The purpose of this study was to investigate the dependence of T, the time constant of left ventricular (LV) isovolumic relaxation, on pericardial pressure and to compare values of r as determined by the methods of previous investigators and by a standard exponential curve fit. All of the more recent methods involve an additional parameter -the pressure to which the exponential relaxation finally declines (PB, the pressure intercept in the method of Craig and Murgo and the asymptote in the exponential fits). An additional purpose of the study was to determine the relation of these parameters to pericardial pressure. In eight closed-chest anesthetized dogs, r was calculated from intracavitary (PI,) and transmural LV pressure (P, =Piv-Pper) by each method as pericardial (Pper) and LV end-diastolic pressure were changed by pericardial infusion and intravenous volume loading. The time constant determined by the method of Weiss et al was dependent on pericardial pressure; the time constants determined by the other methods were not. PB and the asymptotes were found to be similar and to increase almost equally with pericardial pressure. When pericardial

To determine the better method of measuring pericardial constraint, pericardial pressure was recorded by a liquid-filled open-ended catheter and a liquid-containing flat balloon in six open-chest anesthetized dogs. Left ventricular pressure was measured by a micromanometer-tipped catheter and left ventricular anteroposterior diameter was measured by sonomicrometry. Left ventricular end-diastolic pressure was raised to 20 +1.7 (mean -+ SD) mm Hg by intravenous saline. Left ventricular diastolic pressure-diameter loops were constructed (1) with incremental amounts of saline (0 to 50 ml) in the resealed pericardium, (2) with several small holes in the pericardium, and (3) with the pericardium widely open. Measured pericardial pressures were compared with what was assumed to be the correct pericardial pressure, i.e., the calculated difference between left ventricular diastolic pressure (at a given left ventricular diameter) before and after opening the pericardium. Pressure recorded by the flat balloon was similar to the calculated pericardial pressure at all pericardial liquid volumes. Pressure recorded by the open-ended catheter, however, was significantly lower (p < .05) than the calculated pressure unless there was at least 30 ml of liquid in the pericardium. After several holes had been made in the pericardium it still exerted a constraining effect, as shown by a marked rightward or downward shift of the left ventricular diastolic pressure-diameter relationships after completely opening the pericardium. After holes were made in the pericardium pressure recorded by the flat balloon was still similar to the calculated pericardial pressure. However, pressure recorded by the open-ended catheter was significantly (p < .02) lower than the calculated pressure. In four dogs the product of left ventricular anteroposterior and septum-to-free wall diameter was used as a volume parameter; comparison made between measured and calculated pericardial pressures confirmed the results obtained with use of anteroposterior diameter to assess left ventricular size. In conclusion, unless the pericardium is sealed and contains at least 30 ml of liquid, an open-ended catheter significantly underestimates pericardial constraint. However, a flat liquid-containing balloon correctly measures pericardial constraint regardless of the amount of pericardial liquid and also when the pericardium is not sealed. Circulation 71, No. 1, 158-164, 1985. THE QUANTITATIVE EFFECT of pericardial constraint on left ventricular diastolic function remains controversial." It seems clear that the resolution of this controversy depends on the magnitude of pericardial pressure that, in turn, depends on the method of measurement. In the pulmonary literature Agostoni and othersI6 have promulgated the distinction between "liquid pressure" and "surface pressure." Liquid From the Departments of Medicine and Medical Physiology. University of Calgary, Calgary, Alberta, Canada. Supported by a grant-in-aid from the Alberta Heart Foundation. Address for correspondence: Dr. John V. Tyberg, Departments of Medicine and Medical Physiology, Faculty of Medicine, The University of Calgary, 3330 University Dr. N.W., Calgary, Alberta, Canada T2N 4N1. Received June 21, 1984; revision accepted Oct. 11, 1984. Drs. Smiseth, Frais, and Kingma held postdoctoral research fellowships from the Alberta Heritage Foundation for Medical Research during the time when the study was conducted. Dr. Tyberg was a Senior Investigator of the Alberta Heart Foundation and is a Heritage Medical Scientist of the Alberta Heritage Foundation for Medical Research. 