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1.
The effect of structural changes in the N-terminal amino acid of AIV, with respect to AT4 receptor binding, was examined by competition with [125I]AIV in bovine adrenal membranes. Analogues with modifications of the first residue -amino group possessed lower affinities than the primary amine-containing parent compound. Peptides with a residue 1 -carbon in the conformation exhibited poor affinity for the AT4 receptor. Modifications of the residue 1 R-group demonstrate that a straight chain aliphatic moiety containing four carbons is optimal for receptor-ligand binding, as evidenced by the extremely high affinity of [Nle1]AIV (Ki = 3.59±0.51 pM). Replacement of the 1–2 peptide bond of AIV with the methylene bond isostere Ψ (CH2-NH), increased the Ki approximately fivefold, indicating that the peptide bond may be replaced wihle maintaining relatively high-affinity receptor binding.  相似文献   

2.
β-Arrestins play a role in AT1 endocytosis by binding the cytoplasmic, C-terminus region T332–S338, the major site of angiotensin II (Ang II)-induced phosphorylation. However, the processes responsible for recruiting β-arrestin to the activated receptor are poorly defined. In this study, we used CHO-K1 and HEK 293 cells expressing wild-type or mutant AT1 to investigate two possibilities: activated AT1 induces global relocation of β-arrestins to the plasma membrane or the phosphorylated C-terminus acts as bait to attract β-arrestins. Results obtained using high osmolarity and dominant-negative β-arrestin confirmed that internalization of AT1 in both CHO-K1 and HEK 293 cells is predominately via clathrin-mediated endocytosis involving β-arrestin, and substitution of T332, S335, T336 and S338 with alanine to preclude phosphorylation markedly attenuated AT1 internalization. Confocal microscopy revealed that wild-type AT1 induced a time-dependent translocation of GFP-tagged β-arrestins 1 and 2 to the cell surface. In contrast, the TSTS/A mutant did not traffic β-arrestin 1 at all, and only trafficked β-arrestin 2 weakly. Results of rescue-type experiments were consistent with the idea that both β-arrestins are able to interact with the non-phosphorylated receptor, albeit with much lower affinity and β-arrestin 1 less so than β-arrestin 2. In conclusion, this study shows that the high affinity binding of β-arrestins to the phosphorylated C-terminus is the predominant mechanism of agonist-induced β-arrestin recruitment to the cell surface and AT1 receptor.  相似文献   

3.
4.
In the present paper, the modulation of the basolateral membrane (BLM) Na+-ATPase activity of inner cortex from pig kidney by angiotensin II (Ang II) and angiotensin-(1–7) (Ang-(1–7)) was evaluated. Ang II and Ang-(1–7) inhibit the Na+-ATPase activity in a dose-dependent manner (from 10−11 to 10−5 M), with maximal effect obtained at 10−7 M for both peptides. Pharmacological evidences demonstrate that the inhibitory effects of Ang II and Ang-(1–7) are mediated by AT2 receptor: The effect of both polypeptides is completely reversed by 10−8 M PD 123319, a selective AT2 receptor antagonist, but is not affected by either (10−12–10−5 M) losartan or (10−10–10−7 M) A779, selective antagonists for AT1 and AT(1–7) receptors, respectively. The following results suggest that a PTX-insensitive, cholera toxin (CTX)-sensitive G protein/adenosine 3′,5′-cyclic monophosphate (cAMP)/PKA pathway is involved in this process: (1) the inhibitory effect of both peptides is completely reversed by 10−9 M guanosine 5′-O-(2-thiodiphosphate) (GDPβS; an inhibitor of the G protein activity), and mimicked by 10−10 M guanosine 5′-O-(3-thiotriphosphate) (GTPγS; an activator of the G protein activity); (2) the effects of both peptides are mimicked by CTX but are not affected by PTX; (3) Western blot analysis reveals the presence of the Gs protein in the isolated basolateral membrane fraction; (4) (10−10–10−6 M) cAMP has a similar and non-additive effect to Ang II and Ang-(1–7); (5) PKA inhibitory peptide abolishes the effects of Ang II and Ang-(1–7); and (6) both angiotensins stimulate PKA activity.  相似文献   

