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PubMed1993

Effect of 5-lipoxygenase and cyclooxygenase blockade on porcine hemodynamics during continuous infusion of platelet-activating factor.

We hypothesized that 5-lipoxygenase and cyclooxygenase products might be mediators of cardiopulmonary and systemic vascular effects induced by a 4 h continuous infusion of platelet-activating factor (PAF, 10 ng/kg/min) in anesthetized pigs. Indomethacin (cyclooxygenase inhibitor) potentiated and CGS 8515 (5-lipoxygenase inhibitor) attenuated PAF-induced increases in total peripheral resistance (TPR) from 2.5 to 4 h. However, the 5-lipoxygenase inhibitor failed to modify pulmonary vasoconstriction and hypertension caused by PAF. Except for a delay in onset (approximately 44 s) and rate of development of pulmonary hypertension during the initial 10 min of PAF infusion, the pulmonary hemodynamic changes were also not attenuated by indomethacin. On the other hand, at 4 h, the PAF-induced pulmonary hypertension and systemic vasoconstriction were completely or partially reversed, respectively, by WEB 2086 (PAF receptor antagonist). The PAF-induced increases in plasma thromboxane B2 (TXB2) were blocked by indomethacin but not by CGS 8515, and at 4 h the 5-lipoxygenase inhibitor potentiated the levels of TXB2 in pigs treated with PAF. The plasma concentrations of 6-keto-PGF1 alpha and leukotriene B4 (LTB4) were not modified by PAF or CGS 8515 + PAF. We conclude that PAF-induced increases in TPR (2.5-4 h) are potentiated by indomethacin and are dependent on 5-lipoxygenase products other than LTB4. Although the early pulmonary vascular response (< 10 min) to PAF is dependent on cyclooxygenase products, the sustained response (after 10 min) cannot be explained by either 5-lipoxygenase or cyclooxygenase products but may be mediated directly by PAF receptors.

6-Ketoprostaglandin F1 alpha↗

PubMedDate not supplied

Hemodynamic and catecholamine responses associated with extracorporeal shock wave lithotripsy.

Patients undergoing extracorporeal shock wave lithotripsy (ESWL) for nephrolithiasis are anesthetized and immersed in water in a semisitting position. Hypertension and tachycardia have been reported to accompany ESWL, and it was hypothesized that those problems were a result of adrenal medullary release of epinephrine or norepinephrine. Therefore, the effects of ESWL on cardiovascular variables and circulating epinephrine and norepinephrine levels in nine patients anesthetized with 1.1% isoflurane in 50% nitrous oxide and oxygen were studied. End-tidal carbon dioxide (CO2) was maintained at 34 +/- 2 mmHg. Cardiac output (CO) and mean arterial pressure (MAP) were measured, and total peripheral resistance (TPR) was calculated at the following time points: (1) after immersion prior to shock wave therapy (control); (2) after 300 shocks; (3) after 800 shocks; and (4) 5 minutes after the completion of ESWL with the patient still immersed. Circulating epinephrine and norepinephrine concentrations were determined at the above times as well as before and after induction of anesthesia but prior to immersion. There was a statistically significant (p less than 0.05) decrease in CO and an increase (p less than 0.05) in MAP and TPR with ESWL treatment. These values returned to baseline levels when treatment was stopped. Plasma epinephrine and norepinephrine values did not change significantly throughout the study period. It was concluded that these ESWL-associated hemodynamic changes were probably not mediated via epinephrine or norepinephrine.

Adult↗

PubMed2004

The effect of statins on angiotensin II-induced hemodynamic changes in young, mildly hypercholesterolemic men.