158 pressure is familiar to cardiovascular physiologists and can be measured by connecting a manometer to any fluid-filled space as with a liquid-filled catheter. The concept of surface pressure is more difficult; it is the force per unit surface area exerted by, for example, the left ventricular surface on the overlying parietal pericardial membrane. The difference between the pericardial liquid pressure and surface pressure is the compressive contact stress7 developed between the surfaces.4 The oft-quoted work by Kenner and Wood' supports the common view that pericardial pressure is approximately equal to intrathoracic pressure and unchanged by alterations in cardiac volume. They dilated the heart substantially by aortic and pulmonary artery constriction without importantly raising pericardial (liquid) pressure. Some years ago Holt et al.2 used a liquidcontaining balloon and demonstrated that blood volume expansion increased pericardial (surface) pressure CIRCULATION by gest on A ril 4, 2017 http://ciajournals.org/ D ow nladed from LABORATORY INVESTIGATION-HEMODYNAMICS nearly as much as it increased left ventricular diastolic pressure. Recently, using a similar balloon, we have demonstrated important changes in pericardial (surface) pressure following changes in preload or afterload in the failing heart.8 Thus, the aim of the present study was to determine whether an open-ended catheter or a flat, liquid-containing balloon could accurately measure pericardial constraint. To arrive at a "gold standard" of pericardial pressure we postulated a simple, static-equilibrium concept: at a given left ventricular end-diastolic size (diameter) the correct pericardial pressure is that pressure which must be added to left ventricular transmural pressure to equal the intracavitary left ventricular pressure. We measured left ventricular transmural pressure directly as a function of left ventricular diameter at the end of the experiment after removal of the pericardium with the chest widely open and the lungs retracted. Thus, we defined the calculated pericardial pressure as the difference between the left ventricular end-diastolic pressure measured when the pericardium was closed and the left ventricular end-diastolic pressure measured at the same diameter when the pericardium was removed. To determine the dependence of the measured pericardial pressure on the volume of pericardial liquid we infused saline into the resealed pericardial cavity. To test the hypothesis that even a netlike pericardium would induce a measurable, physiologically significant constraint on left ventricular diastolic filling, measurements were repeated after several small holes had been cut in the pericardium. Methods Animal preparation. Experiments were done in six mongrel dogs (22 to 33 kg). Anesthesia was induced by 25 mg/kg iv sodium thiopental (Pentothal, Abbott Laboratories, Montreal, P.Q.) and was maintained by 1.5% halothane and nitrous oxide/ oxygen with use of a constant-volume respirator (model 607, Harvard Apparatus Co. Inc., Millis, MA) and a closed rebreathing system. A midline stemotomy was performed with each dog in the supine position. Left ventricular pressure was measured by a No. 8F micromanometer-tipped catheter with a reference lumen (model PC-480, Millar Instruments, Houston, TX). The ventral surface of the pericardium was incised transversely along the base of the heart. A flat balloon and open-ended catheter were positioned on the anterolateral surface of the left ventricle at the mid left ventricular level and were stitched loosely to the epicardium. The open-ended catheter was composed of a 4 cm terminal silicone rubber segment with an endhole and three side-holes fixed to a stiff 60 cm No. 8F cardiac catheter. Another multiple side-hole catheter was inserted into the pericardium to be used for drainage and saline infusion. The pericardium was sutured and sealed water tight by applying small amounts of glue (The Gripper Super Glue, Via Chem. Inc., Quebec, P.Q.) along the sutures. A snare was placed around the posterior vena cava to transiently restrict left ventricular filling and a catheter for intravenous infusion was placed in a femoral vein. Aortic pressure was monitored through a cathVol. 71, No. 1, January 1985 eter introduced into a femoral artery. Left ventricular anteroposterior diameter (DA-P) and in four dogs septum-to-left ventricular free wall diameter (DS-FW) were measured with ultrasonic crystals. The free wall crystals were sutured to the epicardium at the mid left ventricular level. The septal crystal was pushed halfway through the septum at the mid left ventricular level. A limb-lead electrocardiogram was monitored and body temperature was maintained by a warming lamp. Pressures, diameters, and the electrocardiogram were recorded (Electronics for Medicine/Honeywell, model VRl6, White Plains, NY) at a paper speed of 75 mm/sec. Data were also recorded on analog tape (Hewlett Packard, model 3968A, Palo Alto, CA) for later analysis. Pericardial balloons. The balloons were made from a 0.025 cm thick folded sheet of silicone rubber (Armet Industries Corp., Concord, Ont.) sealed at the edges. (Internally, the balloon measured 3 x 3 cm.) A short silicone rubber tube protruding from the balloon was connected to a 60 cm No. 8F stiff cardiac catheter. The balloon could hold up to 1.8 ml of fluid without developing measurable pressure. Before insertion into the pericardium, the balloon was calibrated by a procedure similar to that used by McMahon et al. ,6 the results of which are illustrated in figure 1. The balloon was also found to accurately measure negative pressures (0 to -20 mm Hg) that were created in a water-containing chamber. The frequency response of the balloon was tested in a water chamber (WGA-200, Millar Instruments, Inc., Houston, TX). The pressure amplitude ratio (balloon-micromanometer) was 1.0 below 14 Hz and increased to 1.1 at 25 Hz (both amplifiers filtered at 2500 Hz). Experimental protocol. To increase pericardial pressure, the dogs received intravenous infusions of saline adjusted to maintain left ventricular end-diastolic pressure at approximately 20 mmHg (mean + SD = 20.2 + 1.7 mmHg) throughoutthe period of pericardial saline infusion. Pericardial suction was applied initially and was discontinued immediately before the fi