5.
Cardiovascular pathogenesis induced by angiotensin II (Ang-II) is a complex process often connected to oxidative stress. In the present study we show that, 4 h after addition, Ang-II induces a four- to fivefold increase in AP-1 activity in cultured neonatal rat cardiomyocytes and that the intracellular level of reactive oxygen species (ROS) correlates with the extent of AP-1 binding activity. Ang-II stimulated ROS generation in rat cardiomyocytes in a dose- and time-dependent manner. These effects of Ang-II were suppressed by the Ang-II receptor type I (AT1) inhibitor CV-11974 as well as by the antioxidants diphenylene iodonium (DPI) and N-acetyl-l-cysteine (NAC), but not by AT2 antagonist PD 122319. Furthermore, Ang-II induced a two- to threefold increase in protein synthesis and cell size during 12–24 h, which could be inhibited by CV-11974 as well as by DPI and NAC. Because the rat cardiomyocytes strongly expressed gp91phox, this suggests that ROS generated in a gp91-containing NADPH oxidase are involved in signal transduction leading to AP-1 activation. Together, these findings indicate that Ang-II elicits the activation of the redox-sensitive AP-1 via ROS through AT1, resulting in effects on cardiomyocyte function such as hypertrophy.  相似文献   

6.
Angiotensin (Ang)-(1–7) is an endogenous peptide hormone of the renin–angiotensin system which exerts diverse biological actions, some of them counterregulate Ang II effects. In the present study potential effect of Ang-(1–7) on phosphoinositide (PI) turnover was evaluated in neonatal rat brain. Cerebral cortex prisms of seven-day-old rats were preloaded with [3H]myoinositol, incubated with additions during 30 min and later [3H]inositol-phosphates (IPs) accumulation quantified. It was observed that PI hydrolysis enhanced 30% to 60% in the presence of 0.01 nM to 100 nM Ang-(1–7). Neither 10 nM [D-Ala7]Ang-(1–7), an Ang-(1–7) specific antagonist, nor 10 nM losartan, an angiotensin II type 1 (AT1) receptor antagonist, blocked the effect of 0.1 nM Ang-(1–7) on PI metabolism. The effect of 0.1 nM Ang-(1–7) on PI hydrolysis was not reduced but it was even significantly increased in the simultaneous presence of [D-Ala7]Ang-(1–7) or losartan. PI turnover enhancement achieved with 0.1 nM Ang-(1–7) decreased roughly 30% in the presence of 10 nM PD 123319, an angiotensin II type 2 (AT2) receptor antagonist. The antagonists alone also enhanced PI turnover. Present findings showing an increase in PI turnover by Ang-(1–7) represent a novel action for this peptide and suggest that it exerts a function in this signaling system in neonatal rat brain, an effect involving, at least partially, angiotensin AT2 receptors.  相似文献   

7.
Vasoactive intestinal peptide (VIP) bound with high affinity (Kd 0.13 nmol/l) to receptors on the human glioma cell line U-343 MG Cl 2:6. The receptors bound the related peptides helodermin. PHM and secretin with 10, 400 and 5000 times lower affinity, respectively. Deamidated VIP (VIP-COOH) and [des-His1]VIP bound with 10 and 100 times lower affinity. The fragment VIP(7–28) displaced 25% of the receptor-bound 125I-VIP whereas VIP(16–28) and VIP(1–22-NH2) were inactive. The binding of 125I-VIP could be completely inhibited by 10 μmol/l of the antagonists [N-Ac-Tyr1,D-Phe2]GRF(1–29)-NH2, [pCl-D-Phe6,Leu17]VIP and VIP(10–28); in contrast, the antagonist L-8-K was inactive. Affinity labeling showed that VIP bound to proteins with Mr's of 75 kDa, 66 kDa and 50 kDa, respectively. Following binding, the peptide was rapidly internalized, and at steady-state only 20% of cell-associated 125I-VIP was bound to receptors on the cell surface. The internalized 125I-VIP was completely degraded to 125I-tyrosine which was released from the cells. Degradation of internalized 125I-VIP was significantly reduced by chloroquine phenantroline and pepstatin-A. Surface binding and internalization of 125I-VIP was increased 3 times by phenantroline, and pepstatin-A caused a 5 times increase in surface binding. Chloroquine reduced surface-bound 125I-VIP, but caused retention of internalized 125I-VIP.  相似文献   

