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T Bennett

Publications and source records attributed to T Bennett.

At least 91 records · Page 5Linked to original sources
PubMed1996

Temporal differences between the involvement of angiotensin II and endothelin in the cardiovascular responses to endotoxaemia in conscious rats.

1. Male, Long Evans rats were instrumented chronically with pulsed Doppler probes and intravascular catheters to allow assessment of regional haemodynamic changes during i.v. infusion of lipopolysaccharide (LPS, 150 micrograms kg-1 h-1). 2. In the presence of the AT1-receptor antagonists, losartan (10 mg kg-1 + 10 kg-1 h-1), the initial (1-2 h) hypotensive and renal, mesenteric and hindquarters vasodilator responses to LPS were enhanced significantly. Thereafter these effects waned, but between 8-23 h after the onset of LPS infusion, a further fall in mean atrial blood pressure (MAP) and increases in renal and hindquarters flows and conductances occurred. All these changes were significantly greater than seen with losartan or LPS alone, and exceeded the sum of their effects. 3. In the presence of captopril (2 mg kg-1 + 2 mg kg-1 h-1), the initial hypotensive and renal vasodilator responses to LPS were enhanced, but less so than in the presence of losartan. However, the effects of LPS in the presence of losartan and captopril together were not different from those in the presence of losartan alone. These observations indicate that the ability of captopril to inhibit the degradation of bradykinin had no additional influence, and the differences between the effect of captopril and losartan on the initial effects of LPS were probably due to more effective suppression of the action of angiotensin II by losartan. 4. In the absence of LPS, co-infusion of losartan and the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 + 600 micrograms kg-1 h-1), caused a substantial, progressive hypotension (-25 +/- 2 mmHg at 24 h) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (31 +/- 13, 44 +/- 9 and 45 +/- 12%, respectively), indicating an involvement of angiotensin II and endothelin in the maintenance of normal cardiovascular status in conscious, Long Evans rats. 5. In the presence of losartan and SB 209670, the initial, LPS-induced fall in MAP (-42 +/- 2 mmHg) was not different from that in the presence of losartan (-39 +/- 4 mmHg), and the increases in renal, in mesenteric, and in hindquarters vascular conductances were similar in the two conditions. However, there was no recovery in MAP, and there were persistent renal, mesenteric and hindquarter vasodilatations. 6. In all experiments involving LPS, administration of the V1- receptor antagonist, d(CH2)5-O-Me-Tyr-AVP (10 micrograms kg-1), 23 h after the start of LPS infusion caused additional hypotension and mesenteric vasodilatation, particularly. This effect was most marked in animals pretreated with losartan and SB 209670. 7. The results indicate that the initial (1-2 h) depressor and dilator effects of LPS infusion in conscious Long Evans rats are opposed by the actions of angiotensins II, rather than endothelin. However, between 2-8 h after the onset of LPS infusion the involvement of endothelin develops and that of angiotensin II fades. By 24 h after the start of infusion of LPS, the pressor and vasoconstrictor actions of endothelin wane, and a role of vasopressin is apparent. At no stage is there clear evidence for an involvement of bradykinin in the haemodynamic sequelae of endotoxaemia in this model.

Angiotensin II↗
PubMed1996

The pathogenesis of multicystic dysplastic kidney disease: insights from the study of fetal kidneys.

The pathogenesis of multicystic dysplastic kidney disease (MCDKD) is unknown. Most morphologic studies of MCDKD kidneys have been performed when the kidneys are resected postnatally, when their architecture has been distorted by massive cyst enlargement. We obtained two MCDKD kidneys at an early stage of development (14 and 19 weeks' gestation) and examined the pattern of nephrogenesis in detail. In both affected kidneys, we identified islands of spatially dislocated metanephric blastema adjacent to zones containing all the normal structural elements of nephrogenesis, including aggregates of induced mesenchyme, S-shaped bodies and maturing glomerull, and proximal and distal tubules. Metanephric blastemal cells displayed characteristic vimentin and smooth muscle actin immunoreactivity and insulin-like growth factor II gene expression, whereas induced elements exhibited appropriate cytokeratin immunoreactivity and Wilms' tumor gene expression. In most other zones, renal cysts were lined with epithelia varying from a flattened squamous to a cuboidal morphology and expression of markers suggested their origin to be from all portions of the nephron including Bowman's space, proximal tubule, and collecting duct. In some cysts, small clusters of epithelial cells were identified within the cyst lumen. These studies suggest that in the early stages of MCDKD, normal nephrogenesis occurs in what seems to be a normal metanephric blastema; however, an intrinsic abnormality in the branching morphogenesis of the ureteric duct might be responsible for the development of the histopathologic changes described.

