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PubMed2000

A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases abeta 42 generation in human cells.

The familial Alzheimer's disease-associated presenilins (PSs) occur as a dimeric complex of proteolytically generated fragments, which functionally supports endoproteolysis of Notch and the beta-amyloid precursor protein (betaAPP). A homologous gene, sel-12, has been identified in Caenorhabditis elegans. We now demonstrate that wild-type (wt) SEL-12 undergoes endoproteolytic cleavage in C. elegans similar to the PSs in human tissue. In contrast, SEL-12 C60S protein expressed from the sel-12(ar131) allele is miscleaved in C. elegans, resulting in a larger mutant N-terminal fragment. Neither SEL-12 wt nor C60S undergo endoproteolytic processing upon expression in human cells, suggesting that SEL-12 is cleaved by a C. elegans-specific endoproteolytic activity. The loss of function of sel-12 in C. elegans is not associated with a dominant negative activity in human cells, because SEL-12 C60S and the corresponding PS1 C92S mutation do not interfere with Notch1 cleavage. Moreover, both mutant variants increase the aberrant production of the highly amyloidogenic 42-amino acid version of amyloid beta-peptide similar to familial Alzheimer's disease-associated human PS mutants. Our data therefore demonstrate that the C60S mutation in SEL-12 is associated with aberrant endoproteolysis and a loss of function in C. elegans, whereas a gain of misfunction is observed upon expression in human cells.

Amyloid beta-Peptides↗

PubMed2000

Germline and somatic loss of function of the mouse cpk gene causes biliary ductal pathology that is genetically modulated.

The mouse cpk mutation is the most extensively characterized murine model of polycystic kidney disease (PKD) and closely resembles human autosomal recessive PKD (ARPKD), with the exception that B6-cpk/cpk homozygotes do not express the biliary ductal plate malformation (DPM) lesion. However, homozygous mutants from outcrosses to other strains, e.g. DBA/2J (D2), CD-1, BALB/c and Mus mus castaneus (CAST), express the DPM. The current study was designed: (i) to characterize the cpk-associated biliary disease in affected F(2) homozygotes from intercrosses with either CAST or D2; and (ii) to evaluate focal biliary cysts identified in heterozygotes from a D2-cpk congenic strain. We found that all F(2) cpk/cpk pups expressed both the typical renal cystic disease and the DPM. The DPM severity, assessed using semi-quantitative histopathological analysis, was markedly variable in these F(2) progeny. We found no correlation between the severity of the DPM and the renal cystic disease in either F(2) cohort. In addition, we identified focal cysts, apparently of biliary origin, in the livers of both aged D2-+/cpk and F(1) heterozygotes. Genetic analysis demonstrated loss of heterozygosity at the cpk interval and supports a loss-of-function model for biliary cysts. We conclude that the cpk allele contains an inactivating mutation which disrupts tubulo-epithelial differentiation in the kidney and biliary tract. Expression of the biliary lesion is modulated by genetic background, and the specific biliary phenotype is determined by whether loss of function of the cpk gene occurs as a germline or a somatic event.

Animals↗

PubMed1994

Central respiratory neuronal activity after axonal regeneration within blind-ended peripheral nerve grafts: time course of recovery and loss of functional neurons.

Autologous segments of peroneal nerve were implanted into the medulla of adult rats to induce axonal regeneration of central neurons axotomised during the grafting procedure. Grafts were inserted in the midline--where respiratory axons decussate--or laterally, either in the nucleus tractus solitarius or in the nucleus ambiguus, close to respiratory cell bodies. The distal part of each graft was left unconnected (blind-ended graft). Between 2 and 30 months post-implantation, unit recordings from single fibres were made from small strands teased from the grafts to investigate activity of neurons regenerating axons. Spontaneous respiratory and non-respiratory activity was present only in grafts examined between 2 and 6 months post-implantation. Respiratory units had discharge patterns identical to those of normal inspiratory or expiratory neurons; their responses to lung inflation and asphyxia were also similar to those of central respiratory neurons. No spontaneous activity was present in the grafts examined 7-30 months post-implantation. Moreover, asphyxia, which normally enhances the activity of central respiratory neurons, failed to elicit activity. These results were similar in all grafts, regardless of the site of implantation. The presence of spontaneous activity only between 2 and 6 months post-implantation indicates that once axonal growth of respiratory neurons is stopped within blind-ended grafts, those neurons still exhibited normal functional properties for 3 months. The absence of activity 6 months after grafting suggests that loss of functional regenerating respiratory neurons does not occur progressively and follows an "all or nothing" rule within blind-ended grafts.