Objective: Circulating endothelin-1 (ET-1) levels have been reported to be associated with vascular complications and endothelial dysfunction in nontransplanted patients. The aim of this study was to investigate the relationship between ET-1 levels and major cardiovascular (CV) risk factors in renal transplant (RTX) patients with stable graft function.Methods: ET-1 levels were determined in 156 RTX patients and the relationship between circulating ET-1 levels and CV risk factors including age, gender, kidney function, blood lipids, diabetes, and hypertension was studied.Results: Circulating ET-1 levels were found to be positively correlated with creatinine (r = 0.25,p < 0.01) and systolic blood pressure (r = 0.20, p < 0.05) and inversely correlated with high-density lipoprotein cholesterol (HDL-C) levels (r = -0.27, p < 0.01). Patients with high and intermediate total cholesterol/HDL-C ratios (TC/HDL-C) had significantly higher ET-1 levels when compared to patients with low ratios (7.02 +/- 3.74, 6.79 +/- 2.67, and 5.37 +/- 3.04 pg/ml, respectively, p < 0.002). Only creatinine, HDL-C, and age >40 years were shown to be independent correlates for ET-1 levels according to multivariate analyses. Interestingly, ET-1 levels were significantly higher (+26%, p < 0.03) in RTX patients with documented CV disease, as compared to those without, when matched for age, gender, and presence of diabetes.Conclusions: Increased circulating ET-1 levels are associated with low HDL-C and documented CV disease in RTX. This is likely a reflection of vascular endothelial damage and dysfunction and therefore may represent an increased risk for atherosclerosis. (C) 2004 The Canadian Society of Clinical Chemists. All rights reserved.

Obesity, hypertension, elevated lipids and increased fasting insulin levels lead to increased risk for cardiovascular disease. They are frequently clustered together compounding the risk. Orlistat has been shown to produce greater reduction in individual risk factors for coronary heart disease, such as weight, diastolic blood pressure and serum lipids than diet alone in obese individuals with treated but insufficiently-controlled hypertension. To examine whether or not there was a greater reduction in predicted coronary heart disease risk in the orlistat-treated participants, we reanalyzed the data, using the algorithm proposed by the Framingham investigators (Wilson, Circulation 1998;97:1837-1847). In obese individuals with inadequately controlled hypertension, we previously reported that 52 weeks of treatment with orlistat plus a calorie reduced 30% fat diet produces greater weight loss than diet alone (-5.4±6.4 vs -2.7±6.4 kg, p<0.001) and greater diastolic blood pressure reduction -11.4±8.3 vs -9.2±8.4 mmHg, p=0.002). The effects on total cholesterol, LDL cholesterol and LDL/HDL ratio were significantly greater in the orlistat treated Group. Systolic blood pressure reduction occurred to a similar extent in the two groups Significant reductions in fasting insulin were obtained in both groups. Although the reduction in fasting insulin in orlistat-treated patients was almost twice that obtained in placebo treated participants, the difference was not statistically significant. Of 554 initially randomized patients, 262 had complete observations available from baseline and after 52 weeks of treatment to use for calculating predicted coronary heart risk. Smoking and diabetic status were set to 0 for everyone. A 30% reduction in cardiovascular risk is accepted as clinically significant and was used here to measure effect. A 30% reduction in cardiovascular risk was observed in a significantly greater percentage of orlistat-treated participants than with placebo (36 vs 24%, P<0.05). We conclude that weight loss with orlistat produces not only a beneficial effect on weight and blood pressure, but also on overall predicted cardiovascular risk.

