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Results for “Mice, Knockout”

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At least 235 records · Page 13Linked to original sources

PubMed1997

p53-knockout mice are protected against the long-term effects of methamphetamine on dopaminergic terminals and cell bodies.

p53-knockout mice provide a useful model to test the role of p53 in the neurotoxic effects of drugs in vivo. To test the involvement of p53 in methamphetamine (METH)-induced toxicity, wild-type mice, as well as heterozygous and homozygous p53-knockout male mice, were administered four injections of three different doses (2.5, 5.0, and 10.0 mg/kg) of the drug given at 2-h intervals within the space of 1 day. METH caused a marked dose-dependent loss of dopamine transporters in both the striatum and the nucleus accumbens of wild-type mice killed 2 weeks after drug administration. However, this METH-induced decrease in dopamine transporters was attenuated in both homozygous and heterozygous p53-knockout mice, with homozygous animals showing significantly greater protection. The possibility for p53 involvement in METH-induced toxicity was also supported by the observation that METH caused marked increases in p53-like immunoreactivity in the striata of wild-type mice and very little change in heterozygous p53-knockout mice, whereas no p53-like immunostaining was detected in the homozygous p53-knockout mice. Further support for p53 involvement was provided by the fact that METH treatment caused significant decreases in dopamine transporter mRNA and the number of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and the ventral tegmental area of wild-type but not homozygous p53-knockout mice killed 2 weeks after cessation of METH administration. These results provide concordant evidence for a role of the tumor suppressor, p53, in the long-term deleterious effects of a drug acting on brain dopamine systems.

Animals↗

PubMed2005

Tendon healing in interleukin-4 and interleukin-6 knockout mice.

Cytokines have been shown to play an important role in tendon and ligament healing by regulating cellular differentiation and activity. The majority of studies that have investigated the role of cytokines in tendon and ligament healing have added them to injured tissue and assessed their effect. Because the efficacy of exogenously applying cytokines is dependent upon many factors such as the correct dosage, timing, and frequency, conflicting results are often reported. To avoid these factors, this study used transgenic mice with knockouts of interleukin-4 (IL4 -/-) and interleukin-6 (IL6 -/-) to investigate their role in tendon healing. Because of the reported roles of both of these cytokines in inflammation and fibroplasia, it was hypothesized that the order of organizational, geometric, and mechanical properties would be (greatest to least) injured IL6 -/-, injured control, and injured IL4 -/- mice. In addition, it was hypothesized that specific cytokines would be upregulated in each knockout group, but not compensate for the lack of IL-4 or IL-6. Mechanical and organizational properties of injured tendons from IL6 -/- mice were inferior to that of control and IL4 -/- mice despite the upregulation of the pro-inflammatory cytokine TNF-alpha. Temporal levels of IL-10 and IL-13 in the IL4 -/- mice resulted in comparable and even superior properties when compared to CTL mice. This study shows that IL-6 could not be compensated for and plays an important role in tendon healing. This study also supports the use of this animal model to further investigate tendon healing.

Animals↗

PubMed2006

Physiological roles of AQP7 in the kidney: Lessons from AQP7 knockout mice.

The aquaporin7 (AQP7) water channel is known to be a member of the aquaglyceroporins, which allow the rapid transport of glycerol and water. AQP7 is abundantly present at the apical membrane of the proximal straight tubules in the kidney. In this paper, we review the physiological functions of AQP7 in the kidney. To investigate this, we generated AQP7 knockout mice. The water permeability of the proximal straight tubule brush border membrane measured by the stopped flow method was reduced in AQP7 knockout mice compared to wild-type mice (AQP7, 18.0+/-0.4 x 10(-3 )cm/s vs. wild-type, 20.0+/-0.3 x 10(-3) cm/s). Although AQP7 solo knockout mice did not show a urinary concentrating defect, AQP1/AQP7 double knockout mice showed reduced urinary concentrating ability compared to AQP1 solo knockout mice, indicating that the contribution of AQP7 to water reabsorption in the proximal straight tubules is physiologically substantial. On the other hand, AQP7 knockout mice showed marked glycerol in their urine (AQP7, 1.7+/-0.34 mg/ml vs. wild-type, 0.005+/-0.002 mg/ml). This finding identified a novel pathway of glycerol reabsorption that occurs in the proximal straight tubules. In two mouse models of proximal straight tubule injury, the cisplatin-induced acute renal failure (ARF) model and the ischemic-reperfusion ARF model, an increase of urine glycerol was observed (pre-treatment, 0.007+/-0.005 mg/ml; cisplatin, 0.063+/-0.043 mg/ml; ischemia, 0.076+/-0.02 mg/ml), suggesting that urine glycerol could be used as a new biomarker for detecting proximal straight tubule injury.