Animals↗

PubMed2006

An LNA-based loss-of-function assay for micro-RNAs.

MicroRNAs (miRNAs) have recently emerged as being essential for development and for the control of cell proliferation/differentiation in various organisms. However, little is known about miRNA function and mode of action at the cellular level. We have designed a miRNA loss-of-function assay, based on chemically modified locked nucleic acids (LNA) antisense oligonucleotides and usable in tissue culture cells. We show that LNA/DNA mixed oligonucleotides form highly stable duplexes with miRNAs in vitro. Ex vivo, the target miRNA becomes undetectable in cells transfected with the antisense oligonucleotide. The effect is dose-dependent, long-lasting, and specific. Moreover, using a reporter assay, we show that antisense LNA/DNA oligonucleotides inhibit short non-coding RNAs at the functional level. Thus LNA/DNA mixmers represent powerful tools for functional analysis of miRNAs.

Cells, Cultured↗

PubMed2007

Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.

BACKGROUND: Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. METHODS AND RESULTS: Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca(v)1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals < or = 360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the alpha1- and beta2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca(v)1.2 channels but normal trafficking of channels containing G490R Ca(v)1.2 or S481L Ca(v beta2b)-subunits. CONCLUSIONS: This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

Adult↗

PubMed1989

A translocation associated, loss-of-function mutation in the nitrogen metabolite repression regulatory gene of Aspergillus nidulans can revert intracistronically.

The areAr-18 mutation is a loss-of-function mutation in areA, the positive acting regulatory gene mediating nitrogen metabolite repression in Aspergillus nidulans. It results from a reciprocal translocation which splits the coding region into 5' and 3' moieties. Surprisingly, we have selected rare intracistronic revertants of areAr-18. From crosses heterozygous for areAr-18 revertant alleles, duplication-deficiency progeny containing two copies of a substantial portion of chromosome IV but lacking part of chromosome III, including the 5' moiety of areA, have been obtained. For all four revertants analysed genetically, growth properties of these duplication-deficiency strains indicate that the reversion events involve the 3' portion of areA and that the 5' portion of areA is unnecessary for the revertant phenotype. This conclusion was directly confirmed for one revertant using Southern blotting. As all four reversion events involve additional chromosomal rearrangements, they probably fuse functional promoters, ribosome binding sites and 'in frame' initiation codons to the 3' portion of the gene. In the course of characterisation of these mutations, new mapping data for a large region of chromosome IV have been generated, and a new reciprocal translocation activating the cryptic regulatory gene areB, whose product can substitute for that of areA, has been identified.

Aspergillus nidulans↗

PubMedDate not supplied

Functional visual loss in Cambodian refugees: a study of cultural factors in ophthalmology.

South East (SE) Asians accounted for a disproportionate percentage of the functional visual loss (FVL) seen in our area between 1983 and 1987. Moreover, 94% of the SE Asian FVL patients were Cambodian, although Cambodians only represented 20-30% of the local SE Asian patient population. Cambodian refugees are, at present, generally from lower socio-economic classes than the Vietnamese, and a much larger percentage of them have a history of camp incarceration and previous trauma. The Cambodians presenting with FVL may have conversion hysteria influenced by their wartime experience and cultural background. This study demonstrates that the SE Asian refugees in California are not a homogenous group with respect to visual problems, and that an awareness of cultural or historical factors can be important to the management of ophthalmic symptoms in our multi-cultural societies.

Adult↗

PubMed2026

Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome associated with dysregulation of GPR37 trafficking.

The endoplasmic reticulum (ER) serves as a key hub for protein homeostasis, maintaining a strict quality-control system that ensures only properly folded proteins reach their destinations, while misfolded proteins are degraded via ER-associated degradation (ERAD) or selective ER-phagy. JKAMP, which encodes an ER-resident transmembrane protein involved in ERAD, has not previously been associated with human disease. Here, we report bi-allelic loss-of-function variants in JKAMP in 14 affected individuals from 10 unrelated families presenting with a neurodevelopmental syndrome characterized by intellectual disability, developmental delay, seizures, hypotonia, microcephaly, and dysmorphic features. An in vivo zebrafish model lacking jkamp recapitulated key aspects of the human disorder, including developmental abnormalities and impaired myelin production, further corroborating its pathogenic role. Mechanistic studies identified GPR37, a brain-enriched orphan G protein-coupled receptor (GPCR) and known JKAMP interactor, as a critical downstream effector. GPR37 plays essential roles in dopaminergic signaling, inflammatory pain regulation, neuroprotection, and myelination. Loss of JKAMP resulted in defective folding and degradation of GPR37, leading to its accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. These findings establish JKAMP as a previously unrecognized contributor to human neurodevelopment and uncover a pathogenic mechanism linking ER protein quality control to GPCR regulation and neurological disease.