The Frank–Starling Law accounts for many changes in cardiac performance previously attributed to changes in contractility in that changes in contractility might have been incorrectly inferred from changing ventricular function curves (i.e. systolic performance plotted against filling pressure) if diastolic compliance also changed. To apply the Frank–Starling Law in the presence of changing diastolic compliance, it is necessary to measure end-diastolic volume directly or to calculate end-diastolic transmural pressure, which requires that pericardial pressure be known. Under most normal circumstances, increased intrathoracic pressure (and other interventions, such as vasodilators or lower-body negative pressure, that decrease central blood volume) decreases the transmural end-diastolic pressures of both ventricles, their end-diastolic volumes and stroke work. However, when ventricular interaction is significant, the effects of these interventions might be quite different; this may be important in patients with heart-failure. Although these interventions decrease RV transmural pressure, they may increase LV transmural pressure, end-diastolic volume, and thus stroke work by the Frank–Starling mechanism.

Alterations in nitric oxide (NO) and endothelin-1 (ET-1) production have recently been reported in erythropoietin (r-HuEPO)-induced hypertension in renal failure rats. The present study was designed to evaluate the effect of NO synthase inhibition with the L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME) on blood pressure (BP) and ET-1 production in control and in uremic rats treated or not treated with r-HuEPO. Renal failure was induced by a two-stage 5/6 nephrectomy. Control and uremic rats were studied separately and subdivided into four groups: vehicle, r-HuEPO, L-NAME + vehicle and L-NAME + r-HuEPO. L-NAME (100 mg/kg/day), r-HuEPO (100 U/kg, subcutaneously, three times per week), the vehicle or both were administered during 4 weeks in control rats and during 2 weeks in uremic rats. Systolic BP was recorded before and after the onset of treatment at weeks 2 and 4 in control rats and at weeks 1 and 2 in uremic rats. Hematocrit, serum creatinine, plasma, blood vessel (thoracic aorta and mesenteric artery bed) and renal cortex immunoreactive (ir) ET-1 concentrations were measured at the end of the protocol. L-NAME enhanced BP in control and uremic rats and the increase was significantly higher in uremic rats under r-HuEPO therapy (222 ± 7 mmHg vs 198 ± 6 mmHg, p<0.05). L-NAME induced an increase in thoracic aorta ir-ET-1 concentrations in control and uremic rats. In contrast, ir-ET-1 concentrations were unchanged in the mesenteric arterial bed and the renal cortex of control and uremic animals. R-HuEPO increased thoracic aorta ir-ET-1 contents in L-NAME treated control and uremic rats. These results underline the important role of NO release in opposing the action of vasopressors on blood vessel tone which appears more important in uremic rats treated with r-HuEPO. L-NAME treatment increased large vessel, but not small resistance artery ir-ET-1 concentrations, suggesting differential regulation of ET-1 production in different vascular beds under chronic NO synthase inhibition.

BACKGROUND:Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown.METHODS:One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation.RESULTS:In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004).CONCLUSIONS:Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life.