Actins↗
PubMed1996

Using relative value units (RVUs) to develop your pricing schedule.

This article presents a methodology by which a practice, using published Medicare Relative Value Units, can develop a logical and consistent pricing structure which recognizes the difference between procedures and is of a similar methodology to that used by Medicare and many major third-party payors in reimbursing practices. This approach utilizes available published information and can be done with relative ease by all physician practices.

Electronic Data Processing↗
PubMed1996

Physician directed networks: the new generation of managed care.

The external pressure to reduce cost while maintaining quality and services is moving the whole industry into a rapid mode of integration. Hospitals, vendors, MCOs, and now, physicians, are faced with the difficult decisions concerning how their operations will be integrated into the larger health care delivery system. These pressures have forced physicians to consolidate, build leverage, and create efficiencies to become more productive; thereby better positioning themselves to respond to the challenges and the opportunities that lie before them. This initial phase of consolidation has given many physicians the momentum to begin to wrestle back the control of health care and the courage to design the next generation of managed care: Physician Directed Managed Care. What will be the next phase? Perhaps, the next step will be fully-integrated specialty and multi-specialty groups leading to alternate delivery sites. "Everyone thinks of changing the world, but no one thinks of changing himself." - Leo Tolstoy

Community Networks↗
PubMed1996

Characterization of fetal ovine renal dysplasia after mid-gestation ureteral obstruction.

OBJECTIVE: The etiology and pathogenesis of renal dysplasia are poorly understood. To characterize the histologic changes in fetal renal dysplasia, we studied a fetal ovine model of urinary obstruction. DESIGN: Animal study. ANIMALS: Seven fetal lambs, and other lambs of the same gestational age as controls. INTERVENTIONS: Unilateral ureteral ligation on fetal lambs at approximately 70 days' gestation (term for sheep is 145 days), during nephrogenesis. Kidneys were subsequently collected, examined histologically and characterized by immunohistochemical tests involving cytokeratin antiserum and a monoclonal antibody to alpha-actin. OUTCOME MEASURES: Histologic changes in ligated fetal lamb kidneys, based on comparison with normal fetal lamb kidneys. RESULTS: At near term (140 days' gestation), the ligated kidney showed distorted and less abundant renal parenchyma than a normal control kidney. Upon microscopic examination, the ligated kidney displayed marked architectural distortion of the outer cortex, with abundant interstitial fibrosis, primitive ductules and glomeruli, and cysts of varying sizes lined by squamous and cuboidal epithelia and surrounded by a loose mesenchyme. The renal medulla contained differentiated collecting ducts, which were structurally distorted and less abundant than in normal control kidneys. The proximal and distal tubule elements were primitive and markedly underdeveloped. Cytokeratin immunoreactivity was present in the collecting duct epithelium and in the cuboidal epithelium lining many of the cortical cysts. Smooth muscle alpha-actin immunoreactivity was localized in the cortical region of the kidney, which highlighted the abundance and disorganization of the undifferentiated mesenchyme and identified the fibromuscular collars of the primitive ductules of the cortex and the distorted collecting ducts of the medulla. CONCLUSIONS: These results highlight the histologic changes resulting from unilateral ureteral ligation in fetal lambs. This model is useful in the study of the pathogenesis of fetal obstructive renal dysplasia.

Actins↗
PubMed1995

Identification of a short form of the P2xR1-purinoceptor subunit produced by alternative splicing in the pituitary and cochlea.

