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PubMed2005

The effect of peripheral resistance on impedance cardiography measurements in the anesthetized dog.

In the vasodilated and septic patient, the impedance method of measuring cardiac output (CO) may underestimate the true value. In this study, we sought to determine whether impedance CO (COIC) measurements are influenced by total peripheral resistance (TPR). In eight anesthetized and ventilated dogs, a high-precision flowprobe was placed on the ascending aorta, and direct CO was measured (CO flowprobe (COFP)). Mean arterial blood pressure was measured from the femoral artery. Simultaneous COIC measurements were made. TPR (mean arterial blood pressure x 80/COFP) was varied over 1-2 h by using infusions of phenylephrine and adrenaline and inhaled halothane. The bias between methods of CO measurement (COIC-COFP) was calculated and compared with TPR by using correlation and regression analysis. A total of 547 pairs of CO measurements were collected from the 8 dogs as TPR was varied. COFP changed by a mean of 190% (range, 89%-425%), and TPR changed by a mean of 266% (range, 94%-580%) during the experiment. The impedance method underestimated CO when TPR was low and overestimated CO when TPR was high. There was a logarithmic relationship between the CO bias and TPR. Correlation coefficients (r) between the CO bias and TPR ranged from 0.46 to 0.89 (P < 0.0001). The bias changed by 0.62 +/- 1.8 L/min, or by 34%, every time TPR halved or doubled. This finding explains the poor agreement between COIC and other methods of CO measurement found in validation studies involving critically ill patients.

Algorithms↗

PubMed1981

Blood pressure regulation in chronic hypotensive and hypertensive patients with chronic renal failure.

We studied the regulatory mechanism of blood pressure in uremic patients (UP) treated with long-term hemodialysis. The cardiac index (CI) was higher in UP than in normal control (NC). Total peripheral resistance (TPR) in hypertensive (U-Hyper) and normotensive (U-Normo) uremic patients was almost the same as that in NC but TPR in hypotensive uremic patients (U-Hypo) was lower than in NC. High CI in U-Hyper and low TPR in U-Hypo seem to be the causes of their blood pressure abnormalities. All patients had severe anemia. There was a significant positive correlation between hematocrit (Ht) and TPR in UP as well as in NC. The regression line of correlation between Ht (x axis) and TPR (y axis) in UP was shifted to the left from that of NC, suggesting TPR was higher even in U-Hypo than in NC. There was a significant negative correlation between Ht and CI in UP as well as in NC. The regression line of correlation between Ht (x axis) and CI (y axis) in UP was shifted to the left from that in NC, suggesting that CI was lower even in U-Hyper than that in NC. Therefore, higher TPR relative to Ht in U-Hyper and lower CI relative to Ht in U-Hypo may actually be principal causes of their blood pressure abnormalities. Circulating plasma volume and extracellular fluid volume were significantly higher in UP even after hemodialysis but there was no significant difference among subgroups of uremia. Plasma renin activity (PRA) was higher in UP than in NC. However, PRA in U-Hypo was significantly lower than that in U-Hyper or U-Normo. PRA in UP, even in U-Hypo, was inappropriately high relative to sodium/volume status. There was a significant positive correlation between TPR and PRA in UP. Therefore, higher TPR in UP relative to Ht than NC might be a result of elevated PRA. The level of blood pressure in UP seems to be regulated mainly by renin-angiotensin system. All patients were dialysed under the same condition. Heart rate and TPR increased after dialysis in U-Hyper and U-Hypo. However, no change occurred in these parameters throughout dialysis in U-Hypo. The responsiveness of renin secretion upon dialysis was lower in U-Hypo than in other two groups. Therefore, autonomic dysfunction may partly contribute to the development and maintenance of chronic hypotension in U-Hypo.

Adult↗

PubMed2005

Mass-dependent signaling between G protein coupled receptors.