BACKGROUND Elevated plasma and urine endothelin-1 (ET-1) levels have been reported in renal failure and may be involved in renal disease progression. We investigated whether these changes are related to increased vascular and renal ET-1 production in the pole resection remnant kidney model of chronic renal failure in the rat. METHODS Uraemic Wistar rats were prepared by surgical renal mass 5/6 ablation and compared with sham-operated controls (protocol 1). Immunoreactive-ET-1 (ir-ET-1) concentration was measured by radioimmunoassay after sample extraction and purification. To investigate the functional role of ET-1 during the progression of chronic renal failure, uraemic rats (protocol 2) were treated with either the vehicle or the ET-1 type A (ET(A)) receptor antagonist LU135252 (LU). RESULTS Systolic blood pressure and serum creatinine, as well as urinary volume and proteinuria, were significantly higher, whereas creatinine clearance was reduced in uraemic rats compared with sham-operated controls. As expected, plasma and urine ir-ET-1 concentrations were increased in uraemic rats (P<0.01) and were related to the increased ir-ET-1 levels in blood vessels and glomeruli (P<0.001). Positive correlation was found between plasma, thoracic aorta and mesenteric arterial bed ir-ET-1 levels and systolic blood pressure, as well as blood vessel hypertrophy. In addition, increased urinary ir-ET-1 excretion correlated with the rise in serum creatinine and proteinuria. In protocol 2, a 3-week treatment period with LU was initiated once uraemia and hypertension were established. In untreated uraemic rats, systolic blood pressure increased further (P<0.05), but this was not the case in LU-treated uraemic rats. At the end of treatment, serum creatinine and proteinuria were significantly lower (P<0.05) and creatinine clearance was higher (P<0.01) in LU-treated rats compared with uraemic-untreated animals. While plasma ir-ET-1 concentration was similar in the two groups, ir-ET-1 concentration in thoracic aorta, mesenteric arterial bed, renal cortex and urine was significantly lower in LU-treated animals (P<0.01). In addition, heart, thoracic aorta and mesenteric arterial wet weight to body weight ratios were also significantly reduced in LU-treated uraemic rats (P<0.05). CONCLUSIONS Elevated plasma ET-1 concentration and urinary ET-1 excretion in rats with renal mass ablation are related to enhanced ET-1 production in vascular and renal tissues, thus suggesting an important role for ET-1 in the aggravation of hypertension and vascular hypertrophy as well as in the progression of renal insufficiency. These pathophysiological effects are prevented by treatment with selective ET(A) receptor blockade.

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120+/-3 mmHg compared to 161 +/-6 mmHg in the Nx + vehicle group (p <0.01) and 199+/-9 mmHg in the Nx + r-HuEPO group (p <0.01 vs Nx + vehicle). Hematocrit in control rats was 41.3+/-0.4% vs 32.6+/-1.8% in the Nx + vehicle group (p <0.01) and 47.6+/-1.5% in the Nx + r-HuEPO group (p <0.01). Plasma ir-ET-1 levels were similar in the Nx + vehicle and Nx + r-HuEPO groups (7.9+/-1.0 and 7.8+/-0.8 pg/ml). In contrast, thoracic aorta ir-ET-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3+/-2.9 vs 13.4+/-1.9 pg, p <0.05). Similar results were obtained in the mesenteric arterial bed. There were significant correlations between blood pressure and ir-ET-1 content in the thoracic aorta (r= 0.45, p<0.05) and in the mesenteric arterial bed (r= 0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension.

The aim of the study was to determine the ET-1 concentration in peritoneal dialysate fluid and to investigate the relationship between peritoneal and plasma ET-1 levels and blood pressure in stable continuous ambulatory peritoneal dialysis (CAPD) patients with and without human recombinant erythropoietin (r-HuEPO) replacement therapy. Twenty-seven stable CAPD patients were investigated. They completed their overnight exchange at the Dialysis Centre. Blood pressure was recorded and a blood sample was drawn. Biochemical parameters and ET-1 were measured in plasma and peritoneal dialysate fluid. Mean plasma ET-1 levels were increased by about four-fold in CAPD patients. ET-1 was detectable in peritoneal dialysate fluid and a significant correlation was observed between plasma and peritoneal ET-1 concentrations (r = 0.65, p < 0.01). The peritoneal clearance of ET-1 was lower than the creatinine clearance (1.69 +/- 0.08 ml/min vs. 3.96 +/- 0.15 ml/min, p < 0.01). There was also a significant correlation between the time (months) on dialysis and plasma (r = 0.68, p < 0.01) or peritoneal dialysate ET-1 levels (r = 0.46, p < 0.05). Mean blood pressure was higher in patients treated with r-HuEPO than in untreated patients (97 +/- 4 mmHg vs. 81 +/- 4 mmHg, p < 0.01). Plasma and peritoneal dialysate ET-1 concentrations were comparable in the two groups with or without r-HuEPO replacement therapy and plasma ET-1 values correlated significantly with mean blood pressure only in r-HuEPO-treated patients (r = 0.63, p < 0.05 vs. r = 0.10, N.S. in untreated patients). In conclusion, plasma ET-1 concentrations are elevated in CAPD patients and the levels appear to increase with time on dialysis. ET-1 is cleared by the peritoneal membrane but at a much lower rate than creatinine. Blood pressure is higher in CAPD patients or r-HuEPO replacement therapy and blood pressure correlates with plasma ET-1 levels in these patients.