A truncated form of the P2xR1 purinoceptor subunit (which we designate P2xR1-2) was detected in rat pituitary gland and the secretory epithelial tissue (stria vascularis) of the cochlea using RT-PCR of solid-phase cDNA libraries. PCR products corresponding to the P2xR1 purinoceptor subunit (1) were obtained from vas deferens, brain and microdissected cochlear sensory epithelial tissues including organ of Corti, sacculus and crista ampullaris. Cloning and sequencing revealed that the P2xR1-2 product included an 85-bp insertion in a region corresponding to a novel C-terminal end of the second membrane spanning domain and continuing as the cytoplasmic domain. A stop codon sequence after the first 51 bp of the insert effectively truncates this subunit, reducing the final cytoplasmic domain by 90% compared with the previously published P2xR1(-1) sequence, thereby reducing the overall peptide by approximately 25%. The region of the receptor lost in the truncated version coded for a number of serine/proline rich regions which may act as potential intracellular regulatory sites.

Alternative Splicing↗
PubMed1995

Independent signal transduction pathways for IL-1 and TNF in LPS-tolerant macrophages.

Macrophages rendered "tolerant" by pretreatment with low-dose endotoxin (LPSp) release less TNF and more IL-1 in response to a second activating endotoxin exposure (LPSa). We hypothesized that LPSp pretreatment alters signal transduction pathways for TNF and IL-1 independently. The effect of pretreatment with LPSp alone was compared to pretreatment with LPSp plus defined second-messenger pathway agonists or antagonists. Murine peritoneal macrophages were pretreated in vitro for 4 hr with LPSp or PMA or LPSp plus protein kinase C inhibitor (PKCi) or 8-bromo-cAMP. Cells were then washed and cultured with medium alone for 20 hr. Macrophages were also pretreated with LPSp plus indomethacin for the total 24-hr pretreatment interval. Cells were then stimulated for 24 hr with LPSa, after which supernatant TNF and IL-1 were measured by bioassay. In the absence of LPSp, mediators were increased by LPSa in a dose-dependent manner. LPSp pretreatment inhibited TNF and augmented IL-1 in response to LPSa. Pretreatment with PMA partially reproduced LPSp pretreatment. Pretreatment with PKCi alone increased both TNF and IL-1 release by LPSa. The combination of LPSp plus PKCi pretreatment further enhanced IL-1 release without affecting TNF inhibition. The addition of indomethacin had a similar effect. The combination of LPSp plus 8-bromo-cAMP blocked the augmentation of IL-1 without changing TNF inhibition. Macrophage endotoxin tolerance following LPSp pretreatment alters LPSa-triggered TNF and IL-1 release by independent signal transduction pathways.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1995

Monitoring of pulmonary arterial diastolic pressure through a right ventricular pressure transducer.

Pulmonary arterial diastolic pressure is an important parameter for hemodynamic monitoring in congestive heart failure. It is traditionally obtained through a pulmonary arterial catheter. If it could be obtained from a sensor in the right ventricle, chronic monitoring would be possible without the use of a pulmonary arterial catheter. This study is based on the hypothesis that pulmonary valve opening and pulmonary arterial diastolic pressure occur at the time of maximum positive rate of pressure development (dP/dt) in the right ventricle, when the pressures should be equal. Thus, right ventricular pressure at the time of maximum dP/dt (PAD index) should be a reasonable estimate of pulmonary arterial diastolic pressure. Eight patients with heart failure were catheterized and exposed to hemodynamic stress. Right ventricular and pulmonary arterial pressures were simultaneously recorded from a Millar (Houston, TX) catheter with two pressure transducers. The distal transducer was positioned in the bifurcation of the pulmonary artery and the proximal transducer was placed in the right ventricle. Pulmonary arterial diastolic pressure and PAD index were stored beat by beat on a bed-side computer. Acceptable recordings were obtained in all patients. Recordings from the individual patients showed a good covariation between PAD index and pulmonary arterial pressure during different hemodynamic manuevers, except during infusion of dobutamine, when the correlation was not as good. Pulmonary arterial diastolic pressure may be estimated from a transducer in the right ventricle, thus eliminating the need for a permanent pulmonary arterial catheter in an implantable hemodynamic monitoring system. Further studies are needed to verify the correlation on a long-term basis.

Aged↗
PubMed1995

Monitoring of mixed venous oxygen saturation and pressure from biosensors in the right ventricle. A 24 hour study in patients with heart failure.