The present study provides evidence that G protein coupled receptor (GPCR) signaling pathways participate in an interactive signaling network governed by the principles of mass action. Using an inducible thromboxane A2 receptor (TPR)/platelet activating factor receptor (PAFR) co-expressing cell model, TPR or PAFR expression was independently up-regulated. Immunostaining and radioligand binding experiments demonstrated that this receptor up-regulation resulted in increased GPCR:G protein mass ratios. This increase in mass ratio impacted both TPR and PAFR ligand affinity. Specifically, up-regulating TPR expression not only decreased TPR ligand affinity, but also decreased the ligand affinity of PAFRs. A similar effect on ligand affinities was observed when PAFRs were up-regulated. In addition, increasing the GPCR:G protein mass ratio for TPRs led to desensitization of the calcium mobilization response to PAFR activation, and increasing PAFR mass desensitized the TPR-mediated calcium response. Finally, it was observed that an increased TPR:G protein mass ratio was associated with a shift in the TPR signaling response, and revealed an additional TPR signaling pathway through G(S). Collectively, these results describe a novel mechanism, i.e., mass-dependent GPCR signaling, by which cells can modulate their GPCR signaling pathways and signaling priorities.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2000

Heat shock cognate protein 70 chaperone-binding site in the co-chaperone murine stress-inducible protein 1 maps to within three consecutive tetratricopeptide repeat motifs.

Murine stress-inducible protein 1 (mSTI1) is a co-chaperone homologous with the human heat shock cognate protein 70 (hsc70)/heat shock protein 90 (hsp90)-organizing protein (Hop). The concomitant interaction of mSTI1 with hsp70 and hsp90 at its N- and C-termini respectively is mediated by the tetratricopeptide repeat (TPR) motifs in these regions. With the use of co-precipitation assays, we show here that the N-terminal TPR domain of mSTI1 without extensive flanking regions is both necessary and sufficient to mediate a specific interaction with hsc70. In contrast, other TPR-containing co-chaperones require TPR flanking regions for target substrate recognition, suggesting different mechanisms of TPR-mediated chaperone-co-chaperone interactions. Furthermore, the interaction between mSTI1 and hsc70 was analysed to ascertain the effect of replacing or deleting conserved amino acid residues and sequences within the three TPR motifs constituting the N-terminal TPR domain of full-length mSTI1. Replacement of a bulky hydrophobic residue in TPR1 disrupted the interaction of mSTI1 with hsc70. A highly conserved sequence in TPR2 was altered by deletion or single amino acid replacement. These derivatives retained a specific interaction with hsc70. These results are consistent with a model in which conserved residues within the N-terminal TPR region of mSTI1 contribute differentially to the interaction with hsc70, and in which TPR1 has a significant role in targeting mSTI1 to hsc70. The contribution of the TPR domain mutations and deletions are discussed with respect to their effect on target substrate interactions.

Amino Acid Motifs↗

PubMed1997

Efficient cellular transformation by the Met oncoprotein requires a functional Grb2 binding site and correlates with phosphorylation of the Grb2-associated proteins, Cbl and Gab1.

The Tpr-Met oncoprotein consists of the catalytic kinase domain of the hepatocyte growth factor/scatter factor receptor tyrosine kinase (Met) fused downstream from sequences encoded by the tpr gene. Tpr-Met is a member of a family of tyrosine kinase oncoproteins generated following genomic rearrangement and has constitutive kinase activity. We have previously demonstrated that a single carboxyl-terminal tyrosine residue, Tyr489, is essential for efficient transformation of Fr3T3 fibroblasts by Tpr-Met and forms a multisubstrate binding site for Grb2, phosphatidylinositol 3' kinase, phospholipase Cgamma, SHP2, and an unknown protein of 110 kDa. A mutant Tpr-Met protein that selectively fails to bind Grb2 has reduced transforming activity, implicating pathways downstream of Grb2 in Tpr-Met mediated cell transformation. We show here that the 110-kDa Tpr-Met substrate corresponds to the recently identified Grb2-associated protein, Gab1. Moreover, we show that tyrosine phosphorylation of the Cbl protooncogene product as well as Gab1 required Tyr489 and correlated with the ability of Tpr-Met to associate with Grb2 and to transform cells, providing evidence that pathways downstream of Gab1 and/or Cbl may play a role in Tpr-Met-mediated cell transformation.