Recently, we have reported that endothelin-1 (ET-1) production is increased in blood vessels and glomeruli of rats with chronic renal failure. This study was design to investigate the role of angiotensin II (Ang II) in endogenous ET-1 production in rats with reduced renal mass. One week after subtotal (5/6) nephrectomy, uremic rats were divided into three groups, and received either no treatment, the Ang II subtype 1 receptor (AT1) antagonist losartan (10 mg/kg/day), or the angiotensin-converting enzyme inhibitor (ACE-I) captopril (30 mg/kg/day) for 6 weeks. Sham-operated rats were used as controls and received no treatment. The levels of immunoreactive ET-1 (ir-ET-1) in plasma and urine, as well as in vascular and renal tissues, were determined by radioimmunoassay (RIA) after extraction. In uremic rats, losartan and captopril completely prevented the increase in systolic blood pressure. At week 6, plasma ir-ET-1 was similar in the different groups of uremic rats and in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed, the thoracic aorta, preglomerular arteries, and glomeruli, as well as urinary ir-ET-1 excretion were significantly greater in uremic-untreated rats compared to controls (P < .01). Treatment of uremic rats with losartan or captopril reduced irET-1 concentration in the thoracic aorta and preglomerular arteries (P < .05), but ir-ET-1 concentration in the mesenteric arterial bed was unchanged. Although both drugs completely prevented the increase in proteinuria, losartan but not captopril significantly reduced ir-ET-1 concentration in glomeruli (P < .05) and normalized urinary ir-ET-1 excretion. This indicates that increased ET-1 production in blood vessels and glomeruli of uremic rats is modulated, at least in part, by Ang II through the AT1 receptor. The beneficial effects of the AT1 antagonist losartan could be attributable to the attenuation of Ang II-induced ET-1 production in this rat remnant kidney model of chronic renal failure, whereas those of the ACE-I captopril are not related to changes in ET-1 production in glomeruli.

To better understand the mechanism of recombinant human erythropoietin (rhEPO)-induced increase in BP, hemodynamic parameters, body fluid volumes, and the hormones implicated in BP regulation were studied in 32 anemic hemodialysis patients before and after 3 to 4 mo of rhEPO therapy. Hemoglobin levels increased from 83 +/- 1.5 to 119 +/- 2.3 g/L (P < 0.01) after rhEPO therapy (25 to 43 U/kg) administered subcutaneously three times weekly. Mean 24-h systolic and diastolic ambulatory BP were significantly increased by 14 +/- 3 and 10 +/- 2 mmHg, respectively (P < 0.01 for both groups). Systemic vascular resistance consistently increased by 28 +/- 5% (P < 0.01), whereas cardiac output was decreased by 6 +/- 3% (P < 0.05). Red blood cell mass increased by 510 +/- 35 ml (P < 0.01), whereas plasma volume decreased by 420 +/- 66 ml (P < 0.01), which resulted in a nonsignificant increase in total blood volume. Extracellular fluid volume and exchangeable sodium were decreased by 873 +/- 255 ml (P < 0.01) and 125 mmol (P < 0.01), respectively. There was a positive correlation between the changes in exchangeable sodium and in systolic BP (r = 0.41, P < 0.05). Furthermore, a greater increase in 24-h systolic BP was observed in patients in whom exchangeable sodium increased or remained unchanged (n = 10) compared with patients (n = 22) with decreased exchangeable sodium (20 +/- 4 mmHg versus 8 +/- 2 mmHg, respectively, P < 0.01). Plasma catecholamines, plasma renin concentration, plasma atrial natriuretic peptide, and plasma endothelin-1 did not significantly change with rhEPO treatment, whereas plasma aldosterone increased significantly (P < 0.01). Although volume-independent mechanisms may contribute to rhEPO-induced BP increase, the results presented here suggest the importance of optimally reducing extracellular fluid volume to prevent, at least in part, the development of hypertension often observed with improved uremic anemia in these patients.

