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Interaction of the Hsp90 cochaperone cyclophilin 40 with Hsc70.

The high-affinity ligand-binding form of unactivated steroid receptors exists as a multicomponent complex that includes heat shock protein (Hsp)90; one of the immunophilins cyclophilin 40 (CyP40), FKBP51, or FKBP52; and an additional p23 protein component. Assembly of this heterocomplex is mediated by Hsp70 in association with accessory chaperones Hsp40, Hip, and Hop. A conserved structural element incorporating a tetratricopeptide repeat (TPR) domain mediates the interaction of the immunophilins with Hsp90 by accommodating the C-terminal EEVD peptide of the chaperone through a network of electrostatic and hydrophobic interactions. TPR cochaperones recognize the EEVD structural motif common to both Hsp90 and Hsp70 through a highly conserved clamp domain. In the present study, we investigated in vitro the molecular interactions between CyP40 and FKBP52 and other stress-related components involved in steroid receptor assembly, namely Hsp70 and Hop. Using a binding protein-retention assay with CyP40 fused to glutathione S-transferase immobilized on glutathione-agarose, we have identified the constitutively expressed form of Hsp70, heat shock cognate (Hsc)70, as an additional target for CyP40. Deletion mapping studies showed the binding determinants to be similar to those for CyP40-Hsp90 interaction. Furthermore, a mutational analysis of CyP40 clamp domain residues confirmed the importance of this motif in CyP40-Hsc70 interaction. Additional residues thought to mediate binding specificity through hydrophobic interactions were also important for Hsc70 recognition. CyP40 was shown to have a preference for Hsp90 over Hsc70. Surprisingly, FKBP52 was unable to compete with CyP40 for Hsc70 binding, suggesting that FKBP52 discriminates between the TPR cochaperone-binding sites in Hsp90 and Hsp70. Hop, which contains multiple units of the TPR motif, was shown to be a direct competitor with CyP40 for Hsc70 binding. Similar to Hop, CyP40 was shown not to influence the adenosine triphosphatase activity of Hsc70. Our results suggest that CyP40 may have a modulating role in Hsc70 as well as Hsp90 cellular function.

Adenosine Triphosphatases↗

Plasma concentrations of atrial natriuretic factor and hemodynamics in pregnancy-induced hypertension.

Plasma values of atrial natriuretic factor (ANF) were evaluated in 31 women with pregnancy-induced hypertension (PIH) and 31 normal pregnant women at the same age of gestation. In 27 women with PIH and 27 normal pregnant women forearm venous tone (FVT) was evaluated by Strain Gauge Plethysmography. Forearm vascular resistance (FVR) was measured as the ratio of mean blood pressure (MBP) to forearm blood flow. In addition Cardiac Index (CI) by means of transthoracic electrical bioimpedance and total peripheral vascular resistance (TPR) (with the Frank Equation) were also measured. In comparison with the normal pregnant women, the women with PIH had similar values of hematocrit (as an index of plasma volume) and significantly higher levels of FVR and TPR, while ANF plasma values did not differ significantly. Subdividing the women with PIH in relation to the presence of proteinuria (greater than or equal to 0.3 g/l), those with proteinuria, in addition to significantly higher levels of FVR and TPR, had significantly higher levels of FVT than normal pregnant women, while ANF plasma values were higher even though the difference was only near the level of significance. Hypertensive women with proteinuria also had higher values of FVT than hypertensive women without proteinuria. By means of multiple regression ANF did not show any significant correlations with hematocrit or sodium excretion. Hypertension with proteinuria seems to represent a more severe form of the disease in which, in addition to the probable influence of other factors such as the renin-angiotensin and prostaglandin systems, a greater increase in peripheral sympathetic tone than in hypertension alone appears to be present, causing a reduction in venous compliance in addition to the elevation in FVR and TPR, with increase in central blood volume and atrial stretch. This may explain the higher ANF plasma levels in these patients in comparison with normal pregnant women, even though the absence of a significant correlation of ANF with hematocrit and the fact that ANF increase was only near the level of significance may suggest a change in the relation between ANF secretion and atrial volume receptors in pregnancy either normal or complicated by hypertension. ANF does not seem to play an important role in water and sodium excretion in PIH probably because of the presence of very high plasma levels of hormones such as aldosterone, progesterone and oestriol which, together with renal prostaglandins, seem to be involved in diuresis and natriuresis in pregnancy.