Humans↗

PubMed1994

Artificial gravity in space flight.

Clearly, physiologic adaptation to terrestrial life for all animals is assured only by frequent encounters with gravity. Indeed, upon exposure to weightlessness in space flight, losses of physiologic functions quickly begin. Some physiologic parameters change more rapidly than others, but the deconditioning process starts rapidly. The rates of functional losses for all affected parameters are interesting in that they appear to approach a limit; i.e., losses of these functions may not continue until indefinitely. The regulation of this functional asymptotic response to space is not known, but probably based on functional requirements of the body to life itself and perhaps genetic expression. The latter controlling mechanism (DNA) functions only on aquatic (weightless) animals on Earth--land animals must stimulate these physiologic functions as they relate to gravity on a regular frequent basis. This loss of regulation upon entering the weightless environment is fascinating since land-based animals including the humans have evolved from millions (perhaps billions) of years of terrestrially adapted ancestors. One would expect some DNA involvement in the regulation of its physiology, but it appears to be absent. Therefore, if the functional debilitation of space is to be denied, we must begin to understand the adaptation process of the sole basis for the control of our physiologic processes on land; i.e., how gravity regulates our biologic functions. To learn about this regulatory mechanism, some inquiry into how aquatic animals first adapted to living on land might be helpful.

Adaptation, Physiological↗

PubMed1997

A simulation of hand impairments: effects on upper extremity function and implications toward medical impairment rating and disability determination.

OBJECTIVES: To determine whether simulation of significant impairment of the hand will have a predictable impact on degree of functional loss at the wrist and hand. DESIGN: Single subject repeat measures using before-after trial comparisons and healthy volunteer subjects. SETTING: Occupational therapy section of a large academic medical center. OTHER PARTICIPANTS: Twenty adult volunteer student subjects from an occupational therapy education (OTE) department were included. All were between ages 18 and 43 years, right hand dominant, and in excellent general health. There were 19 women and 1 man, reflecting gender distribution of the OTE student body. INTERVENTION: A simulated fusion of the carpometacarpal (CMC) joint of the thumb was achieved by immobilization in an individually fabricated splint designed to maximally restrict motion at the first CMC joint. Impairment ratings (baseline vs splinted) according to the AMA Guides were obtained by Greenleaf testing, and upper extremity function was quantitatively assessed before and after splinting. MAIN OUTCOME MEASURES: Measures of upper extremity function included grip and pinch strength, wrist torque, and speed of performance on the Valpar Small Tools test, Jebsen Hand Function test, and an exploratory measure, the Functional Life Activity Test (FLAT). RESULTS: Significant impairments were achieved for all subjects after splinting and according to Greenleaf testing. Splinting resulted in significant reductions in grip and pinch strength, wrist torque, and significant slowing of performance on the Valpar, Jebsen, and FLAT tests. Regressions of degree of impairment on degree of functional loss after splinting, and according to each of the above measures, were not significant. CONCLUSIONS: Impairment of the hand was simulated to a mild-to-moderate degree as measured according to the AMA Guides. This imposed significant reductions in motion at key joints of the wrist and hand as well as significant reductions in grip and pinch strength and wrist torque. A corresponding and significant slowing of performance on a variety of measures of upper extremity function of an industrial and nonindustrial nature was also seen. However, and for the first time, correlation and regression reveals that it is not possible to predict degree of functional loss attributable to degree of impairment for the hand. It thus appears that, for mild-to-moderate clinical impairments, the associated impairment rating is a poor estimator of functional loss at the hand and should be used cautiously, if at all, as a criterion for disability determination.

Activities of Daily Living↗

PubMed1996

Microinjection of in vitro transcribed RNA and antisense oligonucleotides in mouse oocytes and early embryos to study the gain- and loss-of-function of genes.

