SEARCH · PubMed Health

Results for “Mice, Knockout”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 307 records · Page 17Linked to original sources

PubMed2000

Proliferation of hepatic lineage cells of normal C57BL and interleukin-6 knockout mice after cocaine-induced periportal injury.

The cellular response to periportal liver injury, induced by phenobarbital feeding and cocaine injection, is used to compare the restitutive proliferation of hepatocytes, cholangiocytes, and oval cells in the livers of normal control to those of interleukin-6 (IL-6) knockout mice. After this injury hepatocytes in noninjured middle and central zones start to proliferate first, followed by proliferation of cholangiocytes and intraportal oval cells. Proliferation of all cell types peaks at 2 days, but oval cells continue to proliferate and differentiate through days 4 and 6 as they reconstitute the necrotic zone. By day 10, the injured zone is completely repaired, and no dividing cells remain. During the first 3 to 4 days after injury, the number of proliferating hepatocytes, cholangiocytes, and sinusoidal cells is lower in IL-6 knockout mice than in normal mice, whereas the number of dividing oval cells is higher. However, overall repair of the injury is accomplished in the same time period in both groups. During repair of the periportal zone, oval cells acquire differentiation markers of hepatocytes as they cross the zone of injury. In conclusion, the phenobarbital/cocaine injury model is useful to study restitutive proliferation of mouse liver cell lineages. The proliferative response in IL-6 knockout mice shows that IL-6 is not required for proliferation of liver cells; timely repair of liver injury occurs in both normal and IL-6 knockout mice. Increased proliferation of oval cells in IL-6 knockout mice may compensate for the lower proliferation of other liver cell types.

Alanine Transaminase↗

PubMed2000

The cause of infertility of male c-ros tyrosine kinase receptor knockout mice.

Male homozygous transgenic c-ros knockout mice are sterile by natural mating, lack a part of their epididymis, and the epididymal sperm exhibit tail angulation in vivo and in vitro. To ascertain if this abnormal tail form caused the infertility, the number and nature of sperm in the tract of females mated to knockout and wild-type mice were determined. Percentage motility and numbers of sperm in the uterus 1 h after mating were similar between genotypes. The majority of the uterine sperm from the wild-type males had straight flagella, whereas 46-86% of knockout sperm were bent at the cytoplasmic droplet even when motile. Motile knockout sperm showed a 54 and 37% reduction in the straightline and curvilinear velocities compared with straight wild-type sperm. Sequential flushings of the oviduct 4 h after mating with the wild-type males contained sperm: 591 +/- 119 free, 371 +/- 70 loosely, and 122 +/- 47 tightly bound to the epithelium, but no knockout sperm were recovered from the oviduct or observed within the uterotubal junction in tissue sections. The infertility of c-ros knockout male mice can be explained by the sperm's inability to enter the oviduct, as a result of their bent tails forming the entangled sperm mass and their compromised flagellar vigor within the uterus.

Animals↗

PubMed2005

Adenosine-dopamine interactions revealed in knockout mice.

Neurochemical and pharmacological evidence obtained over the past 30 yr has indicated that adenosine and dopamine interact functionally in the basal ganglia and that such interactions have pathophysiological and therapeutic implications. The receptors implicated are adenosine A1 and A2A, and dopamine D1 and D2. There is evidence that dopamine D2 receptor activation in vivo antagonizes tonic activation of adenosine A2A receptors. Thus, acute blockade of dopamine D2 receptors, or disruption of dopamine transmission, unmasks strong adenosine A2A activation. Effects of dopamine D2 blockade are different after adenosine A2A blockade or in A2A knockout mice. Possibly as an adaptation to this increase in adenosine A2A signaling, there is a decreased coupling of A2A receptors to biological effects in dopamine D2 knockout mice. Compared to wild-type mice, adenosine A2A knockout mice show decreased neurodegeneration after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and show improved motor performance in models of Parkinson's disease Adenosine A1 receptors are not specifically located with any dopamine receptor, as is the A2A receptor with D2 receptors. Many A1 receptors are located presynaptically, where they regulate transmitter release. In A1 knockout mice, glutamatergic and dopaminergic transmission is therefore modified.