Right ventricle venous oxygen saturation was studied in 10 heart failure patients over 24 h using a lead equipped with an oxygen biosensor inserted temporarily. At the same time a pressure sensor, incorporated in the same lead to measure right ventricular pulse pressure and maximum positive and negative rate of pressure development (RV dP/dt), was tested to see whether it would interfere with the oxygen sensor. Data from the biosensor lead were continuously compared with mixed venous oxygen saturation obtained from a fibreoptic Swan-Ganz catheter with the tip in the pulmonary artery. For reference, blood samples were drawn at regular intervals from this catheter. A provocative protocol was used to cause haemodynamic changes. There was good correlation between oxygen saturation in the right ventricle (biosensor-derived) and mixed venous oxygen saturation in the pulmonary artery (fibreoptic-derived) (r = 0.86) and between sensor-obtained right ventricular oxygen saturation and oxygen saturation in the blood samples from the pulmonary artery (r = 0.90). Changes in central haemodynamics were also well reflected by changes in pulse pressure and dP/dt derived from the pressure sensor. As it was not possible to obtain absolute pressures no attempt was made to compare the pressure changes with conventional haemodynamics. These 24 h haemodynamic measurements suggest that a biosensor-equipped lead placed in the right ventricle could be a valuable tool for long-term monitoring of mixed venous oxygen saturation and pressure in patients with congestive heart failure.

Aged↗
PubMed1995

Island flaps including the Bezier type in the treatment of malignant melanoma.

Despite the trend in current surgical practice in the treatment on melanoma to produce smaller excisional defects, any technique which can introduce a surgical closure that does not require split skin grafting must be of benefit. This paper introduces and illustrates a range of island flap techniques that employ no skin grafting for the treatment of malignant melanoma defects. The new cutaneous island flap described, termed the Bezier or the French Curve, employs a double V-Y appositional closure method, thus giving a more refined reconstructive result that fits into the line of the body curves aesthetically. The design of the Bezier flap is almost identical in size and shape to the excisional defect, with a facial or muscular base for vascular support. Appropriate guidelines that determine the design and application of this island flap technique are listed. They are illustrated both diagrammatically and clinically. Other flaps illustrated include fasciocutaneous island flaps and myocutaneous island flaps that use a single V-Y flap appositional closure technique. All these flaps were designed with special reference to the dermatomes, which act as an aid memoire upon which the flaps are marked.

Adolescent↗
PubMed1995

Acute and chronic cardiac and regional haemodynamic effects of the novel bradycardic agent, S16257, in conscious rats.

1. We carried out experiments to assess the cardiac and regional haemodynamic effects of single or repeated injections of the novel bradycardic agent. S16257, (7,8-dimethoxy 3-[3-([(IS)-(4,5-dimethoxybenzocyclobutan-1- yl)methyl]methylamino)propyl] 1,3,4,5-tetrahydro-2H-benzapin 2-one), in conscious rats. 2. In the first experiment, male Long Evans rats were chronically instrumented for the measurement of cardiac or regional haemodynamics (n = 9 in each group), and, on separate experimental days, were randomized to receive i.v. bolus injections of vehicle (5% dextrose) or S16257 at a dose of 1 mg kg-1. 3. In animals instrumented for the measurement of cardiac haemodynamics (n = 9), following injection of vehicle, there were no immediate changes, and 7-8 h later there were slight reductions in heart rate and mean arterial blood pressure only. Injection of S16257 caused an immediate, transient, pressor effect but thereafter there were reductions in heart rate, mean arterial blood pressure, cardiac index and total peripheral conductance, together with increases in stroke index and peak aortic flow. The integrated decreases in heart rate, mean arterial blood pressure, cardiac index and total peripheral conductance and increases in stroke index, peak aortic flow, dF/dtmax and central venous pressure following S16257 were all significantly greater than the changes after vehicle injection. After injection of S16257, the fall in heart rate and fall in cardiac index were not linearly related. 4. In animals instrumented for the measurement of regional haemodynamics (n = 9). the bradycardic effect of i.v. S16257 was accompanied by reductions in renal, mesenteric and hindquarters blood flows and vascular conductances that were greater than the changes seen following injection of vehicle, but only for the first 1 h. Considering animals instrumented for the measurement of cardiac and regional haemodynamics together, the bradycardic effect of S16257 was greater the higher the resting heart rate.5. In the second experiment, animals chronically instrumented for the measurement of cardiac or regional haemodynamics (n = 9 in each group) were given s.c. injections of S16257 (1 mg kg-1) on four consecutive days. The general patterns of change in cardiac and regional haemodynamics following s.c.injection of S16257 were as described above for i.v. injection, although the rates of onset of effects were slower. The bradycardic effect of S16257 was less on the first, than on the subsequent, three days.6 Overall, these results indicate that the bradycardic action of S16257 is not associated with any signsof negative inotropic action. Only the initial depressor effect of i.v. S16257 is associated with reductions in renal, mesenteric and hindquarters flow and vascular conductance significantly greater than those seen after vehicle injection. With repeated s.c. injection of S16257, there are no signs of desensitization to its bradycardic actions, nor impairment of regional perfusion. If these results extrapolate to the clinical setting, it seems likely that S16257 will have beneficial bradycardic effects, with no concurrent undesirable actions on other aspects of cardiovascular function.