Acute Kidney Injury↗

PubMed2005

Intrathecally-administered histamine facilitates nociception through tachykinin NK1 and histamine H1 receptors: a study in histidine decarboxylase gene knockout mice.

Intrathecal injection of histamine elicited behavioral responses consisting of scratching, biting and licking in conscious mice. To study the participation of histamine in pain perception, histidine decarboxylase knockout mice were examined for pain threshold by means of three different kinds of noxious stimuli: thermal nociception (hot-plate, tail-flick, and paw-withdrawal), mechanical nociception (tail-pressure), and chemical nociception (formalin test and capsaicin test). Mutant mice lacking histidine decarboxylase showed significantly fewer nociceptive responses to the hot-plate, tail-flick, paw-withdrawal, tail-pressure, formalin and capsaicin tests. Sensitivity to noxious stimuli in the histidine decarboxylase knockout mice was significantly lower when compared to the wild-type mice. The intrathecally-administered histamine (400 pmol) significantly shortened the latency in the histidine decarboxylase knockout mice, but not in the wild-type mice in tail-flick tests. Pyrilamine, a histamine H(1) receptor antagonist, but not ranitidine, a histamine H(2) receptor antagonist, produced inhibition of the induced behavioral responses in the tail-flick test when co-administered with histamine. Sendide, a tachykinin NK(1) receptor antagonist, inhibited histamine-induced nociceptive behavior in the histidine decarboxylase knockout mice. In contrast, the treatment with D-(-)-2 amino-5-phosponovaleric acid (D-APV), an N-methyl-D-aspartate (NMDA) receptor antagonist, did not prevent the induction of the behavioral responses by histamine. These studies substantiate the evidence that nociceptive behavior induced by intrathecal injection of histamine is largely mediated through tachykinin NK(1) and histamine H(1) receptors in the spinal cord.

2-Amino-5-phosphonovalerate↗

PubMed2002

Muscarinic receptor knockout mice: role of muscarinic acetylcholine receptors M(2), M(3), and M(4) in carbamylcholine-induced gallbladder contractility.

Muscarinic receptors play a major role in gallbladder function, although the muscarinic receptor(s) mediating smooth muscle contractility is unclear. This study compared smooth muscle contractile responses to carbamylcholine (10(-7)-10(-3) M) in isolated gallbladder from wild-type and M(2), M(3), and M(4) receptor knockout mice. Carbamylcholine-induced contraction in gallbladder was associated with tachyphylaxis and the release of a cyclooxygenase product because indomethacin (10(-6) M) inhibited carbamylcholine-induced contraction. The M(3) receptor was the major muscarinic receptor involved in contraction because carbamylcholine-induced contractility was inhibited in gallbladder from M(3) receptor knockout mice. Furthermore, the muscarinic receptor antagonists 11-[[[2-diethylamino-O-methyl]-1-piperidinyl]acetyl]-5,11-dihydrol-6H-pyridol[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) and pirenzepine dextrally shifted contraction to carbamylcholine in gallbladder from wild-type, M(2), and M(4) receptor knockout mice, with affinities consistent with M(3) receptor interaction. In addition, maximal contraction to carbamylcholine was reduced in gallbladder from M(2) receptor knockout mice and affinities for AF-DX 116 and pirenzepine in gallbladder from M(3) receptor knockout mice were consistent with their affinities at M(2) receptors. In M(4) receptor knockout mice, contraction to carbamylcholine was dextrally shifted, although the affinities for AF-DX 116 and pirenzepine in gallbladder from M(2) or M(3) knockout mice were not similar to their affinities at M(4) receptors. The M(4) receptor may serve as an accessory protein necessary for optimal potency of M(2) and M(3) receptor-mediated responses. Thus, muscarinic receptor knockout mice provided direct and unambiguous evidence that M(3), and to a lesser extent, M(2) receptors are the predominant muscarinic receptors mediating gallbladder contractility, and M(4) receptors appear necessary for optimal potency of carbamylcholine in gallbladder contraction.