Adenosine↗

PubMed2000

Proprioceptive afferents survive in the masseter muscle of trkC knockout mice.

Peripheral innervation patterns of proprioceptive afferents from dorsal root ganglia and the mesencephalic trigeminal nucleus were assessed in trkC-deficient mice using immunohistochemistry for protein gene product 9.5 and parvalbumin. In trkC knockout mice, spinal proprioceptive afferents were completely absent in the limb skeletal muscles, M. biceps femoris and M. gastrocnemius, as previously reported. In these same animals, however, proprioceptive afferents from mesencephalic trigeminal nucleus innervated masseter muscles and formed primary endings of muscle spindles. Three wild-type mice averaged 35.7 spindle profiles (range: 31-41), six heterozygotes averaged 32.3 spindles (range: 27-41), and four homozygotes averaged 32.8 spindles (range: 26-42). Parvalbumin and Nissl staining of the brain stem showed approximately 50% surviving mesencephalic trigeminal sensory neurons in trkC-deficient mice. TrkC-/- mice (n = 5) had 309.4 +/- 15.9 mesencephalic trigeminal sensory cells versus 616.5 +/- 26.3 the sensory cells in trkC+/+ mice (n = 4). These data indicate that while mesencephalic trigeminal sensory neurons are significantly reduced in number by trkC deletion, they are not completely absent. Furthermore, unlike their spinal counterparts, trigeminal proprioceptive afferents survive and give rise to stretch receptor complexes in masseter muscles of trkC knockout mice. This indicates that spinal and mesencephalic trigeminal proprioceptive afferents have different neurotrophin-supporting system during survival and differentiation. It is likely that one or more other neurotrophin receptors expressed in mesencephalic trigeminal proprioceptive neurons of trkC knockout mice compensate for the lack of normal neurotrophin-3 signaling through trkC.

Animals↗

PubMed2003

Increased bone mineral density in the femora of GDF8 knockout mice.

GDF8 (myostatin), a member of the transforming growth factor (TGF)-beta superfamily of secreted growth and differentiation factors, is a negative regulator of skeletal muscle growth. GDF8 knockout mice have approximately twice the skeletal muscle mass of normal mice. The effects of increased muscle mass on bone modeling were investigated by examining bone mineral content (BMC) and bone mineral density (BMD) in the femora of female GDF8 knockout mice. Dual-energy X-ray absorptiometry (DEXA) densitometry was used to measure whole-femur BMC and BMD, and pQCT densitometry was used to calculate BMC and BMD from cross-sections taken at two different locations: the midshaft and the distal metaphysis. The DEXA results show that the knockout mice have significantly greater femoral BMD than normal mice. The peripheral quantitative computed tomography (pQCT) data indicate that the GDF8 knockout mice have approximately 10% greater cortical BMC (P =.01) at the midshaft and over 20% greater cortical BMC at the metaphysis (P <.001). Likewise, knockouts show approximately 10% greater cortical thickness (P <.001) and significantly greater cortical BMD (P <.001) at both locations. These results suggest that inhibitors of GDF8 function may be useful pharmacological agents for increasing both muscle mass and BMD.

Absorptiometry, Photon↗

PubMed2003

No further loss of dorsal root ganglion cells after axotomy in p75 neurotrophin receptor knockout mice.

The role of the p75 neurotrophin receptor for neuronal survival after nerve crush was studied in L5 dorsal root ganglia (DRG) of knockout mice and controls with assumption-free stereological methods. Numbers of neuronal A- and B-cells were obtained using the optical fractionator and optical disector techniques. At birth, the total number of DRG neurons was 10,000 +/- 2,600 in control mice compared with 5,100 +/- 1,300 in p75 knockout mice. During postnatal development, 1,400 neuronal B-cell bodies were lost in p75 knockouts (2P < 0.05) and 1,100 in controls (NS), whereas the A-cell population remained stable. After a sciatic nerve crush, the total neuron loss in controls was 15.4% +/- 3.5% (2P < 0.05) and 22.7% +/- 5.1% (2P < 0.05) at days 14 and 42, respectively. In contrast, there was no loss in total number of neurons after crush in p75 knockout mice. Neuronal A-cell number was unchanged after the crush in p75 knockouts as well as in controls at both times. At 14 days, the population of B-cells was reduced by 24.8% +/- 3.6% in controls and by 6.1% +/- 3.5% in p75 knockouts, this difference being significant (2P < 0.001). At 42 days, the B-cell loss was 29.6% +/- 5.5% in controls and 4.2% +/- 6.4% in p75 knockouts (2P < 0.001). In conclusion, the lack of the p75 receptor results in neuronal DRG cells that are resistant to nerve injury, pointing to a role for the receptor in apoptosis.

