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N Hübner

Publications and source records attributed to N Hübner.

12 recordsLinked to original sources
PubMed1998

Percutaneous dilatational tracheostomy done early after cardiac surgery--outcome and incidence of mediastinitis.

During November 95 to April 97, 45 percutaneous dilatational tracheostomies were performed in a nonselected patient series of 2788 open cardiac surgery cases. Tracheostomy was performed as early as the 2nd postoperative day (median: 6th day), when extubation was not foreseen within the next few days. Duration of intubation was 13 days (mean). We observed 6 complications in 5 patients (13.3%), namely bleeding, misplacement of the tube, subcutaneous emphysema, and superficial infection of the tracheostoma. Mediastinitis and wound infection of the sternal wound did not occur in any single case. There was no death due to tracheostomy. Clinically evident tracheal stenosis and inadequate granulation of the stoma were not observed after extubation. In our opinion, percutaneous dilatational tracheostomy is justifiable, shows good results, and entails minimal risk if done early after cardiac surgery, and it is also superior to standard surgical tracheostomy. Increased incidence of mediastinitis was not seen.

Adult↗
PubMed1997

Tissue- and development-specific expression of multiple alternatively spliced transcripts of rat neuronal nitric oxide synthase.

Nitric oxide (NO) functions as an intercellular messenger and mediates numerous biological functions. Among the three isoforms of NO synthase that produce NO, the ubiquitously expressed neuronal NO synthase (nNOS) is responsible for a large part of NO production, yet its regulation is poorly understood. Recent reports of two alternative spliceforms of nNOS in the mouse and in man have raised the possibility of spatial and temporal modulation of expression. This study demonstrates the existence of at least three transcripts of the rat nNOS gene designated nNOSa, nNOSb, and nNOSc, respectively, with distinct 5' untranslated first exons that arise from alternative splicing to a common second exon. Expression of the alternative transcripts occurs with a high degree of tissue and developmental specificity, as demonstrated by RNase protection assays on multiple tissues from both fetal and adult rats. Furthermore, terminal differentiation of rat pheochromocytoma-derived PC12 cells into neurons is associated with induction of nNOSa, suggesting, likewise, development- and tissue-specific transcriptional control of nNOS isoform expression. Physical mapping using a rat yeast artificial chromosome clone shows that the alternatively spliced first exons 1a, 1b, and 1c are separated by at least 15-60 kb from the downstream coding sequence, with exons 1b and 1c being positioned within 200 bp of each other. These findings provide evidence that the biological activity of nNOS is tightly and specifically regulated by a complex pattern of alternative splicing, indicating that the notion of constitutive expression of this isoform needs to be revised.

Alternative Splicing↗
PubMed1997

Evidence for primary genetic determination of heart rate regulation: chromosomal mapping of a genetic locus in the rat.

BACKGROUND: We investigated whether an accelerated heart rate (HR), observed in the stroke-prone spontaneously hypertensive rat (SHRSP(HD)), is a primary, genetically determined trait and whether it contributes to blood pressure (BP) regulation in this model of polygenic hypertension. METHODS AND RESULTS: We measured BP and HR in SHRSP(HD) and normotensive Wistar-Kyoto rats (WKY), as well as in F2 hybrids bred from crossing the two strains, at baseline and after 12 days of dietary NaCl loading. Random marker genome screening and cosegregation analysis were performed on F2 hybrids derived from SHRSP(HD)/WKY-0(HD) (n=115) and SHRSP(HD)/WKY-1(HD) (n=139) crosses (WKY-0(HD) and WKY-1(HD) are two congenic WKY strains). HR in SHRSP(HD) was significantly higher than in WKY-0(HD) both at baseline (404+/-30 versus 375+/-46 bpm; P=.0034) and after NaCl (437+/-23 versus 364+/-40 bpm; P=10(-9)). BP in F2 hybrids showed no significant correlation with HR either at baseline or after NaCl loading. HR after NaCl loading but not at baseline was significantly linked in a recessive fashion to a locus on chromosome 3: in animals homozygous for the SHRSP(HD) allele, HR was 414+/-49 compared with 383+/-44 bpm in heterozygotes and WKY homozygotes (F(210,1)=19.7, P=1.4x10(-5), lod score=5.9). The putative BP-relevant gene at this locus, termed HR-SP1, showed no evidence of linkage to any of the BP parameters measured. CONCLUSIONS: Our results demonstrate that a genetic locus on rat chromosome 3, HR-SP1, contributes directly to the regulation of HR in SHRSP(HD) but exhibits no effect on BP. Thus, in addition to its modulation by reflex-mediated neurohumoral mechanisms, HR is also under the direct influence of primary genetic factors.