Animals↗
PubMed1995

Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen-2)27), hypertensive rats.

1. Hypertensive transgenic (TGR(mRen-2)27) (abbreviated to TG) rats (n = 6) and their normotensive Sprague-Dawley (SD) control strain (n = 7) were chronically instrumented for the measurement of cardiac haemodynamics. The hypertension in TG rats (mean blood pressure 181 +/- 9 mmHg) was entirely attributable to a reduction in total peripheral conductance (TG rats = 169 +/- 7, SD rats = 292 +/- 15 microliters min-1 mmHg-1 100g-1) since cardiac index was not different in the two strains (TG rats = 30.5 +/- 1.2, SD rats = 29.5 +/- 1.6 ml min-1 100g-1). 2. In other animals instrumented for the assessment of regional haemodynamics, the extent of peripheral vasoconstriction was similar in renal, mesenteric and hindquarters vascular beds in the TG rats (reduction in vascular conductance relative to SD rats = 42%, 46% and 49%, respectively). 3. During an 8 h observation period with saline infusion, or following injection of losartan (10 mg kg-1) in SD rats there was no hypotension or regional vasodilation. With infusion of the endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1), there was a slight hypotension, but no significant vasodilation; co-administration of losartan and SB 209670 caused a similar profile of effect, although the hypotension was increased. 4. With the same experimental protocol in TG rats, losartan caused a biphasic, progressive fall in mean arterial blood pressure accompanied by renal, mesenteric and hindquarters vasodilation. Although the response to SB 209670 was not biphasic, its hypotensive and vasodilator effects were not different from those of losartan after 8 h. In the combined presence of losartan and SB 209670, mean arterial blood pressure (116 +/- 5 mmHg) was significantly lower than with SB 209670 (132+/-4 mmHg) or losartan(136 +/- 6 mmHg) alone, and renal, mesenteric and hindquarters vascular conductances (61 +/- 3, 90+/-14 and 52+/-4 [kHz nmHg-1]103, respectively) were higher than the corresponding values following either SB 209670 (49 +/- 4, 52 +/- 4 and 34 +/- 3 [kHz mmHg- 1]103, respectively) or losartan (43 +/- 5, 59 +/- 13 and 35+/-4 [kHz mmHg-1]103, respectively) alone. These results indicate the maintenance of hypertension inTG rats is dependent upon renal, mesenteric and hindquarters vasoconstriction, mediated by angiotensinII (AII) and endothelin (ET). Since we found that plasma ET-1 levels in TG rats (12.06+/-2.87 pmol 1-1)were lower than in SD rats (21.53 +/- 3.94 pmol 1-1), then it is possible that locally-generated, rather than circulating ET-l contributes to the widespread vasoconstriction in TG rats.

Angiotensin II↗
PubMed1995

Lack of effect of TNF antibodies on the cardiovascular sequelae of lipopolysaccharide infusion in conscious rats.

