remained stable during the full 120 min of perfusion. Crotoxin administration also diminished the %TK+ (control120 = 69.94 +/- 6.49; CTX120 = 33.28 +/- 4.78) and %TCl- (control120 = 79.53 +/- 2.67; CTX120 = 64.62 +/- 6.93). PLA2 reduced the %TK+, but exerted no effect on the %TNa+ or on that of TCl-. In conclusion, the C. d. collilineatus venom altered the renal functional parameters evaluated. We suggest that crotoxin and phospholipase A2 were involved in this process, since the renal effects observed would be due to the synergistic action of the components of the venom. 相似文献
19.
Respiratory actions of vanilloid receptor agonists in the nucleus of the solitary tract: comparison of resiniferatoxin with non-pungent agents and anandamide 总被引:1,自引:0,他引:1
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1. Activation of vanilloid receptors on sensory nerve terminals in the commissural nucleus of the solitary tract (cNTS) of rats with capsaicin, produces respiratory slowing. In this study, we used microinjection techniques employing pungent and non-pungent vanilloids to further characterize vanilloid receptors in the cNTS. 2. Microinjection of the pungent vanilloid, resiniferatoxin (RTX), into the cNTS of urethane-anaesthetized rats, dose-dependently reduced respiratory rate without affecting tidal volume. RTX was 20 fold more potent at slowing respiration ( approximately ED(50), 100 pmol) than capsaicin ( approximately ED(50), 2 nmol). Doses of RTX greater than 100 pmol caused either irregular (dyspnoeic) breathing or terminal apnoea (>250 pmol). The respiratory slowing response to RTX (75 pmol), was dose-dependently attenuated by injecting RTX (but not vehicle) into the same site 60 min earlier. 3. The non-pungent phorbol derivative of RTX, phorbol 12-phenylacetete 13-acetate 20-homovanillate (PPAHV, 0.1-1 nmol), also slowed respiration (ED(50), approximately 1 nmol) and almost abolished response to RTX (75 pmol) injected into the same site 60 min later. 4. In contrast to RTX, PPAHV and capsaicin, the putative endogenous vanilloid receptor agonist, arachidonyl ethanolamide (AEA), and non-pungent capsaicin derivative, olvanil, had no direct effect on respiration. However, both AEA and olvanil dose-dependently reduced the respiratory response to injection of RTX (75 pmol) 60 min later into the same site (EC(50)s, for AEA and olvanil, approximately 2 and 0.2 nmol, respectively). 5. These studies suggest that both pungent and non-pungent vanilloids interact with vanilloid receptors in the cNTS. However, whereas RTX and PPAHV activate and subsequently desensitize vanilloid receptors on sensory nerve terminals in the cNTS, olvanil and AEA fail to activate despite readily desensitizing responses to RTX in this region. 相似文献
20.
Regional haemodynamic effects of antagonists of angiotensin II, endothelin and adrenoceptors in conscious, vasopressin-deficient, genetically hypertensive rats.
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S. M. Gardiner J. E. March P. A. Kemp T. Bennett 《British journal of pharmacology》1996,118(2):325-334
1. Male, vasopressin-deficient, normotensive (DI/N) and hypertensive (DI/H) rats were chronically instrumented (all surgery under sodium methohexitone anaesthesia) to allow assessment of resting haemodynamic status and responses to antagonism of AT1-receptors (Experiment 1), ET(A-) and ET(B-) receptors (Experiment 2) or adrenoceptors (Experiment 3). 2. Before any treatment, mean arterial blood pressure (MAP) was higher, and hindquarters vascular conductance was consistently lower in all groups of DI/H rats than in DI/N rats. 3. In Experiment 1, losartan (10 mg kg-1 i.v.), an AT1-receptor antagonist, was given 5 h after s.c. injection of saline, (DI/N, n = 8; DI/H, n = 8) or hyperoncotic polyethylene glycol, (DI/N, n = 9; DI/H, n = 9) to induce isosmotic hypovolaemia. In the volume-replete state, losartan caused similar small falls in MAP in the two groups (maximum delta MAP; DI/N, -9 +/- 2; DI/H, -15 +/- 5 mmHg), but the mesenteric and hindquarters vasodilatations were greater in DI/N rats. In the volume-depleted state the effects of losartan were augmented (delta MAP; DI/N, -32 +/- 3; DI/H. -31 +/- 3 mmHg), but its vasodilator effects were still greater in DI/N than in DI/H rats. 4. In Experiment 2, infusion of the ET(A-)ET(B-)receptor antagonist, SB 209670 (600 micrograms kg-1 h-1; DI/N, n = 8; DI/H, n = 9), had haemodynamic effects that were not different from those during saline infusion in DI/N (n = 7) and DI/H rats (n = 8). 5. In Experiment 3, sequential administration of the beta 2-adrenoceptor antagonist, ICI 118551 (0.2 mg kg-1 bolus, 0.1 mg kg-1 h-1 infusion), the alpha 2-adrenoceptor antagonist, idazoxan (0.75 mg kg-1 bolus, 1 mg kg-1 h-1 infusion), and losartan (10 mg kg-1 bolus) had only slight haemodynamic effects in DI/N (n = 8) and DI/H (n = 9) rats. Subsequent administration of the alpha 1-adrenoceptor antagonist, prazosin (0.5 mg kg-1 bolus, 0.8 mg kg-1 h-1 infusion) caused marked hypotension, although MAP was still higher in DI/H (95 +/- 4 mmHg) than in DI/N (75 +/- 4 mmHg) rats. However, in this circumstance there were no significant differences between renal, or mesenteric, or hindquarters vascular conductances in the two groups. 6. The results indicate that the hypertension and hindquarters vasoconstriction in DI/H rats is not dependent on AII or endothelin. Moreover, the relative elevation in MAP in DI/H persists in the presence of antagonism of beta 2, alpha 2- and alpha 1-adrenoceptors, in spite of no significant difference in regional vascular conductances. 相似文献