Biomedical subjects

E Fleck

Publications and source records attributed to E Fleck.

At least 145 records · Page 8Linked to original sources

PubMed1997

Representation of amino acid sequences as two-dimensional point patterns.

An algorithm for the representation of amino acid sequences as two-dimensional point patterns (2-D plot) is described. The algorithm is based on chaos game representation (CGR) for DNA sequences and was extended for amino acid sequences. The 2-D plot depicts the sequentiality of amino acids and the amino acid composition of a protein. Changes in a protein sequence as insertion, deletion and repeats of amino acids are characterized by specific geometrical properties and changes in the 2-D plots. The 2-D plot may be considered as a two-dimensional "fingerprint" of a protein. The properties of the algorithm are explained by user-defined amino acid sequences. As an example the 2-D plots of two selected heart proteins are generated. The sequences of these proteins are obtained from the protein sequence database SWISS-PROT.

Algorithms↗

PubMed1997

Myocardial angiotensin receptor type 1 gene expression in a rat model of cardiac volume overload.

To investigate the regulation of the angiotensin receptor type 1 (AT1) in different organs in cardiac volume overload, we measured AT1 mRNA content in the atria, left and right ventricle, kidney and liver of rats with an aortocaval shunt, produced by infrarenal aortocaval puncture 4 weeks earlier. For angiotensin receptor mRNA quantitation a novel quantitative PCR procedure based on liquid phase hybridization was used that allowed the determination of absolute AT1 mRNA copy numbers and its comparison in different organs. Glyceraldehydephosphate dehydrogenase (GAPDH) mRNA was measured by RT-PCR to control externally equal mRNA content and quality of RNA extraction in shunt animals and controls. Heart weight was increased in the shunt animals, with the greatest increase in the atria. Blood pressure, plasma renin activity, plasma angiotensin I and II and aldosterone concentrations were not significantly altered. The AT1 mRNA content was significantly increased in the atria (shunt: 1167 +/- 350 copies AT1 mRNA/ng RNA vs controls: 803 +/- 240; p < 0.05). No change was found in the right or left ventricle, in the kidney and liver. The findings document that atrial hypertrophy in cardiac volume overload parallel with a significant increase in atrial AT1 mRNA content.

Animals↗

PubMed1997

[Multi-media presentation of radiologic image data with the Internet].

AIM: Recent developments of the Internet (World Wide Web) allow the integration of audio, video, digital film sequences, and three-dimensional data. The applicability of these innovations for medical documentation is demonstrated. METHODS: Our existing software for medical image processing and 3D reconstruction was extended to provide images, film sequences, and complex 3D models in an Internet-compatible data format. RESULTS: The multimedia results of the image processing were integrated into Internet documents. Specialized programs are no longer necessary for visualization. The Internet software allows for user-friendly handling and interactive presentation of the 2D and 3D data. CONCLUSIONS: The Internet offers public-domain software for display of images, audio/video, and 3D data. Thus, the tools of the Internet represent an ideal basis for local hospital information systems, computer-aided medical education, and teleconferencing.

Computer Communication Networks↗

PubMed1997

Registered image subtraction for CT-, MR- and coronary angiography.

Conventional post-processing of digital subtraction angiography (DSA) by 3D spiral CT, 3D MRI and 2D DSA is often hampered by extended artefacts due to patient movements during examination. In this paper an image registration procedure prior to the digital subtraction is introduced allowing an enhanced visualization of the contrast agent. The object displacement is detected by analysis of image deformations in small local regions. The motion pattern is used to compute a new synthetic mask of maximum congruence with the contrast medium image. This new mask image is then used in the subsequent subtraction. The algorithm works fully automatically and does not need any interactive placement of landmarks. Results obtained from subtraction of uncorrected and corrected sequences were compared with each other. The registration procedure provided good results in the suppression of subtraction artefacts and in the enhancement of vascular structures. Results are presented from subtraction of 2D and 3D data from CTA, MR mammography and coronary angiography.

Artifacts↗

PubMed1997

Angiotensin receptor type 1 mRNA in human right ventricular endomyocardial biopsies: downregulation in heart failure.