BACKGROUND: Angiotensin II type 1 (AT(1)) receptors are well known to mediate angiotensin II (Ang II)-induced pro-atherosclerotic effects. It has been found that hypercholesterolemia influences the expression of AT(1) receptors on vascular smooth muscle cells and that increased density of AT(1) receptors exaggerates the hemodynamic response to Ang II. We analyzed to what extent statins and AT(1) receptor antagonists diminish the vasoconstrictive response to Ang II infusion in hypercholesterolemic patients. METHODS: A total of 24 male patients with LDL cholesterol levels >130 mg/dL were enrolled in a randomized, cross-over study. After baseline evaluation, 12 patients received first cerivastatin (0.3 mg/day) and the other 12 patients initially received candesartan (8 mg/day) for 3 weeks, with subsequent cross-over of the medication for the second 3-week drug period. The vascular response was analyzed by the increase in mean arterial pressure (MAP) and total peripheral resistance (TPR) during infusion of increasing doses of Ang II at baseline and the end of each treatment period. Hemodynamic changes were also compared with those in 24 normocholesterolemic subjects without any therapy. RESULTS: At baseline, Ang II provoked a similar increase of MAP and TPR in patients and control subjects. Treatment with cerivastatin did not affect the response to Ang II compared with baseline. By contrast, treatment with candesartan attenuated significantly the response to Ang II compared with baseline and cerivastatin. CONCLUSIONS: Our hemodynamic data indicate the hypothesis that statins do not reduce the responsiveness to Ang II in resistance arteries of young, mildly hypercholesterolemic patients.

Adolescent↗

PubMed2004

Pressor effect of water instilled via a gastrostomy tube in pure autonomic failure.

BACKGROUND: The oral ingestion of water increases seated blood pressure in chronic autonomic failure although the mechanisms of this effect remain unclear. Recent studies in normal subjects suggest that oropharyngeal stimulation during swallowing may be of greater importance in causing a rise in blood pressure (BP) than the gastric effects of water. We therefore assessed the haemodynamic effects of water instilled directly into the stomach via a gastrostomy tube in pure autonomic failure (PAF). METHODS: The subject had longstanding (>20 years) PAF. A gastrostomy tube had been previously placed because of dysphagia. Distilled water (480 ml) was instilled in the seated position with BP and heart rate (HR) measured over the following 40 min while the subject remained seated. Systolic and diastolic BP (SBP and DBP) and heart rate (HR) were recorded intermittently every 3 min with a Dinamap automated syphgmomanometer and continuously using a Portapres device. Subsequent model flow analysis of the Portapres data provided beat-to-beat estimates of cardiac output, stroke volume, and total peripheral resistance (TPR). Subjective orthostatic symptoms were recorded before and after water. RESULTS: Seated SBP and DBP increased after water instillation with increases first noted between 5 and 8 min after the water had been instilled. The BP remained elevated until 35 min post water increase over baseline being +36.5 mm Hg SBP and +24.3 mm Hg DBP. HR, cardiac output, and stroke volume remained unchanged during the study. Total peripheral resistance (TPR) increased post water. These results are similar to those reported in a recent study involving oral ingestion of 480 ml of water in PAF subjects. CONCLUSIONS: Instilling water directly into the stomach in a patient with PAF resulted in similar haemodynamic responses to those seen when water is taken orally. Thus, oropharyngeal factors and swallowing do not appear to be essential in the generation of the water pressor effect in autonomic failure.

Aged↗

PubMed2005

Crystal structure of PilF: functional implication in the type 4 pilus biogenesis in Pseudomonas aeruginosa.

PilF is a requisite protein involved in the type 4 pilus biogenesis system from the Gram-negative human pathogenic bacteria, Pseudomonas aeruginosa. We determined the PilF structure at a 2.2A resolution; this includes six tandem tetratrico peptide repeat (TPR) units forming right-handed superhelix. PilF structure was similar to the heat shock protein organizing protein, which interacts with the C-terminal peptide of Hsp90 and Hsp70 via a concave Asn ladder in the inner groove of TPR superhelix. After simulated screening, the C-terminal pentapeptides of PilG, PilU, PilY, and PilZ proved to be a likely candidate binding to PilF, which are ones of 25 necessary components involved in the type 4 pilus biogenesis system. We proposed that PilF would be critical as a bridgehead in protein-protein interaction and thereby, PilF may bind a necessary molecule in type 4 pilus biogenesis system such as PilG, PilU, PilY, and PilZ.

Amino Acid Sequence↗

PubMed2006

Identification of the functional domains of ANT-1, a novel coactivator of the androgen receptor.