Analysis of Variance↗
PubMed1997

Role of the alpha-, beta-, and gamma-subunits of epithelial sodium channel in a model of polygenic hypertension.

The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the beta- and gamma-subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and a Wistar-Kyoto rat (WKY-1HD) reference strain. We carried out genetic mapping and chromosomal assignment of the alpha-, beta-, and gamma-subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the beta- and gamma-subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the beta-/gamma-subunit locus. The alpha-subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSPHD and WKY-1HD strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSPHD and WKY-1HD. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.

Animals↗
PubMed1995

Genetic linkage of the ACE gene to plasma angiotensin-converting enzyme activity but not to blood pressure. A quantitative trait locus confers identical complex phenotypes in human and rat hypertension.

BACKGROUND: An allelic variant of the ACE gene has been found to be linked to plasma angiotensin-converting enzyme (ACE) activity in humans and has been implicated in the etiology of some common cardiovascular disorders. Previously, we have shown significant genetic linkage of blood pressure to a region on rat chromosome 10 that contains ACE in an experimental F2-intercross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKYHD-0) reference strain. Subsequent investigations revealed marked differences in plasma ACE activity among the SHRSPHD and WKYHD-0 strains. Nonetheless, the physiological relevance of these findings remained obscure. We therefore investigated the genetic determination of plasma ACE activity and its relation to blood pressure and dietary NaCl exposure in a model of experimental genetic hypertension, the SHRSPHD. METHODS AND RESULTS: We conducted a further crossbreeding experiment between SHRSPHD and a congenic reference strain, WKYHD-1, that carries a 6-centimorgan (cM) long, SHRSP-homologous segment introgressed in chromosome 10, 26 cM remote from ACE. This allowed us to contrast effects on blood pressure and ACE activity conferred by the ACE locus with other more remote loci within the congenic chromosomal region. Genetic analysis in this F2 (WKYHD-1 x SHRSPHD) cross revealed that plasma ACE activity was determined almost entirely by genetic effects of the ACE gene locus (lod score = 43). However, neither plasma ACE nor the ACE locus showed any cosegregation with blood pressure before or after dietary NaCl exposure. CONCLUSIONS: These results demonstrate that a molecular variant of the ACE gene determines plasma ACE activity but exhibits no direct effect on blood pressure. Moreover, the findings also exclude the possibility that plasma ACE is secondarily affected by blood pressure or excess dietary NaCl exposure. Our results reconcile the previous discrepancy between findings in human and experimental hypertension.

Animals↗
PubMed1995

Dissection of a quantitative trait locus for genetic hypertension on rat chromosome 10.

We have previously identified a locus on rat chromosome 10 as carrying a major hypertension gene, BP/SP-1. The 100:1 odds support interval for this gene extended over a 35-centimorgan (cM) region of the chromosome that included the angiotensin I-converting enzyme (ACE) locus as demonstrated in a cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKY-0HD) rat. Here we report on the further characterization of BP/SP-1, using a congenic strain, WKY-1HD. WKY-1HD animals carry a 6-cM chromosomal fragment genotypically identical with SHRSPHD on chromosome 10, 26 cM away from the ACE locus. Higher blood pressures in the WKY-1HD strain compared with the WKY-0HD strain, as well as absence of linkage of the chromosome 10 region to blood pressure in an F2 (WKY-1HD x SHRSPHD) population suggested the existence of a quantitative trait locus, termed BP/SP-1a, that lies within the SHRSP-congenic region in WKY-1HD. Linkage analysis in the F2 (WKY-0HD x SHRSPHD) cross revealed that BP/SP-1a is linked to basal blood pressure, whereas a second locus on chromosome 10, termed BP/SP-1b, that maps closer to the ACE locus cosegregates predominantly with blood pressure after exposure to excess dietary NaCl. Thus, we hypothesize that the previously reported effect of BP/SP-1 represents a composite phenotype that can be dissected into at least two specific components on the basis of linkage data and congenic experimentation. One of the loci identified, BP/SP-1a, represents the most precisely mapped locus affecting blood pressure that has so far been characterized by random-marker genome screening.