Animals↗

PubMed1998

Fourfold reduction of water permeability in inner medullary collecting duct of aquaporin-4 knockout mice.

Aquaporin (AQP)-3 and AQP4 water channels are expressed at the basolateral membrane of mammalian collecting duct epithelium. To determine the contribution of AQP4 to water permeability in the initial inner medullary collecting duct (IMCD), osmotic water permeability (Pf) was compared in isolated perfused IMCD segments from wild-type and AQP4 knockout mice. The AQP4 knockout mice were previously found to have normal gross appearance, survival, growth, and kidney morphology and a mild urinary concentrating defect (T. Ma, B. Yang, A. Gillespie, E. J. Carlson, C. J. Epstein, and A. S. Verkman, J. Clin. Invest. 100: 957-962, 1997). Transepithelial Pf was measured in microdissected IMCDs after 18-48 h of water deprivation and in the presence of 0.1 nM arginine vasopressin (to make basolateral Pf rate limiting). Pf values (37 degrees C; means +/- SE in cm/s x 10(-3)) were 56.0 +/- 8.5 for wild-type mice (n = 5) and 13.1 +/- 3.7 for knockout mice (n = 6) (P < 0.001). Northern blot analysis of kidney showed that transcript expression of AQP1, AQP2, AQP3, and AQP6 were not affected by AQP4 deletion. Immunoblot analysis indicated no differences in protein expression of AQP1, AQP2, or AQP3, and immunoperoxidase showed no differences in staining patterns. Coexpression of AQP3 and AQP4 in Xenopus laevis oocytes showed additive water permeabilities, suggesting that AQP4 deletion does not affect AQP3 function. These results indicate that AQP4 is responsible for the majority of basolateral membrane water movement in IMCD but that its deletion is associated with a very mild defect in urinary concentrating ability.

Animals↗

PubMed1999

Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice.

5,6-Dimethylxanthenon-4-acetic acid (DMXAA) is a new antitumor drug currently undergoing clinical trial. Administration of DMXAA to mice with tumors leads to cessation of tumor blood flow and the onset of tumor hemorrhagic necrosis, accompanied by the production of the cytokine tumor necrosis factor (TNF). Previous studies have shown that DMXAA induces both tumor and host cells to synthesize TNF and that induced intratumoral TNF production correlates with the antitumor activity of DMXAA. To explore the hypothesis that TNF production by tumor cells contributed to the induction of hemorrhagic necrosis by DMXAA, TNF-/- (C57Bl/6 background) mice were used as recipients for the s.c. implantation of (TNF positive) colon 38 adenocarcinoma. Tumors removed 24 h after treatment with DMXAA (66 or 100 micromol/kg) were found to be hemorrhagic and necrotic. Cells expressing TNF mRNA in tumors removed 2 h after treatment with DMXAA (160 micromol/kg) were found by in situ hybridization to be comparable in frequency and distribution with those in tumors from C57Bl/6 TNF-positive mice. However, the amount of TNF protein extracted from tumors from TNF knockout mice was lower than that from TNF-positive mice. Spleen and liver tissue from TNF knockout mice, in contrast to that from TNF-positive mice, produced no TNF mRNA. TNF protein was undetectable in liver and spleen tissue from TNF knockout mice, but was evident in tissue from TNF-positive mice. These results confirm that DMXAA has the novel ability of inducing tumors to synthesize TNF in situ.