Previously, we identified a transcriptional coactivator for the activation function-1 (AF-1) domain of the human androgen receptor (AR) and designated it androgen receptor N-terminal domain transactivating protein-1 (ANT-1). This coactivator, which contains multiple tetratricopeptide repeat (TPR) motifs from amino acid (aa) 294, is identical to a component of U5 small nuclear ribonucleoprotein particles and binds specifically to the AR or glucocorticoid receptor. Here, we identified four distinct functional domains. The AR-AF-1-binding domain, which bound to either aa 180-360 or 360-532 in AR-AF-1, clearly overlapped with TAU-1 and TAU-5. This domain and the subnuclear speckle formation domain in ANT-1 were assigned within the TPR motifs, while the transactivating and nuclear localization signal domains resided within the N-terminal sequence. The existence of these functional domains may further support the idea that ANT-1 can function as an AR-AF-1-specific coactivator while mediating a transcription-splicing coupling.

Adenine Nucleotide Translocator 1↗

PubMed2006

Ap58: a novel in situ outer dynein arm-binding protein.

Outer arm dynein is a molecular motor that is positioned at 24 nm intervals on outer doublet microtubules in cilia and flagella. In the present paper, we report identification of a 58 kDa novel protein with a tetratricopeptide repeat (TPR), referred to as ap58 (for 58 kDa axonemal protein) in sea urchin sperm axonemes. Ap58 is extracted along with the outer arm dynein by a high salt solution from axonemes. Sucrose density gradient centrifugation or gel filtration of the extract separates the outer arm dynein core from ap58. Most ap58 sediments to the lower density fraction or elutes in fractions of smaller molecules. However, immunogold localization reveals that ap58 is distributed at approximately 25 nm intervals on doublet microtubules, suggesting that in situ it is associated with the outer dynein arm. Thus, ap58 with the TPR motif is a new member of outer dynein arm-binding proteins distinct from the outer dynein arm-docking complex.

Amino Acid Sequence↗

PubMed2005

FKBP52.

The large molecular-weight immunophilin, FKBP52, is a known target of the immunosuppressive drug FK506. FKBP52 exhibits peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is inhibited by the binding of FK506--properties that it shares with the smaller but better-studied immunophilin, FKBP12. Unlike FKBP12, however, FKBP52 does not mediate the immunosuppressive actions of FK506 and, due to its larger size, contains additional numerous functional domains. One such structure is a series of tetratricopeptide repeat (TPR) domains, which serve as binding sites for the ubiquitous and abundant molecular chaperone, Hsp90. It is this property as a TPR protein that best characterizes the known cellular roles of FKBP52. Here, we review the structural features of FKBP52 and relate them to the evolving and diverse functions of this protein. Although the most recognized role of FKBP52 is in regulation of steroid receptor signaling, other less well-known functions are also discussed.

Animals↗

PubMed2004

Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement.

The ubiquitous protein chaperone hsp90 has been shown to regulate more than 100 proteins involved in cellular signalling. These proteins are called 'client proteins' for hsp90, and a multiprotein hsp90/hsp70-based chaperone machinery forms client protein.hsp90 heterocomplexes in the cytoplasm and the nucleus. In the case of signalling proteins that act as transcription factors, the client protein.hsp90 complexes also contain one of several TPR domain immunophilins or immunophilin homologs that bind to a TPR domain binding site on hsp90. Using several intracellular receptors and the tumor suppressor p53 as examples, we review evidence that dynamic assembly of heterocomplexes with hsp90 is required for rapid movement through the cytoplasm to the nucleus along microtubular tracks. The role of the immunophilin in this system is to connect the client protein.hsp90 complex to cytoplasmic dynein, the motor protein for retrograde movement toward the nucleus. Upon arrival at the nuclear pores, the receptor.hsp90.immunophilin complexes are transferred to the nuclear interior by importin-dependent facilitated diffusion. The unliganded receptors then distribute within the nucleus to diffuse patches from which they proceed in a ligand-dependent manner to discrete nuclear foci where chromatin binding occurs. We review evidence that dynamic assembly of heterocomplexes with hsp90 is required for movement to these foci and for the dynamic exchange of transcription factors between chromatin and the nucleoplasm.

Animals↗

PubMed2004

Solid-phase microextraction coupled with high-performance liquid chromatography for the analysis of heterocyclic aromatic amines.