Mouse oocytes have proven useful in experiments aimed at studying gene function. They have been used to analyze the gain-of-function acquired after microinjection of RNA transcribed in vitro from specific gene constructs, and for establishing loss-of-function mutation obtained by injecting in vitro transcribed antisense RNA and/or synthetic oligonucleotides. This article presents protocols utilized in these studies. Specifically, the acquisition of mouse oocytes and/or embryos, the genesis of the necessary DNA and/or RNA to be used, and procedures for microinjection.

Animals↗

PubMed2006

Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation.

Atrial fibrillation is a rhythm disorder characterized by chaotic electrical activity of cardiac atria. Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder. To identify genetic defects conferring disease susceptibility, patients with idiopathic atrial fibrillation, lacking traditional risk factors, were evaluated. Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria. The heterozygous E375X mutation, present in a familial case of atrial fibrillation and absent in 540 unrelated control individuals, introduced a premature stop codon disrupting the Kv1.5 channel protein. The truncation eliminated the S4-S6 voltage sensor, pore region and C-terminus, preserving the N-terminus and S1-S3 transmembrane domains that secure tetrameric subunit assembly. Heterologously expressed recombinant E375X mutant failed to generate the ultrarapid delayed rectifier current I(Kur) vital for atrial repolarization and exerted a dominant-negative effect on wild-type current. Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity. The pathogenic link between compromised Kv1.5 function and susceptibility to atrial fibrillation was verified, at the organism level, in a murine model. Rescue of the genetic defect was achieved by aminoglycoside-induced translational read-through of the E375X premature stop codon, restoring channel function. This first report of Kv1.5 loss-of-function channelopathy establishes KCNA5 mutation as a novel risk factor for repolarization deficiency and atrial fibrillation.

Animals↗

PubMed1996

Prognostic value of the short-term antiproteinuric response to ACE inhibition for prediction of GFR decline in patients with nondiabetic renal disease.

In chronic renal disease, the severity of proteinuria is associated with the rate of renal function loss. Proteinuria, therefore, was postulated to play a role in the final common pathway of chronic renal function loss. If so, reduction of proteinuria would improve long-term renal outcome. Improvement of long-term renal function outcome has been obtained in several intervention trials; in these studies; regimens providing better renoprotection were associated with more effective reduction of poteinuria than control regimens. As the reduction of proteinuria is mostly associated with a fall in blood pressure, however, it is difficult to delineate the respective roles of the lowering of blood pressure and of proteinuria. Interestingly, the initial reduction of proteinuria (but not of blood pressure) by antihypertensive treatment appears to predict long-term renal outcome in man as well as in experimental renal disease. This suggests that an intervention strategy aimed not only at the normalization of blood pressure, but also specifically at elimination of proteinuria, might be able to improve long-term renal outcome in proteinuric patients. If so, this would provide further evidence in support of the hypothesis that proteinuria is causally involved in the progression of long-term renal function loss.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2025

Loss-of-Function CARS1 Variants in a Patient With Microcephaly, Developmental Delay, and a Brittle Hair Phenotype.

BACKGROUND: Mutations in cysteinyl-tRNA synthetase (CARS1) have been implicated in a multisystem disease including microcephaly, developmental delay, and brittle hair and nail phenotypes. METHODS: Here, we present a patient with hepatopathy, hypothyroidism, short stature, developmental delay, microcephaly, muscular hypotonia, brittle hair, and ataxia. The patient underwent exome sequencing to identify potentially pathogenic genetic variants. In addition, identified variants were assessed using yeast complementation assays to determine functional consequences. RESULTS: Exome sequencing determined that the patient is compound heterozygous for p.Arg341His and p.Arg370Trp CARS1. Yeast complementation assays showed that the p.Arg341His variant has a hypomorphic effect and that the p.Arg370Trp variant causes a complete loss-of-function effect. CONCLUSION: This study is the second report of pathogenic CARS1 variants and expands the allelic and phenotypic heterogeneity of CARS1-associated disease.

Humans↗

PubMed1999

Molecular characterization of eutF mutants of Salmonella typhimurium LT2 identifies eutF lesions as partial-loss-of-function tonB alleles.