Adult↗

[Mitral flow responses to two-week salt loading in elderly hypertensive patients].

The effects of a two-week high sodium diet on mitral flow pattern were assessed in 29 patients with essential hypertension (81.9 +/- 6.9 years). Transmitral flow was recorded during different rates of salt intake; 7 g/day for 8 weeks and 20 g/day for 2 weeks. With sodium loading, 25 patients whose mean blood pressure (MBP) increased by 10 percent or more were termed salt-sensitive (SS) group, and 4 patients whose MBP did not change or increased by less than 10 percent were termed non-salt-sensitive (NSS) group with mitral flow velocity integral, cardiac output (CO) and total peripheral resistance (TPR) were calculated. Thirteen of the SS patients were defined as "SST" in which an increase in TPR was greater than that in CO with sodium repletion. In the remaining 12 SS patients termed "SSc", the increase in CO was greater than that in TPR with salt loading. CO increased significantly in the SSc patients, but did not change in the SST or NSS group with sodium loading. TPR increased significantly in the SST and NSS subjects, and decreased significantly in the SSc patients. Peak velocity of transmitral flow in the rapid filling phase (R) decreased significantly in the SST and NSS patients, and increased significantly in the SSc group. On the other hand peak velocity of transmitral flow in the atrial contraction phase (A) increased significantly in the SST and SSc groups, but remained unchanged in the NSS patients. There was a significant increase in A/R in the SSt group and a significant decrease in A/R in the SSc patients with sodium loading.

Aged↗

The hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors.

A variety of transcription factors and protein kinases involved in signal transduction are recovered from cells in heterocomplexes containing the abundant protein chaperone hsp90. Genetic studies in yeast have demonstrated that binding of steroid receptors, the dioxin receptor, and some protein kinases to hsp90 is critical for their signal transducing function in vivo. These heterocomplexes are formed by a multiprotein chaperone machinery consisting of at least four ubiquitous proteins--hsp90, hsp70, p60 and p23. Four high-molecular-weight immunophilins have been discovered as components of steroid receptor or other transcription factor complexes with hsp90. The immunophilins, protein chaperones with prolyl isomerase activity, bind the immunosuppressant drugs FK506 or CyP-40. These immunophilins all bind via tetratricopeptide repeat (TPR) domains to a single TPR binding site on each hsp90 dimer, and multiple heterocomplexes exist for each protein chaperoned by hsp90 according to the immunophilin that is bound to this TPR binding site at any time. Three components of the MAP kinase signalling system (Src, Raf, and Mek) exist in complexes with hsp90 and a 50-kDa protein that is the mammalian homolog of the yeast cell cycle control protein cdc37. The p50cdc37 binds to hsp90 at a site that is close to but different from the TPR binding site of the immunophilins, and like the immunophilins, p50cdc37 is thought to be involved in targeting and trafficking of the protein kinases. The recent introduction of the benzoquinone antibiotic geldanamycin has facilitated the identification of proteins that are chaperoned by the hsp90-based system. Geldanamycin binds to members of the hsp90 protein family, blocking assembly of hsp90 heterocomplexes and destabilizing preformed heterocomplexes. In the presence of geldanamycin, the function of hsp90-chaperoned proteins is disrupted, and the proteins undergo rapid degradation by an ubiquitin-dependent proteasomal mechanism. It is becoming clear that hsp90 chaperoning is not only essential to a variety of signal transduction pathways, but is critical for proper folding, stabilization, and trafficking of an expanding list of proteins.

Animals↗

Blood rheology in myocardial infarction and hypertension.