Solid-phase microextraction (SPME) coupled with high-performance liquid chromatography (HPLC) with UV diode array detection (DAD) for the analysis of heterocyclic aromatic amines (HAs) is described. Four kinds of fiber coatings: Carbowax-templated resin (CW-TPR), Carbowax-divinylbenzene (CW-DVB), poly(dimethylsiloxane)-divinylbenzene (PDMS-DVB) and polyacrylate (PA) were evaluated for extraction of nine most biologically active heterocyclic aromatic amines. Different parameters affecting to the microextraction and determination of HAs were studied, such as absorption and desorption time, desorption mode, composition of the solvent for desorption, pH, ionic strength, and percentage of methanol in the sample. To determine these amines in food samples a new simplified procedure is proposed, consisting of treatment of the sample with methanolic NaOH prior microextraction by CW-TPR fiber coating and HPLC-DAD determination. The advantages of this new method are the reduced amounts of time and organic solvents required.

Amines↗

PubMed2006

Convergent evolution of receptors for protein import into mitochondria.

BACKGROUND: Mitochondria evolved from intracellular bacterial symbionts. Establishing mitochondria as organelles required a molecular machine to import proteins across the mitochondrial outer membrane. This machinery, the TOM complex, is composed of at least seven component parts, and its creation and evolution represented a sizeable challenge. Although there is good evidence that a core TOM complex, composed of three subunits, was established in the protomitochondria, we suggest that the receptor component of the TOM complex arose later in the evolution of this machine. RESULTS: We have solved by nuclear magnetic resonance the structure of the presequence binding receptor from the TOM complex of the plant Arabidopsis thaliana. The protein fold suggests that this protein, AtTom20, belongs to the tetratricopeptide repeat (TPR) superfamily, but it is unusual in that it contains insertions lengthening the helices of each TPR motif. Peptide titrations map the presequence binding site to a groove of the concave surface of the receptor. In vitro functional assays and peptide titrations suggest that the plant Tom20 is functionally equivalent to fungal and animal Tom20s. CONCLUSIONS: Comparison of the sequence and structure of Tom20 from plants and animals suggests that these two presequence binding receptors evolved from two distinct ancestral genes following the split of the animal and plant lineages. The need to bind equivalent mitochondrial targeting sequences and to make similar interactions within an equivalent protein translocation machine has driven the convergent evolution of two distinct proteins to a common structure and function.

Amino Acid Sequence↗

PubMed2006

Comparison of the cardiovascular effects of tamsulosin oral controlled absorption system (OCAS) and alfuzosin prolonged release (XL).

OBJECTIVE: The cardiovascular (CV) effects of tamsulosin oral controlled absorption system (OCAS) 0.4 mg were compared with those of alfuzosin prolonged release (XL) 10 mg. METHODS: Two single-dose, crossover studies were performed. In study 1, CV alpha1-adrenoceptor antagonism was assessed by measuring the inhibition of phenylephrine (PE)-induced increases in diastolic blood pressure (DBP) and total peripheral resistance (TPR) before and after dosing with placebo, tamsulosin OCAS, and alfuzosin XL in 18 young subjects. In study 2, orthostatic stress tests (OTs) were performed before and after dosing with tamsulosin OCAS and alfuzosin XL in 40 elderly subjects. Pharmacokinetics were assessed in both studies. RESULTS: In study 1, tamsulosin OCAS induced statistically significantly less inhibition of PE-induced increases in DBP at 2 h after dosing and in TPR at 2 and 4 h after dosing than alfuzosin XL. In study 2, tamsulosin OCAS had a lower incidence of positive OTs than did alfuzosin XL, with the difference between both treatments being statistically significant at 6h after dosing and for all time points after dosing combined. This was in line with smaller changes in vital signs observed for tamsulosin OCAS. The t(max) values for both treatments were comparable. CONCLUSIONS: Tamsulosin OCAS 0.4 mg produces smaller vascular effects than does alfuzosin XL 10 mg.

Administration, Oral↗

PubMed2005

Risk factors of sudden death in the Japanese hot bath in the senior population.