1. The aims of the present study were to determine the profile of tumour necrosis factor (TNF) release, and the effect of monoclonal antibodies to TNF, on the changes in regional haemodynamics and the responses to vasodilator and vasoconstrictor challenges, during a continuous 24 h low dose infusion of lipopolysaccharide (LPS) in conscious rats. 2. Male Long Evans rats were chronically instrumented for measurement of regional haemodynamics (renal, superior mesenteric and hindquarters) and were challenged with 3 min infusions of acetylcholine (22 nmol min-1), methoxamine (120 nmol min-1), salbutamol (0.83 nmol min-1) and bradykinin (14.4 nmol min-1). The rats were given either saline, or the TNF antibodies, TN3g1 or TN3g2a, 1 h before the start of a continuous infusion of LPS (150 micrograms kg-1 h-1) and were subsequently re-tested with the vasodilator and vasoconstrictor challenges 2, 6 and 24 h after the start of the LPS infusion. 3. Prior to infusion of LPS, TNF was not detectable in the plasma. During continuous infusion of LPS there was a transient elevation in plasma TNF levels, reaching a maximum (approximately 2300 pg ml-1) after approximately 1 h, and returning to undetectable levels after approximately 3 h of LPS infusion. 4. In the saline pretreated group, after 1-2 h of LPS infusion, there was a small hypotension and a marked renal vasodilation; 6 h after the start of LPS infusion there was a minor elevation in MAP above control levels, renal vasodilatation was maintained and a hindquarters vasoconstriction occurred; after 24 h of LPS infusion, there was a hypotension and renal and hindquarters vasodilatation. There were significant reductions in the tachycardic and renal vasodilator responses and an enhanced depressor response to acetylcholine after 24 h of LPS infusion. LPS infusion also caused a generalized hyporesponsiveness to the cardiovascular effects of methoxamine and salbutamol. The major changes in response to bradykinin were reduced tachycardic and enhanced depressor responses throughout the LPS infusion, a biphasic decrease and increase in renal conductance and enhanced hindquarters vasodilatation at 24 h. 5. Pretreatment with either TN3g1 or TN3g2a antibodies had no major effects on the changes in resting haemodynamics, or on the changes in response to methoxamine, salbutamol or bradykinin challenges during LPS infusion. However, the tachycardic responses to acetylcholine were generally preserved, and its hypotensive effect after 24 h of LPS infusion was not enhanced after TN3g1 or TN3g2a pretreatment. Thus, despite substantial, but transient, elevation of plasma TNF levels during continuous LPS infusion, it appears that the majority of cardiovascular changes were dependent on factors other than plasma TNF.

Acetylcholine↗
PubMed1995

Attenuation by creatine of myocardial metabolic stress in Brattleboro rats caused by chronic inhibition of nitric oxide synthase.

1. The present experiment was undertaken to investigate: (a) the effect of nitric oxide synthase (NOS) inhibition, mediated by oral supplementation of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on measures of myocardial energy metabolism and function: (b) the effect of oral creatine supplementation on these variables, in the absence and presence of L-NAME. 2. In one series of experiments, 4 weeks oral administration of L-NAME (0.05 mg ml-1 day-1 in the drinking water) to Brattleboro rats caused significant reductions in myocardial ATP, creatine, and total creatine concentrations and an accumulation of tissue lactate when compared with control animals. Administration of creatine (0.63 mg ml-1 day-1 in the drinking water) for 4 weeks elevated myocardial creatine and total creatine concentrations and reduced lactate accumulation, but did not significantly affect ATP or phosphocreatine (PCr). Concurrent treatment with creatine and L-NAME prevented the reduction in creatine and total creatine concentrations, and significantly attenuated the accumulation of lactate and the reduction in ATP seen with L-NAME alone. 3. In a second series of experiments, 4 weeks treatment with L-NAME and creatine plus L-NAME increased mean arterial blood pressure in conscious Brattleboro rats. Hearts isolated from these animals showed decreased coronary flow and left ventricular developed pressure (LVDP), and total mechanical performance. Treatment with creatine alone had no measurable effect on either mean arterial blood pressure or coronary flow in isolated hearts. However, there was an increase in LVDP, but not in total mechanical performance, because there was a bradycardia. 4. These results indicate that creatine supplementation can attenuate the metabolic stress associated with L-NAME administration and that this effect occurs as a consequence of the action of creatine on myocardial energy metabolism.

Adenosine Triphosphate↗
PubMed1995

Enhancement of the haemodynamic effects of NG-monomethyl-L-arginine by transforming growth factor-beta 1 in conscious, normal, but not endotoxaemic, rats.

1. Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of regional haemodynamics, and the effects of TGF-beta 1 (25 micrograms kg-1 i.v. bolus) were assessed during infusion of saline (n = 9) or lipopolysaccharide (LPS, 150 micrograms kg-1 h-1; n = 12). In the same animals, responses to NG-monomethyl-L-arginine (L-NMMA 10 mg kg-1 bolus; 10 mg kg-1 h-1 infusion) were determined 18 h after administration of TGF-beta 1. In a separate experiment, the effects of the endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1) on responses to TGF-beta 1 and to L-NMMA subsequently, were determined. 2. In the absence of LPS, TGF-beta 1 had slow-onset bradycardic and pressor effects accompanied by mesenteric and hindquarters, but not renal, vasoconstriction. Eighteen hours after TGF-beta 1, these effects had gone, but the bradycardic, pressor, and mesenteric vasoconstrictor responses to L-NMMA were enhanced. The haemodynamic changes following TGF-beta 1, and the augmentation of the subsequent responses to L-NMMA, were inhibited by SB 209670. These results are consistent with TGF-beta 1 stimulating the synthesis and release of endothelin, and an involvement of the latter in responses to L-NMMA. 3. The pressor effects of TGF-beta 1 were similar in LPS-infused and saline-infused animals, but in the former group the mesenteric vasoconstriction was enhanced and the hindquarters vasoconstriction diminished. Since, in the absence of TGF-beta 1, LPS-infused animals showed a developing hindquarters vasodilatation and mesenteric vasoconstriction, it is feasible that, in the presence of TGF-beta 1 and LPS together, the haemodynamic profile represented an amalgam of the individual effects of the two interventions, rather than a specific effect of TGF-beta 1 on the haemodynamic sequelae of endotoxaemia. 4. In the presence of LPS, haemodynamic responses to L-NMMA were suppressed, and TGF-beta 1 generally did not affect this suppression. A possible explanation of this observation is that LPS increased circulating endothelin levels, and thus resulted in desensitization to the effects of endothelin released following administration of L-NMMA.

Animals↗
PubMed1995

Cardiac and regional haemodynamics, inducible nitric oxide synthase (NOS) activity, and the effects of NOS inhibitors in conscious, endotoxaemic rats.

1. A reproducible model of the hyperdynamic circulatory sequelae of endotoxaemia in conscious, chronically-instrumented Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 micro g kg(-1) h(-1)) for 32 h. Over the first 2 h of LPS infusion, there was a transient hypotension and tachycardia, accompanied by a marked increase in renal flow and vascular conductance, although there were reductions in cardiac and stroke index. Between 4-8 after the start of LPS infusion, there was slight hypotension and tachycardia, and a transient rise in mesenteric flow and conductance, but reductions in the hindquarters vascular bed; the hyperaemic vasodilatation in the renal vascular bed was maintained. At this stage, all cardiac haemodynamic variables were not different from baseline. At this stage, cardiac and stroke index were substantially elevated, in association with marked increases in peak aortic flow, dF/dtmax and total peripheral conductance; these changes were well-maintained over the following 8 h of LPS infusion. 2. By 2 h after the start of LPS infusion, only lung inducible nitric oxide synthase (iNOS) activity was increased, but at 6 h there were significant increases in iNOS activity in lung, liver, spleen, heart and aorta. (43.3 +/- 7.8, 28.8 +/- 3.3, 50.8 +/- 7.2, 3.04 +/- 0.29, 3.76 +/- 0.94 pmol min(-1) mg(-1) protein, respectively). However, by 24 h after the start of LPS infusion, iNOS activity was not elevated significantly in any tissue examined, and kidney iNOS activity did not change significantly during LPS infusion. Plasma nitrite/nitrate levels were increased after 2 h infusion of LPS (from 6.07 +/- 1.23 to 29.44 +/- 7.08 micromol l(-1)), and further by 6 h (228.10 +/- 29.20 micromol l(-1)), but were less 24 h after onset of LPS infusion (74.96 +/- 11.34 micromol l(-1)). Hence, the progressive hypotension, increasing cardiac function and developing hyperaemic vasodilatation in renal and hindquarters vascular beds between 8-24 h after the onset of LPS infusion, occurred when tissue iNOS activity and plasma nitrite/nitrate levels were falling. 3. Pretreatment with NG-monomethyl-L-arginine (L-NMMA, 30 mg kg(-1) bolus, 30 mg kg(-1) h(-1) infusion) 1 h before LPS infusion did not prevent the early hypotension, but abolished the initial renal vasodilatation and the later (6-8 h) fall in mean arterial pressure (MAP), and the additional renal vasodilatation.

Animals↗