Blood rheology was studied in patients with acute myocardial infarction (AMI) and essential hypertension (EH), and the results were correlated with in vivo hemodynamic functions. Blood viscosity (eta B) was elevated as a result of sequential changes of a number of parameters, including increases in hematocrit, plasma fibrinogen and alpha 2-globulin, an enhancement of red cell aggregation and a reduction of red cell filterability in plasma. Total peripheral resistance (TPR) was elevated upon admission, due to increases in both the vascular hindrance (ZS) and eta B. During recovery, the eta B became normalized; alterations in eta B were accompanied by parallel changes in TPR and an inverse change in plasma volume (PV). In EH patients, the increase in eta B showed a correlation with arterial pressure. For both established and borderline hypertensives, the rheological changes were most prominent in the high renin subgroups. In mild EH, the elevation of eta B was compensated by a decrease in ZS (vasodilation), keeping the TPR essentially normal. In EH with higher arterial pressure, the elevation of eta B was accompanied by a normal ZS without compensatory vasodilation, and hence TPR rose to exacerbate the hypertension. These results suggest that the elevation of eta B may be an early event in the development of EH and that its role must be considered with concurrent cardiovascular functions. In EH there is a significant correlation between left ventricular mass and eta B. Experimental manipulations of the hematocrit level in spontaneously hypertensive rats led to a corresponding variation of arterial pressure. The available data implicate a significant role of eta B in the pathophysiology of AMI and EH. Further interdisciplinary, longitudinal studies are needed tin order to unravel the complicated pathophysiological changes in myocardial infarction and hypertension.

Animals↗

Role of PGI2 in the formation and maintenance of hyperdynamic circulatory state of portal hypertensive rats.

AIM: To investigate the role of prostacyclin (PGI(2)) and nitric oxide (NO) in the development and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats. METHODS: Ninety male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) group by injection of CCl(4), prehepatic portal hypertension (PHPH) group by partial stenosis of the portal vein and sham-operation control (SO) group. One week after the models were made, animals in each group were subdivided into 4 groups: saline controlled group (n = 23), Nomega-nitro-L-arginine (L-NNA) group (n = 21) group, indomethacin (INDO) group (n = 22) and high-dose heparin group (n = 24). The rats were administrated 1 mL of saline, L-NNA (3.3 mg/kg.d) and INDO (5 mg/kg.d) respectively through gastric tubes for one week, then heparin (200 IU/Kg/min) was given to rats by intravenous injection for an hour. Splanchnic and systemic hemodynamics were measured using radioactive microsphere techniques. The serum nitrate/nitrite (NO(2)(-)/NO(3)(-)) levels as a marker of production of NO were assessed by a colorimetric method, and concentration of 6-keto-PGF1alpha, a stable hydrolytic product of PGI(2), was determined by radioimmunoassay. RESULTS: The concentrations of plasma 6-keto-PGF1alpha (pg/mL) and serum NO(2)(-)/NO(3)(-) (micromol/L) in IHPH rats (1123.85+/-153.64, 73.34+/-4.31) and PHPH rats (891.88+/-83.11, 75.21+/-6.89) were significantly higher than those in SO rats (725.53+/-105.54, 58.79+/-8.47) (P<0.05). Compared with SO rats, total peripheral vascular resistance (TPR) and spanchnic vascular resistance (SVR) decreased but cardiac index (CI) and portal venous inflow (PVI) increased obviously in IHPH and PHPH rats (P<0.05). L-NNA and indomethacin could decrease the concentrations of plasma 6-keto-PGF1alpha and serum NO(2)(-)/NO(3)(-) in IHPH and PHPH rats (P<0.05). Meanwhile, CI, FPP and PVI lowered but MAP, TPR and SVR increased (P<0.05). After deduction of the action of NO, there was no significant correlation between plasma PGI(2) level and hemodynamic parameters such as CI, TPR, PVI and SVR. However, after deduction of the action of PGI(2), NO still correlated highly with the hemodynamic parameters, indicating that there was a close correlation between NO and the hemodynamic parameters. After administration of high-dose heparin, plasma 6-keto-PGF(1alpha) concentrations in IHPH, PHPH and SO rats were significantly higher than those in rats administrated vehicle (P<0.05). On the contrary, levels of serum NO(2)(-)/NO(3)(-) in IHPH, PHPH and SO rats were significantly lower than those in rats administrated Vehicle (P<0.05). Compared with those rats administrated vehicle, the hemodynamic parameters of portal hypertensive rats, such as CI and PVI, declined significantly after administration of high-dose heparin (P<0.05), while TPR and SVR increased significantly (P<0.05). CONCLUSION: It is NO rather than PGI(2) that is a mediator in the formation and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats.