OBJECTIVE: Atrial angiotensin II receptors type 1 (AT1) are downregulated in end-stage human heart failure at mRNA and protein level. The present study investigated whether AT1 ventricular mRNA content was reduced in myocardial biopsies from heart failure patients. METHODS: AT1 mRNA was quantitated in right ventricular endomyocardial biopsies from 16 patients with decreased left ventricular function (LVEF 36 +/- 3%) due to dilated cardiomyopathy (DCM) and in biopsies from 12 patients with suspected myocardial disease but normal cardiac function (LVEF 62 +/- 2%). Two biopsies per patient were pooled, RNA was extracted and reverse-transcribed after addition of an AT1 cRNA standard. AT1 standard and wild-type RNA were amplified with the same primers in the same PCR tube. The PCR products were hybridized to a microtiter plate and detected and quantitated by an ELISA system. Glyceraldehyde phosphate dehydrogenase (GAPDH) mRNA was determined in the same samples as AT1 mRNA. RESULTS: In the biopsies from 16 patients with heart failure, a 68% decrease in AT1 mRNA content was found in comparison with 12 controls (heart failure 94 +/- 15 AT1 mRNA copies/ng RNA; controls 297 +/- 45; P < 0.001). Relating AT1 mRNA content to GAPDH mRNA confirmed the specific decrease in AT1 mRNA (AT1/GAPDH: heart failure 1.3 +/- 0.15; controls 3.4 +/- 0.5; p < 0.002). The best correlation between AT1 mRNA content and clinical parameters was found for right ventricular ejection fraction (r = 0.59, P < 0.01). CONCLUSIONS: The quantitative RT-PCR procedure indicated a loss of ventricular AT1 mRNA in human heart failure which corresponds to the loss of AT1 protein described previously. It may underlie the decrease in AT1 protein expression in human heart failure.

Adult↗

PubMed1997

Improved assessment of intravascular Doppler coronary flow velocity profile.

Easy and safe in-vivo flow velocity studies in small coronary arteries have become feasible using a 0.014 'or 0.018' guidewire with an integrated Doppler probe in its tip (FloWire, Cardiometrics). Assessment of the flow velocity profile by the ratio of diastolic to systolic flow velocity (DSVR) is used as a diagnostic parameter. However, DSVR is a coarse quantifier of the flow velocity profile, and is subject to large physiologic variance and depends crucially on the quality of the Doppler signal. The aim of our study was to test parameters derived from statistical time series analysis for monitoring the quality of the instantaneous peak velocity (IPV) signal. Improvement of quantification of changes in quality and shape of flow velocity profiles by these parameters as compared to DSVR was a second goal. We investigated analog-digital converted IPV-signals and video registrations of corresponding greyscale spectra of intracoronary Doppler flow velocity signals. The signals were analyzed by using the autocorrelation function (ACF) in the time domain and a fast Fourier transform (FFT) in the frequency domain (standard time series statistics). The first minimum of autocorrelation function turned out to be very sensitive to signal quality, and Fisher's g of the periodogram was the parameter of choice for shape analysis. In 11 patients with coronary artery disease, pre and post PTCA, the sensitivity of DSVR and signal to noise ratio to changes in shape and quality of the flow velocity signals was compared to that of the new parameters. Nineteen Doppler flow velocity samples of good quality from measurements in nonstenotic vessels and 7 flow velocity tracings with visible artefacts were used to assess the value of these parameters in monitoring signal quality. By comparison with corresponding parameters in use (SNR and DSVR) a significantly improved performance of the new statistical parameters was observed with respect to sensitivity to changes in signal quality and flow profile. In view of these results and because of the short calculation time of these variables they should be used for on-line quality control and analysis of flow velocity profiles.

Adult↗

PubMed1997

Changing nursing practice through continuing education: a tool for evaluation.

In light of the current cost-orientated, rapidly changing health service, continuing education providers are challenged to achieve the greatest benefits for the service. Given this culture it is argued that it is essential for nurses to acquire the skills to continually learn, and that for managers there is seen to be a measurable change in a recommended practice or behaviour. To meet these challenges it is essential that continuing educators plan, implement and evaluate programmes in partnership with clinicians and managers. A literature review revealed that most evaluations did not address whether continuing education has resulted in a change in practice. This paper describes a study on the use of goal attainment scaling as an evaluation tool to measure changes in learner behaviour and as a means of promoting self-determination among the participants. It is proposed that goal attainment scaling can be used to measure changes in participant behaviour following an educational programme. In addition, this analysis of participant interviews indicates the tool's usefulness as a self-reporting instrument and this appears to foster the skills of self-assessment and appraisal of performance.

Clinical Competence↗

PubMed1997

[Fractal surface analysis of intrapulmonary space-occupying lesions from high-resolution CT studies].