Animals↗

PubMed2003

Involvement of cholinergic and gabaergic systems in the fragile X knockout mice.

Fragile X syndrome is an inherited cause of mental retardation. We used extra- and intracellular recordings in brain slices obtained from wild type and fragile X knockout mice to establish whether bath application of the cholinergic agent carbachol (5 microM) induces different responses in neurons of the subiculum, a limbic structure involved in learning and memory. We found that carbachol diminished excitatory post-synaptic responses induced by CA1 stratum radiatum stimulation in wild type mice, but caused an unexpected increase in knockout animals. Moreover, these responses augmented in knockout mice after carbachol washout, a phenomenon that resembled the muscarinic long-term potentiation seen in wild type mice during application of carbachol and GABA(A) receptor antagonists. We also used paired-pulse stimulation to determine whether the changes in synaptic excitability induced by carbachol were caused by pre- or post-synaptic mechanism. Under control conditions, this protocol induced facilitation in both wild type and knockout mice; in contrast, during carbachol application, this facilitatory effect was seen in wild type mice only. In conclusion, our data highlight for the first time differences in cholinergic and GABA-ergic mechanisms that may contribute to the phenotype of fragile X patients.

Animals↗

PubMed2000

Hemodynamic changes in apolipoprotein E-knockout mice.

Apolipoprotein E-knockout (ApoE-KO) mice develop advanced atherosclerotic lesions by 1 yr of age and have been well characterized pathologically and morphologically, but little is known regarding their cardiovascular physiology and hemodynamics. We used noninvasive Doppler ultrasound to measure aortic and mitral blood velocity and aortic pulse-wave velocity in 13-mo-old ApoE-KO and wild-type (WT) mice anesthetized with isoflurane. In other mice from the same colony, we measured systolic blood pressure, body weight, heart weight, cholesterol, and hematocrit. Heart rate and blood pressure were comparable (P = not significant) between ApoE-KO and WT mice, but significant decreases (P < 0.001) were found in body weight (-22%) and hematocrit (-11%), and significant increases were found in heart weight (+23%), aortic velocity (+60%), mitral velocity (+81%) (all P < 0.001), and pulse-wave velocity (+13%, P < 0.05). We also found inflections in the aortic arch velocity signal consistent with enhanced peripheral wave reflection. Thus ApoE-KO mice have phenotypic alterations in indexes of peripheral vascular resistance and compliance and significantly elevated cardiac outflow velocities and heart weight-to-body weight ratios.

Animals↗

PubMed2004

Impaired motor performance and learning in glia maturation factor-knockout mice.

Glia maturation factor (GMF) is a unique brain protein localized in astrocytes and some neuronal populations. Studies with overexpression of GMF using adenovirus vector have uncovered its regulatory role in intracellular signal transduction and downstream induction of biologically active molecules, including the neurotrophins and cytokines. The current paper deals with the behavior of mice devoid of GMF protein (knockout). GMF-null mice developed normally without gross abnormality. When tested for simple position discrimination using a T-maze and for spatial memory using a Morris water maze, the knockout mice performed as well as the wild-type, showing no defect in maze learning. However, with beam walking, GMF-knockout mice performed poorly and failed to learn. Knockout mice were also defective in learning the eyeblink classical conditioning. Histologically, the knockout mice showed a loss of neurons in the inferior olive, which is a component of the circuitry of eyeblink conditioning, and is also essential for motor performance. The structural abnormality in GMF-null mice explained their impaired ability for both motor performance and motor learning.