8.
Biological properties of amino-terminal PTHrP analogues modified in the region 11–13 were examined using ROS 17/2.8 cells. [Leu11,D-Trp12,Arg13,Tyr36]PTHrP(1–36)amide had a 17-fold lower binding affinity for the receptor (apparent Kd: 5 × 10−8 M) than [Tyr36]PTHrP(1–36)amide or [Arg11,13,Tyr36]PTHrP(1–36)amide (apparent Kd for both: 2 × 10−9 M). Moreover, it is only a weak partial agonist despite completely inhibiting radioligand binding. [Leu11,D-Trp12,Arg13,Tyr36,Cys38]PTHrP(7–38) and PTHrP(7–34)amide had similar receptor affinities (apparent Kds: 5 × 10−8 M and 8 × 10−8 M), while that of [Nle8,18,Tyr34]bPTH(7–34)amide was more than 10-fold lower (apparent Kd: 2 × 10−6 M). These changes in biological properties suggest that high affinity receptor binding requires both amino- and carboxyl-terminal domains of the PTHrP(1–36) sequence and/or intramolecular interactions which are impaired by the D-Trp substitution for Gly12.  相似文献   

9.
Somatostatin binding to guinea pig pancreatic acinar cell plasma membranes was characterized with an iodinated stable analog of somatostatin 28 (S28): 125I-[Leu8, DTrp22,Tyr25] S28. The binding was highly dependent on calcium ions. In 0.2 mM free Ca2+ medium, binding at 37°C was saturable, slowly reversible and exhibited a single class of high affinity binding sites (KD=0.05±0.01 nM, Bmax=157±33 fmol/mg protein). Dissociation of bound radioactivity occurred with biphasic kinetics. Rate of dissociation increased when dissociation was measured at a time before equilibrium binding was reached. In 30 nM free Ca2+ medium, binding affinity and maximal binding capacity were decreased by about 4-fold. Decreasing calcium concentrations increased the amount of rapidly dissociating form of the receptor. Somatostatin 14 antagonist, Des AA1,2[AzaAla4–5,DTrp8,Phe12–13]-somatostatin was active at the membrane level in inhibiting the binding. We conclude that using 125I-[Leu8,DTrp22,Tyr25]S28 as radioligand allows us to characterize a population of specific somatostatin receptors which are not different from those we previously described with the radioligand 125I-[Tyr11]-somatostatin. Somatostatin receptors could exist in two interconvertible forms. Calcium ions are an essential component in the regulation of the conformational change of somatostatin receptors.  相似文献   

10.
Eighteen corpora striata from normal human foetal brains ranging in gestational age from 16 to 40 weeks and five from post natal brains ranging from 23 days to 42 years were analysed for the ontogeny of dopamine receptors using [3H]spiperone as the ligand and 10 mM dopamine hydrochloride was used in blanks. Spiperone binding sites were characterized in a 40-week-old foetal brain to be dopamine receptors by the following criteria: (1) It was localized in a crude mitochondrial pellet that included synaptosomes; (2) binding was saturable at 0.8 nM concentration; (3) dopaminergic antagonists spiperone, haloperidol, pimozide, trifluperazine and chlorpromazine competed for the binding with IC50 values in the range of 0.3–14 nM while agonists—apomorphine and dopamine gave IC50 values of 2.5 and 10 μM, respectively suggesting a D2 type receptor.

