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K Lindpaintner

Publications and source records attributed to K Lindpaintner.

At least 91 records · Page 5Linked to original sources
PubMed1995

A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease.

BACKGROUND: In a previous study, men with a history of myocardial infarction were found to have an increased prevalence of homozygosity for the deletional allele (D) of the angiotensin-converting-enzyme (ACE) gene. The D allele is associated with higher levels of ACE, which may predispose a person to ischemic heart disease. We investigated the association between the ACE genotype and the incidence of myocardial infarction, as well as other manifestations of ischemic heart disease, in a large, prospective cohort of U.S. male physicians. METHODS: In the Physicians' Health Study, ischemic heart disease as defined by angina, coronary revascularization, or myocardial infarction developed in 1250 men by 1992. They were matched with 2340 controls according to age and smoking history. Zygosity for the deletion-insertion (D-I) polymorphism of the ACE gene was determined by an assay based on the polymerase chain reaction. Data were analyzed for both matched pairs and unmatched samples, with adjustment for the effects of known or suspected risk factors by conditional and nonconditional logistic regression, respectively. RESULTS: The ACE genotype was not associated with the occurrence of either ischemic heart disease or myocardial infarction. The adjusted relative risk associated with the D allele was 1.07 (95 percent confidence interval, 0.96 to 1.19; P = 0.24) for ischemic heart disease and 1.05 (95 percent confidence interval, 0.89 to 1.25; P = 0.56) for myocardial infarction, if an additive mode of inheritance is assumed. Additional analyses assuming dominant and recessive effects of the D allele also failed to show any association, as did the examination of low-risk subgroups. CONCLUSIONS: In a large, prospectively followed population of U.S. male physicians, the presence of the D allele of the ACE gene conferred no appreciable increase in the risk of ischemic heart disease or myocardial infarction.

Alleles↗
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

Animal models of genetic hypertension: what can we learn for human hypertension?

1. The dissection of the genetic components of common complex diseases, such as hypertension, represents a major investigational challenge. The use of inbred experimental animal models of the disease represents a time-honoured approach to reducing the difficulty of this task. 2. Recent progress in molecular genetics has raised expectations that the application of powerful new techniques to established animal models of hereditary hypertension may provide important new insights into the genetic basis of human hypertension and perhaps direct access to genes involved in human hypertension. 3. These methods provide exciting opportunities, but to recognize their full potential will require the revision of many traditional and established strategies used in hypertension research. There can be little doubt that these methods, if applied wisely, will make an important contribution to our understanding of hypertension as a disease that is the result of the interaction of genetic and environmental factors. 4. Whether the applicability of results obtained in experimental animals is primarily conceptual, furthering our understanding primarily of disease mechanisms, or whether newly recognized disease-relevant genes will directly identify their human homologues as being involved in the pathogenesis of hypertension in humans cannot be predicted with certainty. Either possibility fully justifies efforts and resources directed into the application of molecular genetic research to experimental animal models.

Animals↗
PubMed1994

What can the molecular genetics of hypertensive rats teach us about the genetics of hypertension in humans?

Recent progress in molecular genetics has raised expectations that the application of powerful new techniques to established animal models of hereditary hypertension may provide important new insights in the genetic basis of human hypertension. Whereas these methods provide exciting opportunities, we shall have to revise many traditional and established strategies used in hypertension research to recognize their full potential. Although it is probably naive to anticipate the quick identification of genes involved in the pathogenesis of human hypertension from this research, these methods, if applied wisely, are likely to render important conceptual insights into the nature not only of hypertension and cardiovascular disease but of polygenic disorders in general.

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↗
PubMed1994

Caveat emptor.

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Animal Husbandry↗
PubMed1993

Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat.