Animals↗

PubMed2006

Differential actions of NPY on seizure modulation via Y1 and Y2 receptors: evidence from receptor knockout mice.

PURPOSE: Neuropeptide Y (NPY) has been shown to modulate seizure activities. To provide further understanding of the involvement of two of the most abundantly expressed NPY receptors, Y1 and Y2, we assessed the effect of Y1 and Y2 gene deletion on systemic kainic acid-induced seizures. We also examined the effect of rAAV-mediated hippocampal NPY overexpression on seizure susceptibility in these receptor knockout mice. METHODS: Recombinant adeno-associated viral vector overexpressing NPY (rAAV-NPY) or an empty vector control (rAAV-Empty) was injected into the hippocampus of adult C57BL/6-129/SvJ wild-type male mice and mice deficient of Y1 or Y2 receptors on the same background. Four weeks after vector injection, mice were subjected to systemic kainic acid-induced seizures, and the seizure behaviors were scored. RESULTS: The rAAV-mediated hippocampal overexpression of NPY led to a twofold reduction in seizures induced by systemic kainic acid in wild-type mice and Y1 receptor knockout mice but not in mice deficient of Y2 receptors. A differential action by the receptors was observed in the seizure-induced mortality rate, with increased fatality in Y2-/- mice. In addition, although NPY overexpression did not significantly affect the mortality rate in Y2-/- and wild-type mice, it abolished KA-induced mortality in Y1-/-mice. CONCLUSIONS: This study shows for the first time an altered susceptibility to chemically induced seizures in Y1 and Y2 knockout mice and demonstrates a differential seizure modulation mediated by these receptors via a genetic approach.

Animals↗

PubMed2003

Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice.

It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy.

Animals↗

PubMed2000

Lung fluid transport in aquaporin-5 knockout mice.

The mammalian lung expresses water channel aquaporin-1 (AQP1) in microvascular endothelia, AQP4 in airway epithelia, and AQP5 at the apical plasma membrane in type I cells of alveolar epithelia. We previously studied the role of AQP1 and AQP4 in lung fluid transport using knockout mice. Here, we examined the role of AQP5 using AQP5 knockout mice, which were recently shown to manifest defective saliva secretion. AQP5 deletion did not affect lung morphology at the light microscopic level, nor did it affect the distribution or expression of aquaporins 1, 3, or 4. Airspace-capillary osmotic water permeability (P(f)) was measured in isolated perfused lungs by pleural surface fluorescence and gravimetric methods. P(f) was reduced 10-fold by AQP5 deletion and was further reduced by 2- to 3-fold in AQP1/AQP5 double-knockout mice. Hydrostatic lung edema in response to acute increases in pulmonary artery pressure was not affected by AQP5 deletion. Active alveolar fluid absorption was measured in an in situ lung model from the increase in concentration of a volume marker in an isosmolar alveolar instillate. Interestingly, fluid absorption did not differ in litter-matched AQP5 knockout mice, nor was there an effect of AQP5 deletion when fluid absorption was maximally stimulated by pretreatment of mice with keratinocyte growth factor. These results indicate that AQP5 is responsible for the majority of water transport across the apical membrane of type I alveolar epithelial cells. The unimpaired alveolar fluid clearance in AQP5-null mice indicates that high alveolar water permeability is not required for active, near-isosmolar fluid transport.

Animals↗

PubMed2004

Enhanced morphine withdrawal and micro -opioid receptor G-protein coupling in A2A adenosine receptor knockout mice.

Much evidence supports the hypothesis that A2A adenosine receptors play an important role in the expression of morphine withdrawal and that the dopaminergic system might also be involved. We have evaluated morphine withdrawal signs in wild-type and A2A receptor knockout mice and shown a significant enhancement in some withdrawal signs in the knockout mice. In addition, micro -opioid and dopamine D2 receptor autoradiography, as well as micro -opioid receptor-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]GTPgammaS) autoradiography was carried out in brain sections of withdrawn wild-type and knockout mice. No significant changes in D2 and micro -opioid receptor binding were observed in any of the brain regions analysed. However, a significant increase in the level of micro receptor-stimulated [35S]GTPgammaS binding was observed in the nucleus accumbens of withdrawn knockout mice. These data indicate that the A2A receptor plays a role in opioid withdrawal related to functional receptor activation.