Animals↗
PubMed1995

Altered angiotensinogen amino acid sequence and plasma angiotensin II levels in genetically hypertensive rats. A study on cause and effect.

The components of the renin-angiotensin system have been implicated in the development of primary hypertension in humans and genetically hypertensive rats. In humans a mutation in the angiotensinogen gene and elevated plasma angiotensinogen levels have been linked to primary hypertension. Although we had previously excluded a linkage of blood pressure to the angiotensinogen gene in the stroke-prone spontaneously hypertensive rat (SHRSP), elevated angiotensin II (Ang II) levels in this strain compared with the normotensive reference, the Wistar-Kyoto rat (WKY), prompted us to investigate further into the origins and effects of altered Ang II regulation using a range of physiological, biochemical, molecular, and genetic approaches. Ang II plasma levels determined by radioimmunoassay were confirmed to be significantly elevated in SHRSP compared with WKY. Sequence comparison among the two rat strains revealed a mutation in the coding region of the angiotensinogen gene that results in an isoleucine-to-valine substitution in SHRSP at amino acid position 154 (I154V). We performed a cosegregation analysis in an F2 intercross cohort bred from SHRSP and WKY from the University of Heidelberg (SHRSPHD and WKYHD) to address the following questions: (1) whether this or another mutation of the angiotensinogen gene may be casually related to the observed differential Ang II plasma levels, (2) whether Ang II plasma levels may be correlated with blood pressure or organ hypertrophy, and (3) whether genetic linkage to the renin or angiotensin-converting enzyme (ACE) gene loci (the two classic regulatory enzymes of the renin-angiotensin system) may provide an explanation for elevated Ang II plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1995

Genetics in arterial hypertension--clinical and experimental aspects.

Genetic approaches provide a new insight into the understanding of biological mechanisms underlying blood pressure regulation and hypertension. Some progress has been made in elucidating the molecular mechanisms of rare forms of hypertension. Common forms of hypertension are likely to be due to combinations of DNA variants of several genes involved in blood pressure regulation. Only little progress has been made in the identification of the underlying genetic factors, due to the complex nature of this disease. Experimental crosses of hypertensive rats offer an ideal setting for the genetic dissection of mammalian physiology. With the opportunity to study inbred rat strains the problem of genetic heterogeneity becomes irrelevant. Cosegregation studies investigating candidate genes for hypertension have been carried out for a number of genes. Moreover, systematic mapping of quantitative trait loci involved in blood pressure regulation has recently become possible in genetically hypertensive rat models. In contrast, genetic studies involving hypertensive individuals are currently limited to the investigation of candidate genes in association and sib-pair analysis. So far, the angiotensinogen gene is the only locus that has been implicated in the pathogenesis of human hypertension in association as well as sib-pair analysis. Considering the complexities of genetic hypertension, animal models will play an important role in the genetic dissection of this disease. A critical prerequisite for the study of human hypertension is the availability of large patient and family cohorts.

Animals↗
PubMed1994

Unlike human hypertension, blood pressure in a hereditary hypertensive rat strain shows no linkage to the angiotensinogen locus.

Recently, evidence has been presented for genetic linkage between the angiotensinogen gene and primary hypertension in humans. In the present study we examined whether a similar linkage between blood pressure and the angiotensinogen gene locus can be demonstrated in a widely used animal model of primary hypertension, the stroke-prone spontaneously hypertensive rat (Heidelberg colony, SHRSPHD). In 115 F2 hybrids bred from SHRSPHD and a normotensive reference strain, the Wistar-KyotoHD (WKYHD) rat, systolic and diastolic blood pressures and heart rate were determined by indwelling arterial catheters in the presence and absence of dietary sodium loading. In addition, left and right ventricular heart weight was measured. Using a newly developed polymorphic marker assay for the angiotensinogen gene based on polymerase chain reaction amplification of an exon 2 fragment and subsequent restriction endonuclease digestion, we performed a cosegregation study in this cohort. No evidence for cosegregation between the angiotensinogen gene locus and blood pressure or any other phenotypic parameter assessed was found. Although the SHRSP serves as a valuable model of hypertension, our data emphasize that disease-relevant genetic loci in humans and rats cannot be assumed to coincide.

Angiotensinogen↗