Recent studies in both experimental animals and man have demonstrated the unique efficacy of converting enzyme inhibitors to prevent or attenuate ventricular remodeling after myocardial infarction. Concomitantly, evidence for a trophic role of the renin-angiotensin system (RAS), as well as for the existence of an intracardiac tissue-resident RAS, has been presented, raising the question whether altered regulation of this cardiac RAS may be associated with the process of ventricular remodeling. We conducted the present study to examine whether cardiac angiotensinogen gene expression is altered after myocardial infarction. Experiments were performed in rats 5 and 25 days after ligation of the left coronary artery or sham operation. Coronary artery ligation resulted in relative infarct sizes averaging 29% and 36% of total left ventricular mass at 5 and 25 days and in marked elevations of left ventricular end-diastolic pressure (LVEDP). Angiotensinogen mRNA levels, measured by solution hybridization assay and confirmed in a second, independent experimental group by RNAse protection assay, were significantly elevated in the non-infarcted portion of the left ventricle at 5 days after infarction when compared to the sham group (22.1 + 3.3 vs. 13.4 +/- 2.0 fg/microgram total RNA; ratio of densitometric absorbance for angiotensinogen/beta-actin: 0.356 +/- 0.041 vs. 0.156 +/- 0.02), and showed a significant correlation with infarct size (r = 0.93). At 25 days, angiotensinogen gene expression had returned to control values. Similarly, no significant differences in angiotensinogen mRNA levels between animals with and without infarction were found in other cardiac tissues (atria, right ventricle). Plasma renin activity was significantly increased over baseline in the infarct group at 5, but not at 25 days. Our results demonstrate that acute hemodynamic embarrassment early after LV infarction is associated with augmented angiotensinogen gene expression. The potential significance of this finding is discussed.

Angiotensinogen↗
PubMed1993

Gating charge differences between two voltage-gated K+ channels are due to the specific charge content of their respective S4 regions.

Voltage-gated ion channels that differ in their primary amino acid sequence in the putative voltage sensor, the S4 region, show distinct voltage-sensing characteristics. In this study, we directly compared two voltage-gated K+ channels, the mammalian RCK1 with the Drosophila Shab11, and correlated the specific amino acid content of their respective S4 regions with the distinct voltage-sensing properties they exhibit. We find that specific differences in the charge content of the S4 region are sufficient to account for the distinct gating valence of each channel. However, differences in residues inside the S4 region are not sufficient to account for each channel's characteristic voltage range of activation.

Amino Acid Sequence↗
PubMed1993

Molecular genetics of the SA-gene: cosegregation with hypertension and mapping to rat chromosome 1.

OBJECTIVES: The SA-gene shows markedly higher levels of expression in the kidneys of spontaneously hypertensive rats (SHR) than in their non-hypertensive reference strain, the Wistar-Kyoto (WKY) rat. Based on the important role of the kidney in blood pressure regulation, the possibility has been raised that this gene, the translational product of which remains unknown, may participate in the pathogenesis of primary hypertension. The present study was conducted to test this hypothesis and to ascertain the chromosomal localization of the SA-gene. DESIGN: A cosegregation study was performed using an F2 intercross between stroke-prone SHR (SHRSP) and WKY rats, and a previously described restriction fragment length polymorphism of the SA-gene for characterization of genotype. Mapping of the SA-gene was accomplished by screening a somatic cell-hybrid panel and by linkage group analysis. RESULTS: A statistically significant difference in systolic blood pressure was found after sodium loading, but not under basal conditions between groups of rats defined by zygosity at the SA locus, consistent with a hypertensive effect of the SHRSP allele. No effect of SA genotype on diastolic blood pressure was observed. The SA-gene was localized on rat chromosome 1. CONCLUSIONS: This study establishes the SA locus on chromosome 1 as a region in which a gene or genes contributing to blood pressure regulation in this model are localized, and provides further evidence for a possible role of the SA-gene in the pathogenesis of hypertension.

Animals↗
PubMed1993

Membrane microviscosity does not correlate with blood pressure: a cosegregation study.