Adenocarcinoma↗

PubMed2002

High-level expression of receptor tyrosine kinase Ret and responsiveness to Ret-activating ligands in pheochromocytoma cell lines from neurofibromatosis knockout mice.

Pheochromocytoma cell lines derived from neurofibromatosis knockout mice express high levels of the receptor tyrosine kinase Ret, which is involved in the pathogenesis of human pheochromocytomas in hereditary multiple endocrine neoplasia syndrome type 2 (MEN2). Mouse pheochromocytoma (MPC) cells respond to the Ret-activating ligand GDNF by exhibiting Ret phosphorylation, neurite outgrowth, decreased proliferation, and altered expression of catecholamine biosynthetic enzymes. GDNF exerts similar effects on human pheochromocytoma cells in primary cultures. Ret is minimally expressed by normal mouse chromaffin cells, from which pheochromocytomas are derived. Its expression at high levels by MPC cells suggests possible relationships between two previously unrelated tumor syndromes, neurofibromatosis, and MEN2. The responsiveness of these cells to GDNF suggests that they may be a valuable new model for neurobiology.

Animals↗

PubMed1999

Altered baroreflex control of heart rate in bradykinin B2-receptor knockout mice.

Recently, we have shown that a knockout mouse strain lacking the bradykinin B2-receptor gene exhibits an accelerated heart rate (HR) under basal conditions, this alteration being associated with mildly elevated blood pressure (BP) levels and ultimately with the development of cardiomyopathy. The goal of the present study was to determine whether genetic disruption of the B2-receptor alters autonomic cardiovascular reflexes to acute or chronic changes in BP. The direct mean BP and HR levels of unrestrained B2 knockout mice (B2-/-) were higher than those of wild type (B2+/+) controls (131 +/- 2 vs. 105 +/- 2 mm Hg and 480 +/- 5 vs. 414 +/- 8 beats/min, P < 0.01 for both comparisons). The difference in HR observed between groups under basal conditions was nullified by the acute administration of propranolol and atropine as well as by hexamethonium; it was attenuated by long-term blockade of angiotensin AT1 receptors. In B2-/- mice, the presence of an alteration in baroreceptor regulation of HR was supported by a reduced gain in the HR responses to acute nitroprusside-induced hypotension or phenylephrine-induced hypertension (slope of the regression line: 0.82 +/- 0.07 vs. 5.58 +/- 0.08 beats/min per mmHg in B2+/+, P < 0.01), as well as by an exaggerated tachycardic response to chronic hypertension induced by clipping of the left renal artery (60 +/- 3 vs. 15 +/- 3 beats/min in B2+/+, P < 0.01). Our findings indicate that disruption of the bradykinin B2-receptor gene is associated with an impaired baroreflex control of HR. The combination of chronically elevated resting HR and impaired baroreflex control could contribute to the development of cardiomyopathy in these animals.

Anesthetics↗

PubMed2005

Lower force and impaired performance during high-intensity electrical stimulation in skeletal muscle of GAMT-deficient knockout mice.

Force characteristics of skeletal muscle of knockout mice lacking creatine (Cr) due to a deletion of guanidinoacetate methyltransferase (GAMT) were studied in situ. Medial gastrocnemius muscles of anesthetized GAMT-deficient (GAMT-/-) and control (Con) littermates were stimulated at optimum length via the sciatic nerve at different stimulation frequencies (60-250 Hz). GAMT-/- mice showed reduced maximal tetanic and twitch force, reduced relative force at 60 Hz, and increased relaxation times. High-intensity fatigue protocols consisting of 30 successive isometric or dynamic contractions showed a strong reduction in force at the beginning of the series in GAMT-/- mice, followed by a smaller reduction compared with Con littermates toward the end of the series. Cr supplementation for 2 days in GAMT-/- animals (GAMT(Cr)-/-) resulted in normalization to Con values for relaxation times, relative force at lower stimulation frequencies, and relative force during 30 isometric contractions. Force per muscle mass, however, remained decreased. Furthermore,GAMT(Cr)-/- mice showed differences compared with both Con and unsupplemented animals in maximal rates of force rise and relaxation times during the isometric protocol as well as in force during the dynamic protocol. Our results show that the absence of Cr plays a direct role in relaxation times, maximal rate of force rise, and force production during high-intensity fatigue protocols. The lower force per muscle mass, however, is probably caused by other factors; i.e., high intracellular guanidinoacetate concentrations.