Analysis of Variance↗

PubMed2003

Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice.

Sigma (sigma) sites are a type of nonopiate receptor whose role has been associated with several behaviours, including anxiety, depression, analgesia, learning processes and psychosis. Although there are several known sigma receptor types, only the type I receptor (sigma 1) has been cloned. To uncover the in vivo relevance of sigma-receptors, we have generated knockout mice for sigma 1. Despite the broad expression pattern found for the sigma 1-gene, homozygous mutant mice are viable, fertile and do not display any overt phenotype, compared with their wild-type litter-mates, in mixed genetic backgrounds. However, a significant decrease in the hypermotility response has been measured in knockout mice upon challenge with (+)SKF-10 047, in agreement with the involvement of sigma 1-receptors in the induction of psychostimulant actions. The activity of sigma 2-receptors seems to be unaffected in sigma 1-mutant mice. These knockout mice could contribute to better understand the in vivo role of sigma-receptors.

Animals↗

PubMed2006

Attenuation of nicotine-induced rewarding effects in A2A knockout mice.

The non-selective A2A antagonist caffeine has been reported to modify nicotine-induced locomotor and reinforcing effects. In the present study, we have investigated the specific role of A2A adenosine receptors in the behavioural responses induced by nicotine by using genetically modified mice lacking A2A adenosine receptors. Acute nicotine administration induced a similar decrease of locomotor activity in A2A knockout mice and wild-type littermates. Acute antinociceptive responses elicited by nicotine in the tail-immersion and hot-plate tests were unaffected in these mutant mice. The rewarding properties of nicotine were then investigated using the place-conditioning paradigm. Nicotine-induced conditioned place preference was suppressed in A2A knockout mice. Accordingly, in vivo microdialysis studies revealed that the extracellular levels of dopamine in the nucleus accumbens were not increased after nicotine administration in mutant mice. Wild-type and A2A knockout mice were trained in conditioned taste aversion procedure in which drinking a saccharin or saline solution was paired with nicotine or saline injections. A similar reduction in the intake of nicotine-paired solution in this paradigm was obtained in both genotypes. Finally, the administration of the nicotinic antagonist mecamylamine in nicotine-dependent mice precipitated a similar withdrawal syndrome in both genotypes. Together, the present results identify A2A adenosine receptors as an important factor that contributes to the rewarding properties of nicotine.

Animals↗

PubMed2006

Sodium ingestion in oxytocin knockout mice.

Under certain circumstances, central oxytocin (OT) pathways inhibit dietary intake of NaCl in rats and mice. C57BL/6 OT knockout (OT KO) mice were reported to consume greater amounts of saline solution than wild type (WT) cohorts when both were water deprived overnight. In this study, we determined that OT KO and WT mice of C57BL/6 strain demonstrate an equivalent taste aversion for continuously available 0.2 M, 0.3 M or 0.5 M NaCl. The aversion was proportional to the concentration of NaCl, similar to what has been reported in rats. Furthermore, OT KO and WT animals ingested the same daily amounts of a low, 0.01%, regular, 1.0%, and a high, 8.0%, NaCl diet that was provided ad libitum as a single choice. While consuming these diets, mice were given the choice to drink water or saline (0.5 M NaCl). As the amount of NaCl in the diet increased, mice of both genotypes significantly decreased the consumption of saline solution to an equal degree. Additionally, in an experimental model of sustained dehydration previously developed in rats, 0.5 M NaCl was the only available drinking fluid. Like rats subjected to this paradigm, OT KO and WT mice decreased food intake, decreased body weight and increased fluid ingestion with no genotypic differences. These findings suggest that oxytocinergic neuronal pathways cannot be the only regulator of ad libitum intake of NaCl in drinking solutions or diet. It appears that OT pathways may be more critical in controlling NaCl intake over brief intervals when an animal is quickly compensating for a dehydrating stimulus.

Analysis of Variance↗

PubMed2004

Metastatic growth of lung cancer cells is extremely reduced in Vitamin D receptor knockout mice.