3T3 Cells↗

PubMed1991

Role of the kinin-kallikrein system in the vasodilator action of an angiotensin converting enzyme inhibitor (captopril) on the systemic resistance and capacitance vessels of dogs.

We investigated the vasodilator effects of captopril (CAP) on the systemic capacitance and resistance vessels by measuring changes in the mean circulatory pressure (MCP) and total peripheral resistance (TPR) that occurred in response to the intravenous injection of CAP (1 mg/kg) in open-chest dogs. The following five groups of dogs received CAP: (1) Group of untreated dogs, (2) TSA Group in which the dogs were subjected to total spinal anesthesia (TSA), (3) Ang II Group in which the dogs received a continuous intravenous infusion of angiotensin II (Ang II), (4) APR + Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with aprotinin (APR, 25,000 K.I.E.), a kallikrein inhibitor, and (5) IND + APR + Ang II Group in which the dogs received a continuous intravenous infusion of Ang II after pretreatment with indomethacin (IND, 5 mg/kg), a prostaglandin synthesis inhibitor, and APR. 1) CAP significantly decreased TPR and MCP in the untreated Group. 2) CAP significantly decreased TPR and MCP in the TSA Group. There were no significant differences in percentage change of TPR (% delta TPR) and percentage change of MCP (% delta MCP) between the untreated and TSA Groups. 3) In the Ang II Group, CAP decreased the elevated TPR significantly, but hardly affected the elevated MCP. 4) CAP significantly decreased TPR without significant change in MCP in the APR + Ang II Group. The % delta TPR was significantly smaller in this Group than in the Ang II Group. 5) CAP significantly decreased TPR without significant change in MCP in the IND + APR + Ang II Group.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1997

Lung perfusion scans and hemodynamics in acute and chronic pulmonary embolism.

UNLABELLED: To assess the relationship between pulmonary vascular obstruction and hemodynamic status in acute pulmonary embolism (APE) and in chronic thromboembolic pulmonary hypertension (CTEPH), perfusion lung scan and hemodynamic measurements were obtained in 31 consecutive patients with APE and in 45 with CTEPH. METHODS: Lung scans were scored independently by two experience observers who determined the percentage of vascular obstruction (PVOs). Mean pulmonary artery pressure (PAP) and total pulmonary resistance (TPR) were obtained during right heart catheterization. In patients with APE, measurements were recorded within a 1-hr interval before and 12 hours after thrombolysis. This yielded 62 paired PVOs values with concomitant PAP and TPR measurements. In patients with CTEPH, data were recorded within a 3-day interval. RESULTS: Mean PVOs (%) values were similar in APE and CTEPH patients (59 +/- 13 vs. 58 +/- 15), whereas PAP and TPR were significantly higher in CTEPH patients (51 +/- 17 mmHg and 23 +/- 11 U/m2, respectively) than in APE patients (23 +/- 8 mmHg and 9 +/- 5 U/m2, respectively, p < 0.001). In APE patients, significant hyperbolic correlations were found linking PVOs with PAP and TPR (r = 0.75, p < 0.01 for PAP; r = 0.71, p < 0.01 for TPR). In CTEPH, there were no significant correlations between PVOs and PAP or TPR. For the same level of PVOs, patients with CTEPH had higher PAP and TPR value than patients with APE. CONCLUSION: In APE without prior cardiopulmonary disease, increases in PAP and TPR are correlated in a nonlinear fashion with the degree of pulmonary vascular obstruction as assessed by lung scanning. In CTEPH patients, the higher PAP and TPR values as compared to APE patients with comparable degrees of PVOs are consistent with previous reports that pulmonary hypertension in CTEPH is due not only to the obstruction of proximal pulmonary arteries but also to remodeling of small distal arteries in nonoccluded areas.

Acute Disease↗

PubMedDate not supplied

Mean outflow resistance as a marker of left ventricular afterload.