Animals↗

PubMed2001

Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B(2) kinin receptor gene knockout mice.

Using B(2) kinin receptor gene knockout mice (B(2)(-/-)), we tested the hypothesis that (l) lack of B(2) receptors may affect blood pressure and cardiac function and aggravate cardiac remodeling after myocardial infarction (MI), and (2) kinins partially mediate the cardiac beneficial effect of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant), whereas lack of B(2) receptors may diminish this cardioprotective effect. Chronic heart failure (HF) was induced by MI, which was caused by coronary artery ligation in both B(2)(-/-) and 129/SvEvTac mice (wild-type control, B(2)(+/+)). An ACEi (ramipril, 2.5 mg/kg/d) or AT(1)-ant (L-158809, 3 mg/kg/d) was given 1 week after MI and was continued for 12 weeks. Left ventricular (LV) ejection fraction, cardiac output (CO), diastolic LV dimension (LVDd), and LV mass were evaluated by echocardiography. Myocyte cross-sectional area and interstitial collagen fraction were studied histopathologically. We found that basal blood pressure and cardiac function were similar in B(2)(+/+) and B(2)(-/-) mice. After MI, development of HF and remodeling were also similar between the 2 strains. The ACEi improved cardiac function and remodeling in both strains; however, its effects were attenuated in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 64+/-10% versus 21+/-5% [P<0.01]; increase in CO, 69+/-17% versus 23+/-9% [P<0.01]; overall decrease in LVDd, -24+/-3% versus -7+/-4% [P<0.01]; and decrease in LV mass, -38+/-3% versus -6+/-6% [P<0.01]). AT(1)-ant had a beneficial cardiac effect similar to that produced by ACEi, and this effect was also diminished in B(2)(-/-) mice (respective values for B(2)(+/+) versus B(2)(-/-) mice: overall increase in ejection fraction, 46+/-10% versus 25+/-9% [P<0.01]; increase in CO, 44+/-14% versus 15+/-5% [P<0.01]; overall decrease in LVDd, -14+/-4% versus -6+/-3% [P<0.01]; and decrease in LV mass, -33+/-4 versus -16+/-7% [P<0.01]). The effect of ACEi or AT(1)-ant on myocyte cross-sectional area was similar between strains; however, their effect on the interstitial collagen fraction was diminished in B(2)(-/-) mice. We concluded that (1) lack of B(2) kinin receptors does not affect cardiac phenotype or function, either under normal physiological conditions or during the development of HF; and (2) kinins acting via the B(2) receptor play an important role in the cardioprotective effect of ACEi and AT(1)-ant.

Angiotensin Receptor Antagonists↗

PubMed2003

Inhibition of oxytocin receptor and estrogen receptor-alpha expression, but not relaxin receptors (LGR7), in the myometrium of late pregnant relaxin gene knockout mice.

This study used relaxin (RLX) gene knockout mice (Rlx-/-) to investigate the effects of RLX on myometrial oxytocin receptor (OTR) and estrogen receptor (ER)-alpha gene expression in late gestation. We also characterized the temporal expression of the RLX receptor (LGR7) and demonstrated gene transcripts in the myometrium of Rlx+/+ and Rlx-/- mice. There was a significant (P < 0.05) decrease in myometrial LGR7 gene expression on d 17.5 and 18.5 post coitum (pc) compared with earlier stages of gestation, but no differences between Rlx+/+ and Rlx-/- mice. Myometrial OTR mRNA levels increased at the end of gestation in Rlx+/+ but not Rlx-/- mice. ERalpha gene expression was up-regulated on d 14.5 pc in Rlx+/+ mice, with mRNA levels remaining high throughout late gestation. In contrast, ERalpha mRNA levels were significantly lower in Rlx-/- mice on d 14.5 and 18.5 pc. These data show that the increases in myometrial OTR and ERalpha expression in late pregnant Rlx+/+ mice were attenuated in Rlx-/- mice. The effects of RLX on OTRs are probably mediated via activation of ERalpha. Finally, RLX receptor expression in the myometrium of Rlx-/- mice did not differ from wild-type mice, implying that RLX does not influence expression of its receptor.