The eutF locus of Salmonella typhimurium LT2 was identified as a locus necessary for the utilization of ethanolamine as a sole carbon source. Initial models suggested that EutF was involved in either ethanolamine transport or was a transcriptional regulator of an ethanolamine transporter. Phenotypic characterization of eutF mutants suggested EutF was somehow involved in 1,2-propanediol, propionate, and succinate utilization. Here we provide evidence that two alleles defining the eutF locus, Delta903 and eutF1115, are partial-loss-of-function tonB alleles. Both mutations were complemented by plasmids containing a wild-type allele of the Escherichia coli tonB gene. Immunoblot analysis using TonB monoclonal antibodies detected a TonB fusion protein in strains carrying eutF alleles. Molecular analysis of the Delta903 allele identified a deletion that resulted in the fusion of the 3' end of tonB with the 3' end of trpA. In-frame translation of the tonB-trpA fusion resulted in the final 9 amino acids of TonB being replaced by a 45-amino-acid addition. We isolated a derivative of a strain carrying allele Delta903 that regained the ability to grow on ethanolamine as a carbon and energy source. The molecular characterization of the mutation that corrected the Eut- phenotype caused by allele Delta903 showed that the new mutation was a deletion of two nucleotides at the tonB-trpA fusion site. This deletion resulted in a frameshift that replaced the 45-amino-acid addition with a 5-amino-acid addition. This change resulted in a TonB protein with sufficient activity to restore growth on ethanolamine and eut operon expression to nearly wild-type levels. It was concluded that the observed EutF phenotypes were due to the partial loss of TonB function, which is proposed to result in reduced cobalamin and ferric siderophore transport in an aerobic environment; thus, the eutF locus does not exist.

Amino Acid Sequence↗

PubMed1997

Loss of function and p53 protein stabilization.

Wild-type (wt) p53 protein is rapidly degraded, has a short half-life and low intracellular levels. Stabilization of wt p53 protein following an appropriate stimulus (for example DNA damage) is a physiological regulation to increase function. In contrast, stabilization of p53 protein in the absence of a stimulus is always a hallmark of loss of function secondary to a mutation, or interaction with viral or cellular oncoproteins. It is generally accepted that stability of p53 protein depends on its intrinsic biochemical properties such as conformation or protein/protein interactions. However, I will discuss evidence that the stability of p53 is not a consequence of its intrinsic properties, but instead is determined by feedback control of its function. In the absence of an appropriate stimulus, a cell needs to keep p53 levels low, since increased levels can lead to apoptosis. To precisely regulate p53 levels, a cell must sense its level; and sensing its transactivating function, is the simplest way to sense p53. Following an appropriate stimulus (for example, DNA damage), the cell senses a state of 'relative' p53 deficiency and adapts by reducing p53 degradation. When the state of p53 deficiency is a consequence of a mutation or interaction with viral oncoproteins, the cell does not sense p53, and again attempts to adapt by reducing p53 degradation. However, in the latter case, the increase in levels does not restore function, and the adaptation continues until degradation of p53 protein is maximally inhibited. In this case, no further inhibition of degradation is possible after DNA-damage or pharmacological inhibition of proteasomes. Thus lack of wt p53 function always results in increased p53 levels and nonregulation.

Hydrolysis↗

PubMed2005

CDC4 mutations occur in a subset of colorectal cancers but are not predicted to cause loss of function and are not associated with chromosomal instability.

CDC4/FBXW7 is part of a ubiquitin ligase complex which targets molecules such as cyclin E, c-myc, and c-jun for destruction. CDC4 mutations occur in several cancer types and are best described in colorectal tumors. Knockout of CDC4 in vitro in colorectal cancer cells causes changes suggestive of chromosomal instability (CIN). In p53(+/-) mice, radiation-induced lymphomas show deletion or mutation of one copy of CDC4 and knockdown of CDC4 leads to increased aneuploidy in mouse fibroblasts. We screened 244 colorectal tumors and 40 cell lines for CDC4 mutations and allelic loss. Six percent (18 of 284) of tumors, including near-diploid (CIN-) lesions, harbored CDC4 mutations and there was no association between mutation and CIN (polyploidy). The CDC4 mutation spectrum in colorectal tumors was heavily biased towards C:G > T:A changes, either missense mutations at critical arginine residues or nonsense changes in the 5' half of the gene. The reasons for this odd mutation spectrum were unclear but C:G > T:A changes were not found more often than expected at APC, K-ras, or p53 in the same tumors and we found no specific defects in DNA repair to account for the observations. No colorectal tumor was found to carry two CDC4 mutations predicted to abolish protein function; partial loss of CDC4 function may therefore cause tumorigenesis. The in vitro studies, therefore, did not assess the functional effects of mutant alleles which are found in vivo. CDC4 mutations may be selected primarily to drive progression through the cell cycle although CIN might be an important secondary effect in some cancers.

Adenocarcinoma↗

PubMed2006

Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function.

Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of arterial dysfunction. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension.

Animals↗