The changes of mean outflow resistance (MOR) (defined as the ratio between mean aortic ejection pressure and mean ejection rate) and of total peripheral resistance (TPR) together with their relations to some circulatory parameters and to each other were studied under control (NaCl) and six different loading conditions on anesthetized closed chest dogs. Phenylephrine increased both MOR and TPR (ca. 160%, max), pacing increased MOR (p less than 0.01) but not TPR. Isoproterenol and dextran infusion decreased TPR (p less than 0.001) but not MOR. Calcium chloride decreased MOR (p less than 0.05) but increased TPR (NS). The relationship between MOR and TPR was linear in each case (r from 0.63 to 0.91). Both MOR and TPR showed either positive or negative linear correlations with volume and pressure parameters although MOR appeared to be more sensitive to the administered interventions. The present results suggest that, when referring to the pulsatile and discrete nature of the blood-flow-pressure output from the left ventricle, MOR seems to be a more useful measure than TPR in the assessment of the left ventricular afterload.

Animals↗

PubMed2001

Role of endothelin and vasopressin in DOCA-salt hypertension.

1. The relative roles of endothelin (ET) and vasopressin (AVP) in the regulation of blood pressure (BP), cardiac output (CO) and total peripheral resistance (TPR) were investigated in the early stages (24 - 31 days) of development of hypertension in the conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rat model. 2. BP was recorded with radiotelemetry devices and CO with ultrasonic transit-time probes. TPR was calculated from the BP and CO recordings. The contributions of endogenous ET and AVP were studied by infusing [d(CH(2))(5)(1),O-Me_Tyr(2),Arg(8)]-vasopressin, a V(1)-receptor antagonist, and bosentan, a mixed ET(A)/ET(B) receptor antagonist (Study 1). Vascular responsiveness was estimated from the changes in TPR evoked by i.v. infusions of ET-1 and AVP (Study 2). 3. In study 1, infusion of bosentan reduced TPR and BP dramatically in DOCA-salt hypertensive rats but not in SHAM control rats, and this effect was greater when the AVP system had been blocked. In contrast, the V(1) receptor antagonist alone failed to change TPR and BP in DOCA-salt hypertensive rats. However, subsequent infusion of the V(1) receptor antagonist during the plateau phase of the response in bosentan pretreated DOCA-salt hypertensive rats led to significant decreases in both BP and TPR. 4. In study 2, TPR and BP responses to ET-1, but not AVP, were greater in DOCA-salt rats than in control rats. CO responses to ET-1 or AVP were similar in the two groups. 5. The results suggest that both ET and AVP play a role in the maintenance of TPR and BP; when one system is blocked the other compensates. However, the magnitude of the contribution to the hypertensive state appears greater for ET than for AVP. Enhanced vascular responses to ET appear to contribute to this greater role.

Animals↗

PubMed1999

Identification of conserved residues required for the binding of a tetratricopeptide repeat domain to heat shock protein 90.

The sequential binding of heat shock protein 90 (hsp90) to a series of tetratricopeptide repeat (TPR) proteins is critical to its function as a molecular chaperone. We have used site-directed mutagenesis to clarify the structural basis for the binding of hsp90 to the TPR domain of phosphoprotein phosphatase 5 (PP5). This TPR domain was chosen for study because its three-dimensional structure is known. We examined co-immunoprecipitation of hsp90 with wild type and mutant TPR constructs from transfected cells. Only mutations located on one face of the TPR domain affected hsp90 binding. This allowed the identification of a binding groove. Three basic residues that are highly conserved in hsp90-binding TPR proteins extend prominently into this groove. Lys-97 and Arg-101 were absolutely required for hsp90 binding, while mutation of Arg-74 diminished, but did not abrogate, hsp90 binding. Mutation of Lys-32, another conserved basic residue in the binding groove, also blocked hsp90 binding. The TPR domain of PP5 bound specifically to a 12-kDa C-terminal fragment of hsp90. This binding was reduced by mutation of acidic residues in the hsp90 fragment. These data suggest conservation, among hsp90-binding TPR proteins, of a binding groove containing basic residues that interact with acidic residues near the C terminus of hsp90.