Animals↗

The effect of baroreflex adaptation on the dynamic cardiovascular response to head-up tilt.

BACKGROUND: Baroreflex adaptation to repetitive +Gz has been reported previously. The underlying mechanism may involve different responses of stroke volume (SV) and total peripheral resistance (TPR) to +Gz. HYPOTHESIS: The previously observed enhanced mean arterial pressure (MAP) regulation in fighter pilots (FP) is mediated by increases in SV and/or TPR. METHODS: There were 8 pilots and 12 non-pilots who underwent head-up tilt. SV was determined using impedance cardiography. RESULTS: MAP increased significantly in FP, due to heart rate (HR) and TPR increasing more and SV decreasing less. CONCLUSION: Baroreflex adaptation results in better performance of HR, SV and TPR in response to +Gz.

Adaptation, Physiological↗

Effects of prolonged bed rest on the total peripheral resistance baroreflex.

Orthostatic intolerance following prolonged exposure to microgravity continues to be a primary concern of the human space program. Reduced autonomic tone has been demonstrated to contribute to this phenomenon, and the heart rate baroreflex, in particular, has been repeatedly shown to be impaired. However, only the works of Yelle et al. have attempted to address the role of the total peripheral resistance (TPR) baroreflex, a potentially more significant contributor to blood pressure regulation. We applied a previously developed method for estimating the static gains of both the arterial and cardiopulmonary TPR baroreflexes to data obtained before and after 16-day bed rest. Reductions in the estimated static gains of the arterial (statistically significant) and cardiopulmonary TPR baroreflexes were found after bed rest. This study supports the works of Yelle et al, which imply that the TPR baroreflex is reduced after spaceflight.

Adult↗

Splanchnic and peripheral vascular resistance during lower body negative pressure (LBNP) and tilt.

We tested the hypothesis that vasoconstriction in response to LBNP or head up tilt would be reflected in a reduction in splanchnic (portal vein) blood flow (PVF) and increases in forearm and total peripheral vascular resistance (TPR). Changes in vascular resistance indicators were obtained from measurement of PVF from portal vein cross-sectional area and blood velocity by Doppler ultrasound, from forearm vascular resistance (FVR, by Doppler) and total peripheral resistance (TPR, by impedance cardiography). 21 subjects were tested during LBNP (0, -10, -20 and -30 mmHg) and 9 subjects during tilt (0, 45 and 70 degrees). During progressive LBNP, PVF decreased approximately linearly with LBNP (-30, -48 and -64% at -10, -20 and -30 mmHg) and with tilt angle (-39 and -58% at 45 and 70 degrees). The increase in FVR approximately mirrored these changes during LBNP (20.1, 44.7 and 55.3%) and tilt (45.6 and 63.6%). However, the changes in TPR during LBNP (12.0, 16.9 and 26.4%) and tilt (25.2 and 29.2%) were markedly less. This observation of different percent changes in forearm versus total peripheral resistance might reflect true physiological differences in the forearm (and splanchnic) circulations compared with the whole body, or the data might suggest that impedance cardiography did not provide a reliable indicator of cardiac output and therefore TPR under these conditions. The primary observation in this study was that Doppler ultrasound measurement of portal vein blood flow provided a non-invasive estimate of splanchnic vascular resistance during postural or LBNP challenge and that using the reduction in portal vein flow as an index of increased vasoconstriction paralleled the change in forearm vascular resistance.

Arm↗

Automated peritoneal dialysis has significant effects on systemic hemodynamics.