PURPOSE: The visual assessment of shape and surface structures of pulmonary nodules (PN) (smooth edges vs. spiculae) serves as a qualitative, subjective criterion in differential diagnosis. These properties must be quantified by computer-assisted evaluation, an adequate mathematical model, and new quantitative shape parameters. METHODS: 12 patients were investigated by high resolution CT. Based on 3D reconstructions with increasing thresholds, the PN surface S, volume V, fractal dimension (FD = In(S)/ In(square root of V)), and fractal index (F1 = square root of S/ square root of V) were calculated. RESULTS: The relations between the reconstruction threshold and the calculated tumour surface, respective volume, are of a fractal nature: S = c1 x thres1/d, V = c2 x thres1/D (c1, c2, d, D: real constants). Whereas the absolute values of surface and volume strongly depend on the chosen threshold (mean volume differences of 249%), the derived parameter of the fractal dimension for a specific PN is nearly constant for all thresholds under review (r = 0.998, SD = 0.05). CONCLUSIONS: FD and FI are new diagnostic features for the assessment of PN surface structure and morphology. Thus, the assessment of pulmonary nodules can be supported by new quantitative parameters representing surface irregularity due to invasive tumour growth into adjacent tissue.

Aged↗

PubMed1997

[Value of Doppler blood flow velocity measurements in peripheral percutaneous laser-assisted angioplasties].

PURPOSE: The aim of the study was to establish the prognostic value and clinical implications of blood flow velocity measurements by Doppler guide wires during peripheral laser-assisted percutaneous transluminal angioplasty (PTLA). METHODS: 39 patients presenting with symptomatic peripheral arterial obstructive disease underwent angiography and blood flow velocity assessment by Doppler guide wire (0.018") prior to and following PTLA. Both quantitative angiography (QCA) for measurement of luminal diameters and Doppler assessment of maximum peak velocities (MPV) were performed 2 cm proximal, over and 2 cm distal to stenoses. The results were compared with the following clinical endpoints: 1. Short-term clinical improvement by AHA-criteria during first follow-up examination and 2. criteria for patency suggested by Rutherford [12] within 1 year (1-22 months). RESULTS: Angiography demonstrated initial success of PTLA in all patients. Relative diameter stenosis decreased from 70 +/- 0.04% to 17 +/- 0.05%. Mean clinically category improved from 2.7 +/- 0.1 to 1.2 +/- 0.1 following intervention. Mean grade of clinical improvement was 2.8 +/- 0.1. 22/39 patients demonstrated event-free follow-up examinations. Doppler measurements of MPV post PTLA in the proximal reference segment correlated with clinical outcome. MPV > or = 90 cm/s was associated with good primary success, unlimited walking capacity and event-free follow-up. MPV > or = 70 cm/s predicted an improvement of short-term clinical outcome by 2 grades (predictive value 80%). MPV < 70 cm/s was associated with both minor primary clinical improvement (+/- 0, +1) and increased incidence of restenosis during follow-up. CONCLUSION: Following PTLA, MPV adds information to angiographic success. MPV > or = 90 cm/s in a proximal reference segment following PTLA predicts good clinical outcome, whereas MPV < 70 cm/s is associated with minor primary clinical success and increased rates of restenosis.

Adult↗

PubMed1997

Stress echocardiography in special groups: in women, in left bundle branch block, in hypertension and after heart transplantation.

The non-invasive diagnosis of coronary artery disease by exercise electrocardiography is less accurate in women than in men, with a high rate of false-positive results in women. In contrast, recent studies have demonstrated that stress echocardiography in women is more accurate than exercise echocardiography and that the significantly higher specificity of stress electrocardiography may have the benefit of avoiding unnecessary angiography in women. Exercise-induced changes in the electrocardiogram are non-diagnostic in the presence of left bundle branch block or basal ST changes. In these patients, stress echocardiography can be used instead of conventional scintigraphy for the detection of coronary artery disease, but further echocardiographic studies are needed to confirm the promising results. Exercise electrocardiography and exercise echocardiography have been reported to be disappointing in the early detection of cardiac allograft vasculopathy after heart transplantation, and dobutamine stress echocardiography overestimates the incidence of angiographic evidence of cardiac allograft vasculopathy. However, compared to intravascular ultrasound imaging, dobutamine stress echocardiography seems to be a suitable non-invasive method for detecting cardiac allograft vasculopathy.