A series of experiments were carried out to clarify the cause of death and the risk factors related to sudden death in the Japanese senior population while bathing in a Japanese style "hot bath." The biodynamic changes while bathing were carefully monitored under actual bathing situations occurring in both the winter and summer seasons. We observed double product (DP), total peripheral blood vessel resistance (TPR), cardiac output (CO), and blood vessel compliance (COMP) by measuring blood pressure, heart rate, pulse wave, and electrocardiogram (ECG). The finding of a high level of DP in the elderly suggests that more myocardial oxygen consumption is needed than for young adults, particularly in subjects with arrhythmia. Although the values for TPR and CO changed somewhat during bathing, the changes were considered normal and to be expected. However, more significant and substantial changes were observed during the winter experiment than during the summer experiment, no doubt owing to lower temperature of the bathing room. The value of COMP did not vary significantly between winter and summer subjects. Twelve subjects in the elderly developed ECG changes while bathing such as supraventricular extrasystole or ventricular tachycardia. No clinical significance was found in the biochemical analyses of the blood obtained before and after bathing. In conclusion, some subjects in the elderly showed risky changes in the above parameters and ECG, factors which may partially explain some of the causes of the many reported cases of lapse of consciousness and unexpected sudden death in the elderly while bathing especially in the winter season. Cold climate, hot water immersion, and hydrostatic pressure may affect their physiological compensation along with existing of coronary stenosis or weakness of respiratory function as a normal consequence of advanced age.

Adult↗

PubMed2006

Vibration training: benefits and risks.

The main results of our recent several studies, i.e. the measurements of vibration training results for single case and group studies as well as the cardiovascular parameter measurements during vibrations and the corresponding hydrodynamic analysis, are summarized. Our studies and previous work all confirm that vibration training is an effective training method in order to improve maximal strength and flexibility as well as various other factors if the training is properly designed. Some recommendations regarding the proper ranges of frequencies, amplitudes and exposure duration of vibration training are made based on the existing vibration training practice and mechanism analysis, although much work remains to be carried out in order to set up clear rules for various groups of people so that maximal training results could be expected and in the meantime potential dangerous effects could be avoided. Cardiovascular parameter measurements confirm that total peripheral resistance (TPR) to the blood flow is increased during body vibration. Hydrodynamic analysis offers the mechanism for the increase of TPR through the deformation of vessels. As a reaction of compensation, more capillaries are probably opened in order to keep a necessary level of cardiac output needed for the body, resulting in more efficient gas and material metabolism between the blood and muscle fibres. This might be one of the reasons for the various potential beneficial effects of vibration training.

Adult↗

PubMed2007

Segmentation of blood vessels from red-free and fluorescein retinal images.

The morphology of the retinal blood vessels can be an important indicator for diseases like diabetes, hypertension and retinopathy of prematurity (ROP). Thus, the measurement of changes in morphology of arterioles and venules can be of diagnostic value. Here we present a method to automatically segment retinal blood vessels based upon multiscale feature extraction. This method overcomes the problem of variations in contrast inherent in these images by using the first and second spatial derivatives of the intensity image that gives information about vessel topology. This approach also enables the detection of blood vessels of different widths, lengths and orientations. The local maxima over scales of the magnitude of the gradient and the maximum principal curvature of the Hessian tensor are used in a multiple pass region growing procedure. The growth progressively segments the blood vessels using feature information together with spatial information. The algorithm is tested on red-free and fluorescein retinal images, taken from two local and two public databases. Comparison with first public database yields values of 75.05% true positive rate (TPR) and 4.38% false positive rate (FPR). Second database values are of 72.46% TPR and 3.45% FPR. Our results on both public databases were comparable in performance with other authors. However, we conclude that these values are not sensitive enough so as to evaluate the performance of vessel geometry detection. Therefore we propose a new approach that uses measurements of vessel diameters and branching angles as a validation criterion to compare our segmented images with those hand segmented from public databases. Comparisons made between both hand segmented images from public databases showed a large inter-subject variability on geometric values. A last evaluation was made comparing vessel geometric values obtained from our segmented images between red-free and fluorescein paired images with the latter as the "ground truth". Our results demonstrated that borders found by our method are less biased and follow more consistently the border of the vessel and therefore they yield more confident geometric values.