Epinephrine and norepinephrine inhibited the binding much less efficiently while mianserin at 10 μM and serotonin at 1 mM concentration did not inhibit the binding. Bimolecular association and dissociation rate constants for the reversible binding were 5.7 × 108 M−1 min−1 and 5.0 × 10−2 min−1, respectively. Equilibrium dissociation constant was 87 pM and the KD obtained by saturation binding was 73 pM.

During the foetal age 16 to 40 weeks, the receptor concentration remained in the range of 38–60 fmol/mg protein or 570–1080 fmol/g striatum but it increased two-fold postnatally reaching a maximum at 5 years Significantly, at lower foetal ages (16–24 weeks) the [3H]spiperone binding sites exhibited a heterogeneity with a high (KD, 13–85 pM) and a low (KD, 1.2–4.6 nM) affinity component, the former accounting for 13–24% of the total binding sites. This heterogeneity persisted even when sulpiride was used as a displacer. The number of high affinity sites increased from 16 weeks to 24 weeks and after 28 weeks of gestation, all the binding sites showed only a single high affinity.

GTP decreased the agonist affinity as observed by dopamine competition of [3H]spiperone binding in 20-week-old foetal striata and at all subsequent ages. GTP increased IC50 values of dopamine 2 to 4.5 fold and Hill coefficients were also increased becoming closer to one suggesting that the dopamine receptor was susceptible to regulation from foetal life onwards.  相似文献   


11.
Previous studies delineated two classes of δ binding sites; a δ binding site not associated with the opioid receptor complex, termed the δncx site, and a δ site associated with the opioid receptor complex, termed the δcx site. The δncx site has high affinity for [ -Pen2, -Pen5]enkephalin, and is synonymous with what is now identified as the δ1 binding site. Pretreatment of membranes with the δ-selective acylating agents FIT, or (+)-trans-SUPERFIT, deplete membranes of the δncx binding site, which permits the selective labeling of the δcx binding site with [3H][ -Ala2,Leu5]enkephalin. The present study compared the properties of the δcx binding site present in brain membranes pretreated with (+)-trans-SUPERFIT with the properties of the δcx site present in untreated membranes. The major findings are: 1) pretreatment of membranes with (+)-trans-SUPERFIT decreased the IC50 values of δ-preferring drugs, and increased the IC50 values of μ-preferring drugs, for the δcx binding site; 2) the degree of δ selectivity was highly correlated with the magnitude of the (+)-trans-SUPERFIT-induced shift in the IC50 values; 3) the ligand-selectivity patterns of the μ and δcx sites present in (+)-trans-SUPERFIT-pretreated membranes were poorly correlated; 4) whereas μ-preferring drugs were noncompetitive inhibitors of [3H][ -Ala2,Leu5]enkephalin binding to the δcx site, δ-preferring drugs were competitive inhibitors. Viewed collectively, these data support the hypothesis that the μ and δcx binding sites are distinct, provide additional evidence for δ receptor heterogeneity, and suggest that ( (+)-trans-SUPERFIT-pretreated membranes will provide a useful preparation for studying the δcx binding site.  相似文献   

12.
To investigate receptor selectivity and possible species selectivity of a number of NPY analogues and fragments, receptor binding studies were performed using cell lines and membranes of several species. NPY displays 4–25-fold higher affinity for the Y2 receptor than for the Y1 receptor. The affinity of [Leu31,Pro34]NPY is 7–60-fold higher for the Y1 receptor when compared with the Y2 subtype. Species selectivity within the Y2 receptors is demonstrated by PYY(3–36), NPY(2–36), NPY(22–36), and NPY(26–36). It is shown that NPY(22–36) is species selective for the human Y2 subtype (Ki of 0.3 nM) compared with the rabbit and rat Y2 receptor (Ki of 2 and 10 nM, respectively). PYY(3–36) displays highest affinity for the human and rabbit Y2 subtype (Ki of 0.03 and 0.17 nM). The screening of NPY analogues and fragments revealed that highest affinity for the human Y2 receptor is shown by NPY(2–36) and PYY(3–36). In addition, PYY(3–36) and NPY(2–36) are not only subtype selective, but also species selective.  相似文献   