Bundle-Branch Block↗

PubMed1997

Intravascular ultrasound assessment of direct percutaneous transluminal coronary angioplasty in patients with acute myocardial infarction.

BACKGROUND: Acute myocardial infarction is caused by sudden thrombotic occlusion of the coronary artery due to a previous rupture of atherosclerotic plaque. OBJECTIVE: To use intracoronary ultrasound measurements to evaluate lumen and plaque changes in patients with acute myocardial infarction. METHODS: Patients (n = 103) with acute myocardial infarction who had been scheduled to undergo primary percutaneous transluminal coronary angioplasty (PTCA) were selected. Both before and after successful coronary angioplasty, intracoronary 30 MHz ultrasound studies were performed using a 3.5F monorail catheter. The ultrasound catheter was successfully advanced into the occluded vessel segment without major complications prior to PTCA in 79 of 103 (76.7%) patients and after PTCA in 88 of 103 (85.3%) patients. RESULTS: The plaques were eccentric in 66 patients (83.5%). The plaque morphology was purely low echogenic in 14 (17.7%), highly echogenic in six (7.6%) and mixed in 59 (74.7%) patients. Partial (59 of 79, 74.7%) or ring-like calcification (3 of 79, 3.8%) was observed in 62 patients (78.5%). Plaque fissuring or dissection was detected prior to PTCA in 25 patients (31.7%). Coronary angioplasty successfully enlarged the inner luminal area from 2.1 +/- 0.7 to 7.4 +/- 1.9 mm2 (P < 0.01), whereas the plaque-thrombus area decreased significantly (13.8 +/- 1.7 mm2 before and 9.0 +/- 1.9 mm2 after PTCA; P < 0.01). The total vessel area remained virtually constant (15.9 +/- 1.9 mm2 before and 16.4 +/- 2.5 mm2 after PTCA, NS). PTCA-induced plaque rupture or dissection was observed in only 13 (16.5%) patients. CONCLUSION: Intracoronary ultrasound imaging can be performed safely and successfully prior and subsequent to PTCA in selected patients with acute myocardial infarction. Early reperfusion via PTCA seems to be attributable to a significant reduction in the amount of low-echogenic plaque and thrombus material, whereas factors like balloon-induced dissection and stretching of vessels play only a minor role.

Aged↗

PubMed1997

Effects of tolbutamide on ATP-sensitive K+ channels from human right atrial cardiac myocytes.

In order to gain further insight into possible deleterious effects on ischaemia-induced myocardial damage induced by sulfonylureas when administered to humans, the effects of tolbutamide on ATP-sensitive K+ (KATP) channels from human right atrial myocytes were studied. Single myocytes were enzymatically isolated from human right atrium. The cell-attached and inside-out configuration of the patch-clamp technique were employed at room temperature (both the pipette and the bath solution contained high [K+]). KATP channels in inside-out patches showed slight inward rectification, had a slope conductance of 75.1 +/- 2.4 pS (mean +/- S.E.M.; n = 5) at negative membrane potentials and these channels were blocked by ATP (half-maximal block (EC50) at 39 microM; Hill coefficient = 1.65). In cell-attached recordings, cromakalim (300 microM) opened KATP channels (with a slope conductance of 73.3 +/- 1.8 pS (n = 16) at negative membrane potentials) in previously silent patches. Cromakalim-induced openings of KATP channels were not markedly affected by 100 or 300 microM tolbutamide but were blocked by tolbutamide at millimolar concentrations (1-3 mM). The concentration-response relationship for tolbutamide-induced block of KATP channels in the presence of 300 microM cromakalim in cell-attached patches was calculated to values for the EC50 of 1.325 mM and for the Hill coefficient of 1.0, respectively. 1 mM tolbutamide-induced block of cromakalim-induced KATP channel openings was not different at room temperature when compared to 37 degrees. It is concluded that KATP channels from human right atrial myocytes have a low sensitivity towards tolbutamide-induced block.

Adenosine Triphosphate↗

PubMed1997

Protein kinase C-dependent regulation of the human AT1 promoter in vascular smooth muscle cells.