OBJECTIVES: Maintenance of residual renal function (RRF) is an important determinant of outcome in peritoneal dialysis patients. It remains contentious as to whether automated peritoneal dialysis (APD) leads to an increased rate of decline of RRF compared with continuous ambulatory peritoneal dialysis (CAPD). We studied whether APD was associated with significant systemic hemodynamic changes that may play a role in the accelerated loss of RRF. METHODS: As a follow-on from a previous study, 8 well-established CAPD patients underwent a 4-hour APD treatment consisting of 3 drain/fill cycles using 2 x 2.5 L 1.36% glucose and 1 x 3.86% glucose dialysate. Each dwell phase lasted 76 minutes. Blood pressure (BP) and a full range of hemodynamic variables, including pulse (HR), stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR), were measured noninvasively using continuous arterial pulse wave analysis. RESULTS: BP fell during 2 of the 3 drain/fill periods when dialysate was drained from the peritoneal cavity, but then rose upon instillation of dialysate fluid. The fall in BP was associated with a fall in TPR, matched by an inadequate rise in SV and CO. Over the entire study period, TPR progressively rose to +53.4% above baseline (p = 0.032). Both SV and CO fell over the same period, to -21.1% (p = 0.060) and -22.4% from baseline (p = 0.037) respectively. This did not result in any significant difference between start and end BP. CONCLUSIONS: This study demonstrates that APD is associated with significant systemic hemodynamic effects. The increased number of drain/fill cycles compared to CAPD, or the progressive rise in TPR and reduction in CO (possibly due to a cooling effect), may potentially be factors that adversely affect RRF in APD patients.

Aged↗

Cardiocirculatory responses to upright tilt at sea level and high altitude.

A collaborative study was conducted to measure the cardiocirculatory responses to upright tilt in eight young men at sea level (SL); after 1h at 4300m simulated altitude (SA) and at 18h, 66h and 114h during residence at 4300m (HA). Heart rate (HR), stroke volume (SV), cardiac output (CO), calf blood flow (CBF), blood pressure (BP) and total peripheral resistance (TPR) were obtained during supine rest and after 13 min of 60 degrees head-up tilt using an impedance monitor and an electrosphygmomanometer. SL to HA changes in blood volume (BV) were calculated from hematocrit and hemoglobin values. Supine HR, TPR and BP were increased while SV, CO and CBP were reduced SL to HA (P less than .05). HR and BP in the upright position were increased SL to HA (P less than .05). The responses to tilt (delta supine to upright) were unaltered SL vs SA. With prolonged exposure, SV, CO, TPR and CBP responses to tilt were reduced (P less than .05). The reduced responses to tilt at HA were associated with a 10% decline in BV (P less than .01). It was concluded that the reduction in SV during tilt at SL and SA was compensated for by increases in HR and TPR in order to maintain BP. After 18h HA, BP in the upright position was maintained only by an increase in HR.

Adult↗

[Mitral flow responses to three-week salt loading in elderly hypertensives].

Three-week effects of a high sodium diet on mitral flow pattern were assessed in 23 patients with essential hypertension (81.8 +/- 6.8 years). Transmitral flow was recorded during different rates of salt intake: 7 g/day for 8 weeks, 20 g/day for 3 weeks. With sodium loading, 19 patients whose mean blood pressure (MBP) increased by 10 percent or more were termed the salt-sensitive (SS) group, and 4 patients whose MBP did not change, or increased by less than 10 percent were termed the non salt-sensitive (NSS) group. With mitral velocity integral, cardiac output (CO) and total peripheral resistance (TPR) were calculated. Fourteen of the SS patients, in which an increase in TPR was greater than that in CO with sodium repletion, were defined as "SST". In the remaining 5 SS patients, termed "SSC", an increase in CO was greater than that in TPR with salt loading. CO increased significantly in the SSC patients, but did not change in the SST or NSS group with sodium loading. TPR increased significantly in the SST, and remained unchanged in the SSC or NSS patients. Peak velocity of transmitral flow in the rapid filling phase (R) decreased significantly in the SST patients, increased significantly in the SSC group, and remained unchanged in the NSS subjects. While, peak velocity of transmitral flow in the atrial contraction phase (A) increased significantly in the SSC group, it remained unchanged in the SST and NSS patients. There was a significant increase in A/R in the SST group and a significant decrease in A/R in the SSC patients with sodium loading.

Aged↗

Analysis by pulsed field gel electrophoresis reveals complex rearrangements in two MET alleles in a chemically-treated human cell line, MNNG-HOS.