13.
Recent pharmacological data strongly support the hypothesis of δ receptor subtypes as mediators of both supraspinal and spinal antinociception (δ1 and δ2 receptors). In vitro ligand binding data, which are fully supportive of the in vivo data, are still lacking. A previous study indicated that [3H][ -Ala2, -Leu5]enkephalin labels two binding sites in membranes depleted of μ binding sites by pretreatment with the site-directed acylating agent, 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidazole-HCI (BIT). The main goal of the present study was to develop a ligand-selectivity profile of the two δncx binding sites. The data indicated that naltrindole and oxymorphindole were relatively selective for site 1 (20-fold). [ -Ser2,Thr6]Enkephalin and deltorphin-II were only 2.7-fold and 2.2-fold selective for site 1. [ -Pen2, -Pen5]Enkephalin and deltorphin-I were 80-fold and 38-fold selective for site 2.3-Iodo-Tyr- -Ala-Gly-Phe- -Leu was 52-fold selective for site 1. Morphine had moderate affinity for site 1 (Ki = 16 nM), and was about 11-fold selective for site 1. Thus, of the 10 drugs studied, only DPDPE and DELT-I were selective for site 2. Viewed collectively with other data, it is likely that the δ1 receptor and the δncx binding site are synonymous.  相似文献   

14.
To study structure-activity relationships of growth hormone-releasing hormone (GHRH), a competitive binding assay was developed using cloned porcine adenopituitary GHRH receptors expressed in human kidney 293 cells. Specific binding of [His1,125I-Tyr10,Nle27]hGHRH(1–32)-NH2 increased linearly with protein concentration (10–45 μg protein/tube). Binding reached equilibrium after 90 min at 30°C and remained constant for at least 240 min. Binding was reversible to one class of high-affinity sites (Kd = 1.04 ± 0.19 nM, Bmax = 3.9 ± 0.53 pmol/mg protein). Binding was selective with a rank order of affinity (IC50) for porcine GHRH (2.8 ± 0.51 nM), rat GHRH (3.1 ± 0.69 nM), [N-Ac-Tyr1, -Arg2]hGHRH(3–29)-NH2 (3.9 ± 0.58 nM), and [ -Thr7]GHRH(1–29)-NH2 (189.7 ± 14.3 nM), consistent with their binding to a GHRH receptor. Nonhydrolyzable guanine nucleotides inhibited binding. These data describe a selective and reliable method for a competitive GHRH binding assay that for the first time utilizes rapid filtration to terminate the binding assay.  相似文献   