OBJECTIVE: To determine whether elevated microviscosity is associated with elevated arterial pressure in segregating (F2) hybrids produced by crossing stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. METHODS: SHRSP and WKY rats were obtained from the colony at the University of Heidelberg. F2 progeny were obtained by brother-sister mating of the F1 progeny of the cross between SHRSP and WKY rats. Membrane microviscosity (the inverse of fluidity) was measured as a fluorescence anisotropy of trimethylammonium diphenylhexatriene incubated with the erythrocyte membranes. The measurements were made using a luminescence spectrometer with computer-controlled excitation and emission polarizers. RESULTS: Membrane microviscosity was significantly greater (fluidity was lower) in erythrocyte membranes obtained from SHRSP than in those obtained from WKY rats. In the F2 cohort there were no significant correlations between membrane microviscosity and systolic blood pressure, diastolic blood pressure, salt-loaded systolic blood pressure or salt-loaded diastolic blood pressure. A similar lack of relationship between these parameters was shown in a subgroup analysis, in which males or females with a male WKY rat progenitor and males or females with a male SHRSP progenitor were analysed separately. CONCLUSIONS: Erythrocyte membrane microviscosity is elevated in SHRSP compared with WKY rats. In segregating F2 hybrid rats the membrane microviscosity trait does not correlate with blood pressure. These results eliminate the microviscosity trait as being directly related to the cause of genetic differences in blood pressure between WKY rats and SHRSP.

Animals↗
PubMed1993

Role of the cardiac renin-angiotensin system in hypertensive cardiac hypertrophy.

The unique efficacy of converting-enzyme inhibitors in inducing regression, or preventing the occurrence, of ventricular hypertrophy associated with systemic hypertension has for many years pointed to a possible direct effect of the renin-angiotensin system in the pathogenesis of cardiac hypertrophy. Over the last 10 years evidence has been forthcoming about direct trophic effects of angiotensin II in several experimental systems, and we now have conclusive evidence for the existence of a local, intracardiac renin-angiotensin system. This system is capable of local synthesis of all components of the renin-angiotensin system, and has been demonstrated to be capable to cleave, via the classic pathway, angiotensin peptides from the precursor, angiotensinogen. Moreover, a number of studies have demonstrated the capacity of regulatory response and modulation of activity of the local system in response to a variety of pharmacological perturbations, and differential regulation of expression of specific components under pathological conditions. There is, thus, fairly solid evidence for participation of the cardiac renin-angiotensin system in the pathogenesis of hypertensive cardiac hypertrophy. Whether this participation is causative in character, or only a secondary event, and what precisely are the stimuli that modulate the activity of the cardiac renin-angiotensin system, are questions that are still poorly understood, but being actively researched.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

The cardiac renin-angiotensin system. From basic research to clinical relevance.

Local, tissue-resident renin-angiotensin systems are increasingly being recognized as important neurohumoral regulatory units which may act independently of the circulating system. Here, the evidence supporting the existence, functional integration, and physio-pathological role of the cardiac renin-angiotensin system is reviewed. The elements of the catalytic cascade of the system, renin, angiotensinogen, angiotensin-converting enzyme, and the specific angiotensin receptor have all been identified in cardiac tissues as synthesized there by local expression of the respective genes. Modulation of gene expression in response to various perturbations has been demonstrated, and may be regulated independently of the plasma or other tissue renin-angiotensin systems. In isolated hearts, generation of the biologically active peptides, angiotensin I and II, has been documented, establishing the capability of this system to act as a functionally integrated catalytic pathway for the production of angiotensin II. Through its specific receptors angiotensin mediates profound effects on cardiomyocyte function and, as we are beginning to learn, on structure and growth. The remarkable therapeutic potential of drugs that inhibit the renin-angiotensin system in a number of cardiovascular disorders emphasizes the likely role that the cardiac RAS plays in health and disease. Continued efforts at elucidating the precise nature of this role will not only enhance our understanding of this system, but also translate into further clinical progress.

Animals↗
PubMed1992

Incremental reductions of positive charge within the S4 region of a voltage-gated K+ channel result in corresponding decreases in gating charge.

The S4 region of voltage-dependent ion channels is involved in the voltage-sensing mechanism of channel activation. Previous studies in fast inactivating channels have used non-steady-state measurements and thus have not allowed the quantitative assessment of activation parameters. Using site-directed mutagenesis and voltage-clamp recordings in a noninactivating channel (RCK1), we demonstrate that stepwise reductions of positive charge within the S4 region correlate with a progressive decrease in the channel's overall gating valence. In addition to testing for electrostatic behavior of individual charged residues, our study was designed to probe nonelectrostatic influences on charge movement. We provide evidence that individual charged residues behave differentially in response to the electric field, so that purely electrostatic influences cannot fully account for the gating movement of certain charges.

Amino Acid Sequence↗