Amino Acid Sequence↗

PubMed2006

Conditional activation of MET in differentiated skeletal muscle induces atrophy.

Skeletal muscle atrophy is a common debilitating feature of many systemic diseases, including cancer. Here we examined the effects of inducing expression of an oncogenic version of the Met receptor (Tpr-Met) in terminally differentiated skeletal muscle. A responder mouse containing the Tpr-Met oncogene and GFP (green fluorescent protein) as a reporter was crossed with a transactivator mouse expressing tTA under the control of the muscle creatine kinase promoter. Tpr-Met induction during fetal development and in young adult mice caused severe muscle wasting, with decreased fiber size and loss of myosin heavy chain protein. Concomitantly, in the Tpr-Met-expressing muscle the mRNA of the E3 ubiquitin ligases atrogin-1/MAFbx, MuRF1, and of the lysosomal protease cathepsin L, which are markers of skeletal muscle atrophy, was significantly increased. In the same muscles phosphorylation of the Met downstream effectors Akt, p38 MAPK, and IkappaBalpha was higher than in normal controls. Induction of Tpr-Met in differentiating satellite cells derived from the double transgenics caused aberrant cell fusion, protein loss, and myotube collapse. Increased phosphorylation of Met downstream effectors was also observed in the Tpr-Met-expressing myotubes cultures. Treatment of these cultures with either a proteasomal or a p38 inhibitor prevented Tpr-Met-mediated myotube breakdown, establishing accelerated protein degradation consequent to inappropriate activation of p38 as the major route for the Tpr-Met-induced muscle phenotype.

Animals↗

PubMed1995

Mechanism of systemic vasodilation during normovolemic hemodilution.

In the nonfailing heart, normovolemic hemodilution increases cardiac output and decreases total peripheral resistance (TPR). Putative mechanisms mediating the decrease in TPR include reflex vasodilation and changes in the local regulation of blood flow. Our objectives were to determine whether ablation of reflex neural mechanisms or the inhibition of nitric oxide (NO) synthase, the enzyme responsible for the synthesis of the endothelium-derived relaxing factor (EDRF-NO), modulates the systemic vasodilator response to normovolemic hemodilution. Three groups of male Sprague-Dawley rats were subjected to acute normovolemic hemodilution, which was achieved by exchanging a volume of blood equivalent to 3.8% of body weight with hydroxyethyl starch. Hemodilution increased cardiac output and decreased TPR. Subsequent administration of the NO synthase inhibitor, L-nitroarginine (LNA), returned both cardiac output and TPR to control values. Pretreatment with LNA prior to hemodilution increased TPR, an effect that was partially reversed by the NO donor, sodium nitroprusside. In this setting, hemodilution failed to decrease TPR. After spinal cord destruction by "pithing," hemodilution decreased TPR to the same extent as that observed in intact rats. This hemodilution-induced decrease in TPR was abolished by the subsequent administration of LNA. These results indicate that neural reflexes do not modulate the systemic vascular response to hemodilution. Moreover, the systemic vasodilator response to hemodilution is abolished after inhibition of endogenous NO synthesis.

Amino Acid Oxidoreductases↗

PubMed1993

The effects of N omega-nitro-L-arginine methyl ester, sodium nitroprusside and noradrenaline on venous return in the anaesthetized cat.