Lung metastatic neoplasms are the major cause of cancer mortality. Despite the progress of diagnostic techniques and improvements in surgical procedures, the prognosis of patients with lung cancer is generally poor, even in the early stages of cancer [Cancer: Principles and Practice of Oncology, vol. 1, fifth ed., Lippincott-Raven, New York, 1997, p. 849]. Epidemiological studies indicate a positive correlation with the prevalence of cancers and low serum levels of Vitamin D metabolites [Am. J. Clin. Nutr. 54 (1991) 193s; Cancer Epidemiol. Biomark. Prev. 9 (2000) 1059]. 1alpha,25-Dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is a potent inhibitor of cancer cell proliferation in vitro [Proc. Natl. Acad. Sci. U.S.A. 78 (1981) 4990; Endocrinol. 139 (1998) 1046; Mol. Endocr. 15 (2001) 1127]. There is, however, no report demonstrating that 1alpha,25(OH)(2)D(3) is operative in vivo to inhibit metastatic growth of cancer cells. To verify this possibility, we generated a stable transfectant of the Lewis lung carcinoma (LLC) cell expressing green fluorescent protein (GFP) and examined its metastatic activity in wild-type mice and Vitamin D receptor (VDR) knockout mice that exhibit no Vitamin D-dependent calcemic activity and extremely high serum levels of 1alpha,25(OH)(2)D(3) due to the overexpression of the 1alpha-hydroxylase gene [Nat. Genet. 16 (1997) 391; Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 9831]. Here, we show that 1alpha,25(OH)(2)D(3) inhibits metastatic growth of lung cancer cells in the defined animal model and may work as an intrinsic factor for prevention of metastasis in intact animals. These findings establish a critical role for 1alpha,25(OH)(2)D(3) in lung metastatic neoplasms and provide a new model for metastasis of malignant cells.

Actins↗

PubMed2002

Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure.

The beneficial effects of ACE inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant) are reportedly mediated by NO in heart failure (HF). We hypothesized that in the absence of endothelial NO synthase (eNOS), (1) left ventricular (LV) dysfunction and myocardial remodeling would be more severe after myocardial infarction (MI), and (2) the cardioprotective effect of ACEi and AT(1)-ant would be diminished or absent in mice with HF after MI. eNOS knockout mice (eNOS-/-) and wild-type C57BL/6J (C57) mice (+/+) were subjected to MI by ligating the left coronary artery. One month after MI, each strain was treated with vehicle, ACEi (enalapril, 20 mg/kg per day), or AT(1)-ant (valsartan, 50 mg/kg per day) for 5 months. Echocardiography was performed, and systolic blood pressure was measured before MI and monthly thereafter. Interstitial collagen fraction and myocyte cross-sectional area were examined histologically. We found that (1) compared with C57 mice, eNOS-/- mice that underwent sham surgery had significantly increased systolic blood pressure (P<0.05) and increased LV mass both initially and at 1 to 3 months, although cardiac function and histological findings did not differ between strains; (2) the development of HF and myocardial remodeling were similar after MI in both strains; and (3) ACEi improved cardiac function and remodeling in C57 mice, as evidenced by increased LV ejection fraction (LVEF) and LV shortening fraction (LVSF) and decreased diastolic LV dimension, mass, myocyte cross-sectional area, and interstitial collagen fraction, but these benefits were absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after ACEi, 14.2 +/- 2% versus -4.9 +/- 2.5%, respectively [P<0.001]; increase in LVSF, 8.6 +/- 2.1% versus -7.2 +/- 2.8%, respectively [P<0.01]; and decrease in LV mass, -16.6 +/- 15 versus 73 +/- 23 mm(3), respectively [P<0.01]). AT(1)-ant had benefits similar to those of ACEi, which were also absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after AT(1)-ant, 13.5 +/- 1.8% versus -9.8 +/- 3%, respectively [P<0.001]; increase in LVSF, 6.1 +/- 1.6% versus -3.8 +/- 3.1%, respectively [P<0.01]). Our data suggest that the absence of NO does not alter the development of HF after MI; however, it significantly decreases the cardioprotective effects of ACEi or AT(1)-ant.

Angiotensin Receptor Antagonists↗