We have previously shown that two alleles of the MET locus are independently rearranged in the chemically-treated human cell line MNNG-HOS. One allele is the TPR-MET oncogene which was activated by fusion of the MET locus on chromosome 7 with the TPR locus on chromosome 1. The second allele is found on a der(7)t(1;7)(q23;q32) chromosome and is characterized by a deletion of the amino-terminus of the MET extracellular ligand binding domain. Here we present a pulsed field gel electrophoresis analysis which reveals that the two MET allele rearrangements in MNNG-HOS cells are more complex than originally thought. The breakpoint in MET on der(7) has been molecularly cloned and, unexpectedly, we found that rearrangement in this allele involves sequences derived from chromosome 2. Moreover, the rearrangement producing der(7) involves an inversion of the MET locus or a more complex alteration. Analysis of hybrid cells containing TPR-MET demonstrated that both the upstream and downstream portions of MET are conserved in this rearrangement and that oncogene activation occurred by an insertion of TPR sequences into the MET locus. These findings illustrate that when examined at the molecular level some chromosome abnormalities can be extremely complex and, thus, are of limited value in gene mapping studies.

Alleles↗

Conducting a third-party reimbursement survey: experience of the Connecticut Nutrition Services Payment Systems Committee.

Third-party reimbursement (TPR) has emerged as a crucial issue for dietetics in the past decade. To investigate the level of TPR being obtained by individuals receiving nutrition services from registered dietitians in ambulatory settings, the Connecticut Nutrition Services Payment Systems (NSPS) Committee conducted an audit. Sixty survey packets were distributed to consulting dietitians in private practice and to dietitians in outpatient nutrition clinics. Twenty dietitians participated in the audit process, providing 99 client responses to the survey. Sixty-seven percent of clients submitted the charges for nutrition services to their insurance companies, but only 17% received reimbursement for the claims submitted. This audit process raised the level of awareness of the state membership regarding the need to aggressively pursue TPR for nutrition services at all levels, and it provided a model for dietitians to use to conduct periodic audits and assess TPR being received by their clients.

Connecticut↗

Hemodynamic effects of acute and prolonged administration of nitrendipine in essential hypertension.

In six hospitalized subjects with mild or moderate and untreated essential hypertension, we measured mean blood pressure (MBP, brachial artery catheter), heart rate (HR, electrocardiogram), cardiac output (CO, thermodilution), and total peripheral resistance (TPR, MBP divided by CO) at rest and during a cold pressor test (CPT, 60 s), a hand-grip exercise (HG, 40% maximum strength for 90 s), and a cyclette exercise (CE, 50 W for 5 min). The study was performed in a no-drug condition, 1 h after 20 mg oral nitrendipine (aN) and 1 week after daily administration of 20 mg oral nitrendipine (pN). Compared with the no-drug condition, aN reduced resting MBP from 137.3 +/- 7.3 (mean +/- SEM) to 112.3 +/- 9 mm Hg (p less than 0.05), increased resting HR from 72.3 +/- 6.9 to 85.3 +/- 8.8 beats/min) (p less than 0.05), increased resting CO from 6,191 +/- 508, to 8,700 +/- 1,050 ml/min (p less than 0.05), and reduced resting TPR from 1,807 +/- 119 to 1,140 +/- 228 dynes/s/cm5 (p less than 0.05). The reduction in resting MBP and TPR were unchanged by pN, whereas the increase in HR and CO were attenuated by 47 and 42%, respectively (p less than 0.05). Neither aN nor pN altered the hemodynamic responses to CPT, HG, and CE. As a result, the peak MBP and TPR values that were measured during these maneuvers were always lower (p less than 0.05) during aN and pN than in the no-drug condition. Thus, nitrendipine exerts marked antihypertensive and vasodilatatory effects that are evident at rest and during conditions elevating BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

[Potassium agonists: regional vasodilator profile in rats].