1. The vascular actions of N omega-nitro-L-arginine methyl ester (L-NAME), sodium nitroprusside and noradrenaline were investigated in cats under chloralose anaesthesia with controlled vascular tone and ventilation. Cardiac output, heart rate, vascular pressures and mean circulatory filling pressure (MCFP) were measured. Total peripheral resistance (TPR) and resistance to venous return (Rvr) were calculated from steady-state readings. 2. L-NAME (37 mumol kg-1, i.v.) administered to ten cats receiving noradrenaline (6 nmol kg-1 min-1, i.v.) increased aortic pressure by 47.5 +/- 7.1 mmHg from 106 mmHg, and MCFP by 1.56 +/- 0.36 mmHg from 10.0 mmHg (means +/- s.e. means). Mean changes in portal venous pressure, RAP and heart rate were not significant. Cardiac output fell by 29.7 +/- 3.3% from 130 ml min-1 kg-1. TPR rose by 108 +/- 7.2% from 796 mmHg l-1 min kg and Rvr by 58.4 +/- 4.5% from 64 mmHg l-1 min kg. 3. Infusion of sodium nitroprusside into cats receiving noradrenaline evoked dose-related falls in aortic pressure, MCFP, TPR and Rvr. Changes in portal venous pressure, RAP and heart rate were not significant and cardiac output fell slightly. After L-NAME, sensitivity to nitroprusside was increased by 139 +/- 34% for MCFP, 176 +/- 19% for TPR and 351 +/- 39% for Rvr, and cardiac output rose slightly. The nitroprusside infusion required to restore TPR after L-NAME was estimated to be 5.8 x 10(+/- 0.41) nmol kg-1 min-1, which was approximately three times more than that required to restore MCFP. 4. Infusion of noradrenaline evoked dose-related increases in aortic and portal venous pressures, heart rate, cardiac output, MCFP, TPR and Rvr. After L-NAME and nitroprusside (4.4 nmol kg-1 min-1, i.v.),TPR and Rvr were not significantly different, but MCFP was reduced by 1.76 +/- 0.24 mmHg, and cardiac output by 22 +/- 1.9%. After subsequent expansion of the circulating blood volume (5-7.5 ml kg-1 dextran-saline), mean values for all parameters were restored to their previous levels. Sensitivity to noradrenaline was not significantly altered for heart rate, TPR and Rvr but was reduced by 31.8 +/- 12%for MCFP and by 66.5 +/- 18% for cardiac output.5. The depression of cardiac output by L-NAME is attributed to the increase in Rvr, partly compensated by the rise in MCFP. For a given rise in MCFP, the increase in R, was seven times greater after L-NAME than after noradrenaline, and the difference in the relative actions of the two drugs on resistance and capacitance vessels largely accounts for their contrasting effects on venous return. A procedure is suggested for replacement of vascular nitric oxide by nitroprusside infusion and blood volume expansion.

Anesthesia↗

PubMed2001

Is the pleural fluid transudate or exudate? A revisit of the diagnostic criteria.

BACKGROUND: Pleural effusions are classified into transudates and exudates based on criteria developed in the 1970s. However, their accuracy has not been evaluated. We compared the performance of the pleural fluid absolute lactic dehydrogenase level (FLDH), fluid to serum ratio of LDH (LDHR), and fluid to serum ratio of total protein (TPR). TPR has been used instead of the absolute value of fluid protein based on the observation that fluid protein is influenced by changes in the serum protein concentration. However, the rationale for using LDHR remains unexplored. METHODS: Of 212 consecutive patients with pleural effusions, four with multiple causes and eight with an uncertain diagnosis were excluded. ROC curves were generated using sensitivity and 1-specificity values for TPR, FLDH, and LDHR and positive likelihood ratios (LR+ve) were computed using the optimum cut off values. The correlation between pleural fluid and serum concentrations of total protein and LDH was also estimated. RESULTS: Of 200 effusions studied, 156 were exudates and 44 were transudates. The optimum cut off levels were: FLDH 163 IU/l, TPR 0.5, LDHR 0.6, and the FLDH-TPR combination 163 and 0.4, respectively. The area under the curve (AUC) with 95% confidence interval (CI) was: 0.89 (0.86 to 0.96) for FLDH, 0.86 (0.80 to 0.91) for TPR, 0.82 (0.77 to 0.89) for LDHR, and 0.90 (0.86 to 95) for FLDH-TPR. A significant correlation was observed between serum and pleural fluid protein levels in transudates and exudates (r=0.5 and 0.6, respectively), but the correlation between serum and pleural fluid LDH levels was insignificant. CONCLUSION: FLDH is the most accurate marker for the diagnostic separation of transudates and exudates and LDHR has no role in this process. Combining TPR with FLDH appears to improve the diagnostic accuracy slightly.