Animals↗

PubMed2004

Forefront of Na+/Ca2+ exchanger studies: role of Na+/Ca2+ exchanger--lessons from knockout mice.

We used Na+/Ca2+ exchanger (NCX) knockout mice to evaluate the effects of NCX in cardiac function and the infarct size after ischemia/reperfusion injury. The contractile function in NCX KO mice hearts was significantly better than that in wild type (WT) mouse hearts after ischemia/reperfusion and the infracted size was significantly smaller in NCX KO mice hearts compared with that in WT mice hearts. NCX is critically involved in the development of ischemia/reperfusion-induced myocardial injury, and therefore the inhibition of NCX function may contribute to cardioprotection against ischemia/reperfusion injury.

Animals↗

PubMed2002

Enhanced antinociception by intrathecally-administered morphine in histamine H1 receptor gene knockout mice.

We previously reported that histamine H(1) receptor gene knockout mice (H1KO) showed lower spontaneous nociceptive threshold to pain stimuli when compared to wild-type mice. The objective of the present study was to examine the antinociceptive effect of intrathecally-administered morphine in H1KO mice. The antinociceptive effects of morphine were examined using assays for thermal (tail-flick, hot-plate, paw-withdrawal), mechanical (tail-pressure) and chemical nociception (formalin and capsaicin tests) using H1KO and wild-type mice. In these nociceptive assays, intrathecally-administered morphine produced significant antinociceptive effects in wild-type mice. The antinociceptive effect produced by intrathecally administered morphine was enhanced in the knockout mice. We also examined the effect of an histamine H(1) receptor antagonist, an active (d-) isomer of chlorpheniramine, on morphine-induced antinociception in ICR mice. The intrathecal co-administration of d-chlorpheniramine enhanced the effect of morphine in all nociceptive assays examined. The pharmacological experiments using d-chlorpheniramine further substantiate the evidence for the histamine H(1) receptor-mediated suppression of morphine-induced antinociception. These results suggest that existing H(1) receptors play an inhibitory role in morphine-induced antinociception at the spinal cord level.

Analgesics↗

PubMed2003

Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice.

Several studies have shown a functional relationship between the endogenous cannabinoid and opioid systems. However, acute effects of Delta9-tetrahydrocannabinol (THC) and physical dependence were not modified in knockout mice with single deletion of mu (MOR), delta (DOR) or kappa (KOR) opioid receptors. To further investigate the neurobiological basis of cannabinoid dependence, we have evaluated acute pharmacological responses, rewarding effects, tolerance and dependence to THC in double MOR/DOR knockout mice. Antinociception and hypolocomotion induced by acute THC administration remained unaffected, whereas the hypothermic effect was slightly attenuated in these double knockout mice. During chronic THC treatment, knockout mice developed slower tolerance to the hypothermic effect, but the development of tolerance to antinociceptive and hypolocomotor effects was unchanged. The rewarding properties of THC, measured in the conditioned place preference paradigm, were reduced in knockout mice. Interestingly, the somatic manifestations of THC withdrawal were also significantly attenuated in mutant mice, suggesting that a cooperative action of MOR and DOR is required for the entire expression of THC dependence.

Analgesics, Non-Narcotic↗

PubMed1999

P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdr1a knockout mice.