Algorithms↗

PubMed2005

The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity.

We have identified an immunophilin of the FKBP family in Plasmodium falciparum that contains a conserved peptidyl prolyl isomerase (PPIase) and tetratricopeptide repeat (TPR) domains. The 35 kDa protein was named FKBP35 and expressed in bacteria. Recombinant FKBP35 exhibited potent PPIase and protein folding activities against defined substrates in vitro, suggesting that it is a parasitic chaperone. Both activities were inhibited by macrolide immunosuppressant drugs, ascomycin (a FK506 derivative) and rapamycin, but not by cyclosporin A, providing biochemical evidence of its inclusion in the FKBP family. Interestingly, FKBP35 inhibited purified plasmodial calcineurin (protein phosphatase 2B) in the absence of any drug. In the parasite's cell, FKBP35 exhibited a stage-specific nucleocytoplasmic shuttling and did not co-localize with calcineurin. FKBP35 associated with plasmodial heat shock protein 90 (Hsp90), another member of the chaperone superfamily, via the TPR domain. Geldanamycin, a Hsp90 inhibitor, and ascomycin inhibited P. falciparum growth in a synergistic fashion. Extensive search of the P. falciparum genome revealed no other FKBP sequence, implicating PfFKBP35 as a highly significant antimalarial drug target. Thus, the single FKBP of Plasmodium is an essential parasitic chaperone with a novel drug-independent calcineurin-inhibitory activity.

Amino Acid Sequence↗

PubMed2005

Chaperoned ubiquitylation--crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex.

CHIP is a dimeric U box E3 ubiquitin ligase that binds Hsp90 and/or Hsp70 via its TPR-domain, facilitating ubiquitylation of chaperone bound client proteins. We have determined the crystal structure of CHIP bound to an Hsp90 C-terminal decapeptide. The structure explains how CHIP associates with either chaperone type and reveals an unusual asymmetric homodimer in which the protomers adopt radically different conformations. Additionally, we identified CHIP as a functional partner of Ubc13-Uev1a in formation of Lys63-linked polyubiquitin chains, extending CHIP's roles into ubiquitin regulation as well as targeted destruction. The structure of Ubc13-Uev1a bound to the CHIP U box domain defines the basis for selective cooperation of CHIP with specific ubiquitin-conjugating enzymes. Remarkably, the asymmetric arrangement of the TPR domains in the CHIP dimer occludes one Ubc binding site, so that CHIP operates with half-of-sites activity, providing an elegant means for coupling a dimeric chaperone to a single ubiquitylation system.

Animals↗

PubMed2005

The lord of the ring: mandatory role of the kidney in drug therapy of hypertension.

Strong evidence supports the idea that total peripheral resistance (TPR) is increased in all forms of human and experimental hypertension. Although the etiological participation of TPR in the origin and long-term maintenance of hypertension has been extensively debated, it now seems clear that the renal, nonadaptive, infinite gain-working, pressure-sensitive natriuresis and diuresis is the main mechanism of blood pressure control in the long term. The tissue, cellular, biochemical, and genetic sensors and executors of this process have not been fully identified yet, but the role of the renal medulla has gained growing attention as the physiopathological scenario in which the key regulatory elements reside. Specifically, the functionality of the renomedullary vasculature seems to be highly responsible for blood pressure control. The vasculature of the renal medulla becomes a new and more specific target for the therapeutic intervention of hypertension. Recent data on the effect of baroreceptor-controlled renal sympathetic activity on the long-term regulation of blood pressure are integrated. The renomedullary effects of the main antihypertensive drugs are discussed, and new perspectives for the therapeutic intervention of hypertension are outlined. Comparison of the genetic program of the renal medulla before and after the development of hypertension in spontaneously hypertensive and experimentally induced animal models might provide a mechanism for identifying the key genes that become activated or suppressed in the development of high blood pressure. These genes, their encoded proteins, or other elements related to their signalling and genetic pathways might serve as new and more specific targets for the pharmacological treatment of abnormally elevated blood pressure. Besides, proteins specifically located to the luminal side of the renomedullary vascular endothelium may serve as potential targets for site-directed drug and gene therapy.

Animals↗