The systemic and regional (kidney, mesentery, hindlimb) hemodynamic effects of (a) two potassium agonists: cromakalim (1 to 8 micrograms.kg-1.min-1/15 min) and SR 44866 (0.125 to 2 micrograms.kg-1.min-1/15 min) and (b) a calcium antagonist, nicardipine (0.5 to 2 micrograms.kg-1.min-1/15 min) have been investigated by the pulsed doppler technique, and compared in the anesthetized normotensive rat. The two potassium agonists and nicardipine lowered blood pressure (BP) and total peripheral resistance (TPR) dose-dependently and slightly increased heart rate. Cardiac output (QC) remained unchanged. SR 44866 was as potent as nicardipine in reducing BP and about three to four times more potent than cromakalim (the DE20s, doses producing a 20 p. 100 decrease in BP, being: SR 44866: 0.7 micrograms.kg-1.min-1, cromakalim: 2.8 micrograms.kg-1, nicardipine: 0.8 micrograms.kg-1.min-1). At these equihypotensive doses, the three drugs (a) similarly decreased TPR (SR 44866: -16 p. 100, cromakalim: -17 p. 100, nicardipine: -19 p. 100, (b) reduced mesenteric vascular resistance (MVR) (SR 44866: -18 p. 100, cromakalin: -20 p. 100, nicardipine: -21 p. 100) and renal vascular resistance (RVR) (SR 44866: -16 p. 100, cromakalim: -21 p. 100, nicardipine: -13 p. 100 to the same extent as TPR, but (c) SR 44866 and nicardipine reduced hindlimb vascular resistance (HVR) to a larger extent than TPR (SR 44866: -25 p. 100, nicardipine: -25 p. 100.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

[Effect of Polygonum cuspidatum No 4 on the enhancement of cardiac function during burn shock].

A burn shock model was produced in rats by scalding the lumbus and lower extremities with 80 degrees C water for 30 seconds. The variable of cardiac functions were measured with a Cardiac-II-R cardio-output computer. It was shown that heart functions decreased as early as 10 min following scalding. Cardiac output (CO), cardiac index (CI), and stroke volume index (SVI) were reduced by 40% of normal, and stroke work (SW) by 47%. With the decrease of CO, total peripheral resistance (TPR) increased. Two hour later TPR was increased 2.6-fold more than pre-burn level, which made BP maintain nearly normal. TPR started to reduce at 3 hr post-burn, resulting in decrease of BP. The decreased heart function returned to near normal by administration of crystal of Polygonum cuspidatum No 4 (p.c), e.g, CO and CI were increased to 91.0% of pre-burn value, SW to 100.1%, and SVI to 102.0%. The increased TPR was reduced to near normal. Half of p.c.-treated animals survived within 24 hr, but all of simple burn animals and n.s.-treated animals died within 24 hr. Under the condition of no fluid infusion, administration of p.c. could restore the decreased heart function, which showed that besides loss of plasma, direct myocardial depression was one of the reason for the decrease of cardiac output during burn shock. The survival rate of animals with burn shock was enhanced by injection of p.c., which indicated that increasing heart function was a very important measure for the treatment of burn shock.

Animals↗

[Acute hemodynamic effects of nicardipine in patients with chronic congestive heart failure].

We evaluated haemodynamic parameters in 13 patients suffering from chronic heart failure (CHF) in III and IV NYHA class. They were 10 males and 3 females, average age 57 +/- 11 years. Haemodynamic monitoring was made at basal condition and for 40 min after the administration of nicardipine (10 mg iv). We observed that mean arterial pressure and systemic vascular resistances (SVR) showed an important decrease (respectively -10.8%, p less than 0.001 and -22%, p less than 0.001); total pulmonary resistances (TPR) also decreased (-16.6%, p less than 0.001), while mean pulmonary pressure did not show significant reduction. Cardiac index increased with the highest value at the fifteenth minute (-11.7%, p less than 0.01). Pulmonary wedge pressure (PWP) did not show statistic variations, and heart rate too. Cardiac index (CI) did not rise in 3 patients with clinical worsening during the monitoring (patients non responders) (CI increase was less than 15%); while in 10 patients CI increased more than 15% (patients responders). Patients non responders did not show any decrease of TPR and only a transitory reduction of SVR; patients responders showed an important decrease of TPR, SVR, PWP. We observed that at baseline, the difference between the 2 groups was based on the value of TPR and PWP. We conclude that nicardipine is an efficient drug in patients affected by CHF without severe hemodynamic failure.

Aged↗