Recently, it was reported that blood vessel immunoreactive endothelin-1 (irET-1) content is increased in hypertensive uremic rats treated with recombinant human erythropoietin (rhEPO). The present study was designed to evaluate whether ET-1 receptor blockade can prevent the progression of hypertension in renal failure rats receiving rhEPO and, if so, whether selective ET(A) and nonselective ET(A)/ET(B) receptor antagonists are equally effective. Renal failure was induced by a two-stage 5/6 nephrectomy; the animals developed uremia, anemia, and hypertension. After a 4-wk stabilization period, the animals received either rhEPO (100 U/kg, subcutaneously, three times per week) or the vehicle for 4 wk. In protocol A, half of the rats in each group were simultaneously treated with the ET(A)/ET(B) receptor antagonist bosentan (100 mg/kg per d). In protocol B, half of the rats in each group received the selective ET(A) receptor antagonist LU 135252 (50 mg/kg per d). Systolic BP was recorded before and at 2 and 4 wk after the onset of treatment. Serum creatinine levels and hematocrit were measured before treatment and at the end of the study. Creatinine clearance rates and plasma irET-1 concentrations were determined at the end of the study. rhEPO corrected the anemia, but aggravated the hypertension. There was a slight and similar increase in serum creatinine throughout the treatment period in all groups of rats. Both ET-1 receptor antagonists bosentan and LU135252 were effective in attenuating the progression of hypertension in uremic rats receiving the vehicle (P < 0.05). Treatment with LU135252 corrected the increase in BP in rhEPO-treated rats (160+/-7 mmHg versus 187+/-9 mmHg, P < 0.05). In contrast, bosentan did not attenuate the progression of hypertension in rhEPO-treated rats (172+/-10 mmHg versus 168+/-9 mmHg, NS). In summary, selective ET(A) but not ET(A)/ET(B) receptor blockade can prevent the aggravation of hypertension in renal failure rats treated with rhEPO. These results suggest that the endothelin system may be involved in the pathogenesis of rhEPO-induced hypertension in uremic rats with a differential role for ET(A) and ET(B) receptors.

BACKGROUND:The CD8+CD38+ T-cell subset can predict progression to acquired immune deficiency syndrome among human immunodeficiency virus-positive subjects. This T-cell subset usually increases during other active viral infections (cytomegalovirus [CMV], Epstein Barr virus). We report on its usefulness in the early detection of CMV infection in kidney transplant recipients.METHODS:Quantitation of CD8+CD38+ T cells was monitored by dual-color flow cytometry analysis on 77 patients during the posttransplantation period. Seventeen of the 52 patients at risk for CMV disease (33%) had primary infection or reactivation and three patients had herpes simplex virus infection only.RESULTS:In every patient with CMV disease, high values for the CD8+CD38+ subset were detected with a 90% positive predictive value for the primary infections. Elevated values were observed at the very first clinical signs of the viral disease or within the few preceeding days. Acute rejection episodes did not provoke false-positive results.CONCLUSION:This immunologic marker is sensitive and easily obtainable on a daily basis. It may help to direct therapy during rejection or serve as a tool for early detection of clinical viral diseases.

This pilot economic evaluation was performed as part of the Canadian arm of an international randomized, controlled, double-blind safety and tolerability trial (OLM-105/NOF-2). The clinical study compared the safety and tolerability of a new microemulsion oral formulation of cyclosporine A (Neoral) with the oral cyclosporine. A preparation currently in use (Sandimmune SGC)/(SGC). To assess the economic impact of Neoral in newly grafted renal transplant patients, primary cost data were collected at the five participating Canadian centers and evaluated from the Ministry of Health (MOH) and hospital perspectives. The results of this cost analysis are presented in this paper. Since the new formulation has shown more consistent absorption and a more predictable pharmacokinetic profile, medical resource utilization and, consequently, cost of treatment could be expected to be lower for those renal transplant recipients treated with Neoral than for those receiving standard SGC. The findings of this study support this hypothesis. Robustness of the conclusion was confirmed with sensitivity analyses. Reduced health care costs for patients treated with Neoral were primarily a result of fewer hospitalization days and lower physician costs for inpatient and outpatient procedures.