Adolescent↗

PubMed2004

Continuous peripheral resistance measurement during hemorrhagic hypotension.

We tested the hypotheses that continuous total peripheral resistance (TPR) measurements are superior to intermittent data collection and that variables related to TPR can be used to distinguish between survivors and nonsurvivors (NS), respectively, of prolonged hemorrhagic hypotension (HH). One week after a transit-time ultrasound probe was implanted on their ascending aortas, 21 rats were subjected to 4 h of HH at 40 mmHg. Measurements were made before and up to 4 h after initiation of HH. Additional bleeding or Ringer L-lactate (RL) infusion was used to maintain HH. TPR was continuously measured online using recordings of blood flow and arterial pressure. Approximately 67% of the rats survived > or =3 h; others were considered NS. Data collected at 30-min intervals failed to detect the maximum value of TPR (TPRmax). The times to reach TPRmax were similar for survivors and NS and were strongly correlated with the bleeding end points and with the RL infusion-onset times. However, survivors showed higher TPRmax values than NS (P <0.005) and had a significantly longer period than NS during which TPR was above baseline level (116 +/- 20 vs. 51 +/- 10 min). In conclusion, 1) the transit-time ultrasound technique at high sampling rate allowed continuous and accurate real-time monitoring of TPR, 2) the bleeding end point and RL infusion-onset times may be used as surrogates of the time to TPRmax, 3) TPRmax of survivors and NS could be detected only using a continuous TPR measurement, and 4) differences between survivors and NS could be revealed by the continuous TPR curve.

Animals↗

PubMed2005

Estimation of arterial and cardiopulmonary total peripheral resistance baroreflex gain values: validation by chronic arterial baroreceptor denervation.

Feedback control of total peripheral resistance (TPR) by the arterial and cardiopulmonary baroreflex systems is an important mechanism for short-term blood pressure regulation. Existing methods for measuring this TPR baroreflex mechanism typically aim to quantify only the gain value of one baroreflex system as it operates in open-loop conditions. As a result, the normal, integrated functioning of the arterial and cardiopulmonary baroreflex control of TPR remains to be fully elucidated. To this end, the laboratory of Mukkamala et al. (Mukkamala R, Toska K, and Cohen RJ. Am J Physiol Heart Circ Physiol 284: H947-H959, 2003) previously proposed a potentially noninvasive technique for estimating the closed-loop (dimensionless) gain values of the arterial TPR baroreflex (GA) and the cardiopulmonary TPR baroreflex (GC) by mathematical analysis of the subtle, beat-to-beat fluctuations in arterial blood pressure, cardiac output, and stroke volume. Here, we review the technique with additional details and describe its experimental evaluation with respect to spontaneous hemodynamic variability measured from seven conscious dogs, before and after chronic arterial baroreceptor denervation. The technique was able to correctly predict the group-average changes in GA and GC that have previously been shown to occur following chronic arterial baroreceptor denervation. That is, reflex control by the arterial TPR baroreflex was virtually abolished (GA = -2.1 +/- 0.6 to 0.3 +/- 0.2; P < 0.05), while reflex control by the cardiopulmonary TPR baroreflex more than doubled (GC = -0.7 +/- 0.4 to -1.8 +/- 0.2; P < 0.05). With further successful experimental testing, the technique may ultimately be employed to advance the basic understanding of TPR baroreflex functioning in both humans and animals in health and disease.

Animals↗

PubMed1997

Endogenous nitric oxide on arterial hemodynamics: a comparison between normotensive and hypertensive rats.