The expression level of angiotensin II (ANG II) type 1 receptors (AT1) determines the magnitude of ANG II signaling in vascular smooth muscle cells (VSMC). AT1 mRNA expression in cultured bovine VSMC increased twofold after 8 h of protein kinase C (PKC) activation with phorbol 12-myristate 13-acetate (PMA), whereas stimulation with forskolin did not alter the AT1 mRNA level. The expression of AT1 promoter/exon 1 [-513/+92 base pairs (bp)] luciferase constructs transfected into VSMC increased 2.4-fold with PMA stimulation. In-gel kinase assays demonstrated rapid phosphorylation of mitogen-activating protein kinases (MAPK) ERK1 and ERK2 by PMA. Electrophoretic gel mobility shift assays showed sequence-specific binding of nuclear proteins from PMA-activated VSMC, identified as activator protein 1 (AP-1) complex in competition assays, to a radiolabeled AT1-promoter fragment (-368/-399 bp). Recombinant AP-1 binds in a sequence-specific manner to the -386/-399-bp region. Site-specific mutagenesis destroying the AP-1 site, the adjacent polyoma enhancer activator 3 element, or both sites simultaneously indicated that both sites together are necessary and sufficient to control basal and PMA-induced activation of the human AT1 promoter in transfected VSMC. The capability of the phorbol ester PMA to activate the human AT1 promoter in VSMC via an AP-1 element suggests a prominent role for PKC/MAPK and Ets proteins in AT1 regulation.

Animals↗

PubMed1997

Mitogen-activated protein kinase activation is involved in platelet-derived growth factor-directed migration by vascular smooth muscle cells.

Migration of vascular smooth muscle cells (VSMCs) is a crucial response to vascular injury resulting in neointima formation and atherosclerosis. Platelet-derived growth factor (PDGF-BB) functions as a potent chemoattractant for VSMCs and enhances these pathologies in the vasculature. However, little is known about the intracellular pathways that mediate VSMC migration. In the present study, we investigated the role of mitogen-activated protein kinase (MAPK) activation in this function, since PDGF-BB as well as other growth factors activate this pathway. Using an in-gel kinase assay, we observed that PD 98059 an inhibitor of MEK that activates MAP kinase, inhibited PDGF-BB-induced activation of ERK-1 and ERK-2 in cultured rat aortic smooth muscle cells in a concentration-dependent manner. In contrast, PDGF-mediated activation of intracellular calcium release was not affected by PD 98059. The chemotactic response of both rat aortic smooth muscle cells (RASMCs) and human umbilical vein smooth muscle cells (HUSMCs) toward PDGF-BB (10 ng/mL) was significantly reduced by PD 98059 (10 mumol/L) to 41.7 +/- 7.1% in RASMCs (P < .01) and to 47.2 +/- 5.3% in HUSMCs (P < .01). Similar inhibition was seen at 30 mumol/L, less at 1 mumol/L. To further confirm the specificity of these results implicating the MAPK pathway, an antisense oligodeoxynucleotide (ODN) directed against the initiation translation site of rat ERK-1 and ERK-2 mRNA was used to suppress MAP kinase synthesis and function in rat VSMCs. Liposomal transfection with 0.4 mumol/L antisense ODN reduced ERK-1 and ERK-2 protein by 65% (P < .01) after 48 hours. The chemotactic response to PDGF-BB (10 ng/mL) was reduced by 75% (P < .01) in rat VSMCs transfected with the same antisense ODN concentration. Sense and scrambled control ODNs (0.4 mumol/L) did not affect ERK-1 and ERK-2 protein concentrations or chemotaxis of VSMCs induced by PDGF-BB. These experiments provide the first evidence that activation of MAPK is a critical event in PDGF-mediated signal transduction regulating VSMC migration.

Animals↗

PubMed1997

Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin.

Clinical data suggest a link between the activation of the renin-angiotensin system and cardiovascular ischemic events. Leukocyte accumulation in the vessel wall is a hallmark of early atherosclerosis and plaque progression. E-Selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are adhesion molecules participating in mediating interactions between leukocytes and endothelial cells and have been found to be expressed in athero-sclerotic plaques. We investigated whether angiotensin II, the effector of the renin-angiotensin system, influences the endothelial expression of E-selectin, VCAM-1, and ICAM-1. In coronary endothelial cells derived from explanted human hearts, angiotensin II (10(-11) to 10(-5) mol/L) induced a concentration-dependent increase in E-selectin expression. The effect was measured by cell ELISA and duplex reverse-transcription polymerase chain reaction (RT-PCR) and reached its maximum at 10(-7) mol/L. Angiotensin II induced only a small increase in E-selectin expression in cardiac microvascular endothelial cells. VCAM-1 and ICAM-1 were not affected by angiotensin II stimulation. In addition, the effect of angiotensin II-induced E-selectin expression on leukocyte adhesion was quantified under flow conditions. Angiotensin II (10(-7) mol/L) increased leukocyte adhesion significantly to 67% of the maximal effect by tumor necrosis factor-alpha at a wall shear stress of 2 dyne/cm2. This adhesion was found to be E-selectin dependent, as demonstrated by blocking antibodies. The AT1-receptor antagonist DUP 753 significantly reduced E-selectin-dependent adhesion, whereas the AT2-receptor antagonist PD 123177 had no inhibitory effect. In addition, only AT1-receptor, but not AT2-receptor, mRNA could be detected by RT-PCR in coronary endothelial cells. Therefore, it is suggested that AT1 receptors mediate the effects of angiotensin II on E-selectin expression and leukocyte adhesion on coronary endothelial cells.