15.
WAY–100635 is the first selective, silent 5–HT1A (5-hydroxytryptamine1A, serotonin-1A) receptor antagonist. We have investigated the use of [3H]WAY–100635 as a quantitative autoradiographic ligand in post-mortem human hippocampus, raphe and four cortical regions, and compared it with the 5–HT1A receptor agonist, [3H]8–OH–DPAT. Saturation studies showed an average Kd for [3H]WAY–100635 binding in hippocampus of 1.1 nM. The regional and laminar distributions of [3H]WAY–100635 binding and [3H]8–OH–DPAT binding were similar. The density of [3H]WAY–100635 binding sites was 60–70% more than that of [3H]8–OH–DPAT in all areas examined except the cingulate gyrus where it was 165% higher. [3H]WAY–100635 binding was robust and was not affected by the post-mortem interval, freezer storage time or brain pH (agonal state). Using [3H]WAY–100635, we confirmed an increase of 5–HT1A receptor binding sites in the frontal cortex in schizophrenia, previously demonstrated with [3H]8–OH–DPAT. Compared to [3H]8–OH–DPAT, [3H]WAY–100635 has two advantages: it has a higher selectivity and affinity for the 5–HT1A receptor, and it recognizes 5–HT1A receptors whether or not they are coupled to a G-protein, whereas [3H]8–OH–DPAT primarily detects coupled receptors. Given these considerations, the [3H]WAY–100635 binding data in schizophrenia clarify two points. First, they indicate that the elevated [3H]8–OH–DPAT binding seen in the same cases is attributable to an increase of 5–HT1A receptors rather than any other binding site. Second, the enhanced [3H]8–OH–DPAT binding in schizophrenia reflects an increased density of 5–HT1A receptors, not an increased percentage of 5–HT1A receptors which are G-protein-coupled. We conclude that [3H]WAY–100635 is a valuable autoradiographic ligand for the qualitative and quantitative study of 5–HT1A receptors in the human brain.  相似文献   

16.
S. Harvey  S. Hayer 《Peptides》1993,14(6):1187-1191
Parathyroid hormone (PTH) has been shown to have actions within the brain, suggesting the presence of central PTH receptors. This possibility was examined by determining the binding of 125I-labeled [Nle8,18,Tyr34]bovine PTH to the plasma membranes of rat and rabbit brains. Specific binding of the tracer to membranes of the whole brain was time and tissue dependent, and was greater with membranes from the hypothalamus than with membranes from the cerebellum, cerebrum, or brain stem. The binding of the tracer to rat hypothalamic membranes was saturable and competitively displaced by unlabeled PTH(1–34), PTH(3–34), [Nle8,18,Tyr34]PTH(1–34), and by PTH-related protein, indicating the presence of a single class of high-affinity (dissociation constant = 2–5 nM), low-capacity (maximum binding capacity, Bmax = 110–250 fmol/mg protein) binding site. The binding of radiolabeled PTH to these sites was not displaced by unrelated peptides of comparable molecular size (calcitonin, calcitonin-gene related peptide, adrenocorticotropin). The binding of PTH to these sites did not, however, appear to stimulate adenylate cyclase activity, as in peripheral PTH target sites. Thus, although these results indicate the presence of PTH receptors in the brain, these binding sites have a lower affinity than those in peripheral tissues and may utilize a different signal transduction system.  相似文献   

17.
Guo RW  Yang LX  Li MQ  Liu B  Wang XM 《Peptides》2006,27(12):3269-3275
Angiotensin II (Ang II) is the main active peptide of the renin–angiotensin system (RAS), producing a number of inflammatory mediators that lead to endothelial dysfunction and the progression of atherosclerosis. Ang II-induced NF-κB nuclear translocation plays a pivotal role in this response. This study examines the NF-κB activation mechanism elicited by Ang II in human umbilical vein endothelial cells (HUVEC). Electrophoretic mobility shift assays and Western blotting revealed that Ang II, signaling via AT1, produces a time-dependent increase in NF-κB DNA binding and IκB degradation. These results also demonstrate that Ang II leads to MAPK phosphorylation and p38MAPK pathway-induced NF-κB activation. Furthermore, AT1 is required for p38MAPK phosphorylation induced by Ang II. This study provides evidence that Ang II elicits NF-κB activation via the p38MAPK pathway in HUVEC.  相似文献   