PURPOSE: This study was performed to evaluate the involvement of P-glycoprotein in disposition kinetics of tacrolimus (FK506), a substrate of P-glycoprotein, in the body. METHODS: The blood and tissue concentrations of FK506 after i.v. or p.o. administration (2 mg/kg) to normal and mdr1a knockout mice were measured by competitive enzyme immunoassay. RESULTS: The blood concentrations in knockout mice were significantly higher than those in normal mice. The value of the total clearance (CLtot) for knockout mice (19.3 mL/min/kg) was about 1/3 of that for normal mice (55.8 mL/min/kg)(P < 0.001), although there was no significant difference in the distribution volume at the steady-state (Vd(ss)) (about 4.6 L/kg) between both types of mice. FK506 rapidly penetrated the blood-brain barrier and the brain concentration reached a maximum, which was about 10 times higher in knockout mice than in normal mice, 1 hr after administration. The brain concentration in normal mice thereafter decreased slowly, whereas in knockout mice, an extremely high concentration was maintained for 24 hr. CONCLUSIONS: The pharmacokinetic behavior of FK506 in the tissue distribution is related with the function of P-glycoprotein encoded by the mdrla gene. The brain distribution of FK506 is dominated by the P-glycoprotein-mediated drug efflux and presumably also by the binding to FK-binding proteins (immunophilins) in the brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Methamphetamine sensitization in nociceptin receptor knockout mice: locomotor and c-fos expression.

The role of endogenous nociceptin in the development and expression of sensitization to repeated methamphetamine administration in a novel environment was studied in nociceptin receptor knockout mice. No differences in acute or sensitized locomotor responses were found in nociceptin receptor knockout mice. However, analysis of c-fos expression revealed significant interactions between chronic methamphetamine treatment and genotype in the nucleus accumbens and lateral septum. This was due to increased c-fos expression in chronically methamphetamine-treated nociceptin receptor knockout mice contrasted with reduced c-fos expression in chronically vehicle-treated nociceptin receptor knockout mice. Two further regions (nucleus accumbens core and ventromedial caudate putamen) showed significant interactions between genotype, chronic, and acute methamphetamine treatment due to accentuated c-fos expression in nociceptin receptor knockout mice sensitized and challenged with methamphetamine. These findings suggest endogenous nociceptin modulates the response of the central nervous system to repeated psychostimulant administration, although this is little reflected in locomotion.

Animals↗

PubMed2000

Defective fluid and HCO(3)(-) absorption in proximal tubule of neuronal nitric oxide synthase-knockout mice.

Using renal clearance techniques and in situ microperfusion of proximal tubules, we examined the effects of N(G)-monomethyl-L-arginine methyl ester (L-NAME) on fluid and HCO(3)(-) transport in wild-type mice and also investigated proximal tubule transport in neuronal nitric oxide synthase (nNOS)-knockout mice. In wild-type mice, administration of L-NAME (3 mg/kg bolus iv) significantly increased mean blood pressure, urine volume, and urinary Na(+) excretion. L-NAME, given by intravenous bolus and added to the luminal perfusion solution, decreased absorption of fluid (60%) and HCO(3)(-) (49%) in the proximal tubule. In nNOS-knockout mice, the urinary excretion of HCO(3)(-) was significantly higher than in the wild-type mice (3.12 +/- 0.52 vs. 1. 40 +/- 0.33 mM) and the rates of HCO(3)(-) and fluid absorption were 62 and 72% lower, respectively. Both arterial blood HCO(3)(-) concentration (20.7 vs. 25.7 mM) and blood pH (7.27 vs. 7.34) were lower, indicating a significant metabolic acidosis in nNOS-knockout mice. Blood pressure was lower in nNOS-knockout mice (76.2 +/- 4.6 mmHg) than in wild-type control animals (102.9 +/- 8.4 mmHg); however, it increased in response to L-NAME (125.5 +/- 5.07 mmHg). Plasma Na(+) and K(+) were not significantly different from control values. Our data show that a large component of HCO(3)(-) and fluid absorption in the proximal tubule is controlled by nNOS. Mice without this isozyme are defective in absorption of fluid and HCO(3)(-) in the proximal tubule and develop metabolic acidosis, suggesting that nNOS plays an important role in the regulation of acid-base balance.

Acid-Base Equilibrium↗