Angiotensin II↗

PubMed1997

Use of manganese in RT-PCR eliminates PCR artifacts resulting from DNase I digestion.

The precise quantification of rare mRNA copies from intronless genes by reverse transcription polymerase chain reaction (RT-PCR) requires the complete removal of genomic DNA because discrimination of cDNA and DNA amplification products by differing sizes of PCR products is not possible. Elimination of DNA is achieved by treating the RNA sample with RNase-free DNase I before RT-PCR. The lack of a PCR product from DNase-treated RNA samples before RT is usually accepted as a proof of efficient DNA destruction. However, this may vary depending on the metal cofactor used in the DNase I cleavage. Treating DNA-contaminated RNA samples with DNase I and magnesium as a cofactor creates a negative PCR control after digestion without further RT. Paradoxically, after additional RT-PCR, the original intron-containing DNA fragment size may be produced again. In the presence of manganese as cofactor, RT-created DNA fragments do not appear. This is because in the presence of manganese, DNase I cleaves both DNA strands at approximately the same site, yielding DNA fragments that are blunt-ended or that have protruding termini of only one or two nucleotides in length. However, overlapping fragments with the potential to recombine are created by DNase digestion with magnesium as cofactor. Because one cannot differentiate between a PCR signal produced by RNA and one produced by recombined DNA after DNase I digestion and RT, all such DNase I assays should be performed with manganese instead of magnesium.

Artifacts↗

PubMed1996

The construction of the World Wide Web-accessible myocardial two-dimensional gel electrophoresis protein database "HEART-2DPAGE": a practical approach.

The construction of the two-dimensional electrophoresis (2-DE) gel protein database "HEART-2DPAGE" for human heart proteins, accessible via the World Wide Web (WWW), is described. This database provides the opportunity to retrieve descriptive information interactively by mouse clicking on a protein spot within a 2-DE gel image or to retrieve the position of a protein if its protein name or a search expression is given. The realization of searching for proteins, the creation of clickable spots, marked by crosses or textual information, and interactive viewing opportunities are discussed from a software-oriented point of view. The database takes into account that some human heart proteins are chamber specific. Several Common Gateway Interface (CGI) scripts are described and some practical experience is discussed.

Computer Communication Networks↗

PubMed1996

Molecular biology of angiotensin receptors and their role in human cardiovascular disease.

The actions of angiotensin II in the cardiovascular system are transmitted by two known and possibly some unknown angiotensin receptor types. AT1 and AT2 both correspond to G-protein-coupled receptors with seven hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and promoter sequences contributed to the understanding of receptor protein function and regulation. Angiotensin receptors with atypical binding properties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human ulcrus. In several animal models, receptors with high affinity for angiotensin (1-7) have been described. AT1 stimulation is mediated by the generation of phospholipid-derived second messengers, activation of protein kinase C, the MAPkinase pathway and of immediate early genes. Recently, phosphorylation and dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphorylation, internalization, modification of transcription rate and mRNA stability. Regulation is highly cell and organ specific and includes upregulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the cardiovascular system is relatively well established, there is little information regarding the role of AT2. Recent hypotheses suggest an antagonism between AT1 and AT2 at the signal transduction and the functional level. Transgenic animal models, particularly with targeted disruption of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been described in the AT1 and AT2 gene or neighbored regions and are used to analyze the association between gene defects and cardiovascular diseases. AT1 antagonists are now being introduced into the treatment of hypertension and potentially heart failure, and more interesting pharmacological developments are expected from the ongoing basic studies.

Angiotensin I↗