Endogenous nitric oxide (NO) plays an important role in maintaining a vasodilator tone. In the present study, we compared the effects of NO blockade on the steady and pulsatile components of arterial hemodynamics between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto strain (WKY), 22-26 wk of age. In the first series of experiments, various doses (1-30 mg/kg i.v.) of N(G)-nitro-L-arginine methyl ester (L-NAME) were administered to block the NO release in anesthetized WKY and SHR. In both WKY and SHR, L-NAME caused a dose-dependent increase in arterial pressure (AP) with a decrease in heart rate (HR). The maximal effects of L-NAME on AP and HR occurred at a dose of 10 mg/kg. Both the AP increase and HR decrease were higher in SHR (AP, +38 +/- 4 mmHg; HR, -49 +/- 5 beats/min) than WKY (AP, +22 +/- 3 mmHg; HR, -33 +/- 5 beat/min). In other series, the technique of impedance spectral analysis was employed to investigate the effects of L-NAME (10 mg/kg i.v.) on the arterial hemodynamics. The aortic pressure and flow waves were recorded and subjected to Fourier transform for the analysis of impedance spectra. Both in WKY (n = 12) and in SHR (n = 12), L-NAME significantly increased AP and total peripheral resistance (TPR). The pulsatile and frequency-dependent hemodynamics including characteristic impedance, wave reflection, and ventricular work were only slightly altered. Despite higher resting values of AP and TPR in SHR (mean AP, 154 +/- 7 mmHg; mean TPR, 204 +/- 17 x 10(3) dyn x s x cm(-5)) than WKY (mean AP, 94 +/- 6 mmHg; mean TPR, 98 +/- 12 x 10(3) dyn x s x cm(-5)), the magnitudes of AP and TPR increments after NO blockade were significantly higher in SHR (AP, +37 +/- 3 mmHg; TPR, +124 +/- 16 x 10(3) dyn x s x cm(-5)) than in WKY (AP, +24 +/- 3 mmHg; TPR, +45 +/- 7 x 10(3) dyn x s x cm(-5)). The continuous formation of endogenous NO affects predominantly the AP and peripheral resistance in both WKY and SHR. The windkessel functions, such as impedance spectra, pulse-wave reflection, and ventricular work, are less affected after NO blockade. In addition, the effects of NO release on the AP and TPR appear to be enhanced in rats with established hypertension.

Animals↗

PubMed2005

A selective small molecule c-MET Inhibitor, PHA665752, cooperates with rapamycin.

PURPOSE: c-MET is believed to be an attractive receptor target for molecular therapeutic inhibition. TPR-MET, a constitutively active oncogenic variant of MET, serves as excellent model for testing c-MET inhibitors. Here, we characterized a small molecule c-MET inhibitor, PHA665752, and tested its cooperation with the mammalian target of rapamycin inhibitor as potential targeted therapy. EXPERIMENTAL DESIGN: The effect of PHA665752 treatment was determined on cell growth, motility and migration, apoptosis, and cell-cycle arrest of TPR-MET-transformed cells. Moreover, the effect of PHA665752 on the phosphorylation on MET, as well as its downstream effectors, p-AKT and p-S6K, was also determined. Finally, growth of TPR-MET-transformed cells was tested in the presence of PHA665752 and rapamycin. H441 non-small cell lung cancer (NSCLC) cells (with activated c-Met) were also tested against both PHA665752 and rapamycin. RESULTS: PHA665752 specifically inhibited cell growth in BaF3. TPR-MET cells (IC(50) < 0.06 micromol/L), induced apoptosis and cell cycle arrest. Constitutive cell motility and migration of the BaF3. TPR-MET cells was also inhibited. PHA665752 inhibited specific phosphorylation of TPR-MET as well as phosphorylation of downstream targets of the mammalian target of rapamycin pathway. When combined with PHA665752, rapamycin showed cooperative inhibition to reduce growth of BaF3. TPR-MET- and c-MET-expressing H441 NSCLC cells. CONCLUSIONS: PHA665752 is a potent small molecule-selective c-MET inhibitor and is highly active against TPR-MET-transformed cells both biologically and biochemically. PHA665752 is also active against H441 NSCLC cells. The c-MET inhibitor can cooperate with rapamycin in therapeutic inhibition of NSCLC, and in vivo studies of this combination against c-MET expressing cancers would be merited.

Animals↗