18.
Angiotensin II receptor binding sites in rat liver and PC12 cells differ in their affinities for a nonpeptidic antagonist, DuP 753, and p-aminophenylalanine6 angiotensin II. In liver, which primarily contains the sulfhydryl reducing agent-inhibited type of angiotensin II receptor, which we refer to as the AII alpha subtype, DuP 753 displays an IC50 of 55 nM, while p-aminophenylalanine6 angiotensin II displays an IC50 of 8-9 microM. In PC12 cells, which primarily contain the angiotensin II receptor type whose binding affinity is enhanced by sulfhydryl reducing agents (AII beta), DuP 753 displays an IC50 in excess of 100 microM, while p-aminophenylalanine6 angiotensin II displays an IC50 of 12 nM. p-Aminophenylalanine6 angiotensin II binding affinity in liver is decreased in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) suggesting that this analogue is an agonist.  相似文献   

19.
The effects of a 3-day water deprivation were studied in adult female rats in order to know what are the different zones of the adrenal gland and the hormonal factors involved in the growth and the activity of the adrenal gland. Water deprivation significantly increased plasma renin activity (PRA), plasma Angiotensin II (AII), vasopressin (AVP), epinephrine, aldosterone and corticosterone concentrations but did not modify the plasma adrenocorticotropin hormone (ACTH) level. Water deprivation significantly increased the absolute weight of the adrenal capsule containing the zona glomerulosa without modification of the density of cells per area unit suggesting that the growth of the adrenal capsule was due to a cell hyperplasia of the zona glomerulosa. Water deprivation significantly increased the density of AII type 1 (AT1) receptors in the adrenal capsule but did not modify the density of AII type 2 (AT2) receptors in the adrenal capsule and core containing the zona fasciculata, the zona reticularis and the medulla. The treatment of dehydrated female rats with captopril, which inhibits the angiotensin converting enzyme (ACE) in order to block the production of AII, significantly decreased the absolute weight of the adrenal capsule, plasma aldosterone and the density of AT1 receptors in the adrenal capsule. The concentration of corticosterone in the plasma, the density of AT2 receptors and the density of cells per unit area in the zona glomerulosa of the adrenal capsule were not affected by captopril-treatment. In conclusion, these results suggest that AII seems to be the main factor involved in the stimulation of the growth and the secretion of aldosterone by the adrenal capsule containing the zona glomerulosa during water deprivation. The low level of plasma ACTH is not involved in the growth of the adrenal gland but is probably responsible for the secretion of corticosterone by the zona fasciculata.  相似文献   

20.
Bhargava, H. N., V. M. Villar, J. Cortijo and E. J. Morcillo. Binding of [3H][D-Ala2, MePhe4, Gly-ol5]enkephalin, [3H][D-Pen2, D-Pen5]enkephalin, and [3H]U-69,593 to airway and pulmonary tissues of normal and sensitized rats. Peptides 18(10) 1603–1608, 1997.—The role of endogenous opioid peptides in the regulation of bronchomotor tone, as well as in the pathophysiology of asthma is uncertain. We have studied the binding of highly selective [3H]labeled ligands of μ-([D-Ala2, MePhe4, Gly-ol5]enkephalin; DAMGO), δ ([D-Pen2, D-Pen5]enkephalin; DPDPE), and κ-(U-69,593) opioid receptors to membranes of trachea, main bronchus, lung parenchyma and pulmonary artery obtained from normal (unsensitized) and actively IgE-sensitized rats acutely challenged with the specific antigen. [3H]DAMGO, [3H]DPDPE and [3H]U-69,593 bound to membranes of normal and sensitized tissues at a saturable, single high-affinity site. The rank order of receptor densities in normal tissues was δ- ≥ κ- ≥ μ-, with lung parenchyma exhibiting the greatest binding capacity for δ- and μ- receptors compared to the other regions examined. The Kd values showed small differences between ligands and regions tested. The μ- and δ-opioid receptor densities were decreased in sensitized main bronchus and lung parenchyma, respectively, compared to normal tissues. By contrast, κ-opioid receptor density was augmented in sensitized lung parenchyma but an increase in Kd values was also observed. These differential changes in the density and affinity of opioid receptor types may be related to alterations in endogenous opioid peptides during the process of sensitization.  相似文献   

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