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The mechanism of erythropoietin-induced hypertension in dialysis patients is unclear. Intracellular calcium ([Ca2+]i) may be altered in both hypertension and uraemia, and the effects of both uraemia and r-HuEPO on vascular smooth muscle [Ca2+]i and blood pressure (BP) in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were therefore studied. Male WKY and SHR underwent partial nephrectomy or sham operation. Three weeks later a 28-day period of treatment with either r-HuEPO 100 U/kg, s.c., 3 times/week or buffer was commenced (n = 10-12 for each subgroup). BP was measured weekly, by noninvasive Doppler tail-cuff assessment. [Ca2+]i was measured following loading with fura-2 in pooled, primary aortic vascular smooth muscle cells (VSMC). Serum urea and creatinine rose 3- to 4-fold after partial nephrectomy. Treatment with r-HuEPO did not change renal function further in either uraemic or control WKY or SHR. Haemoglobin increased in both non-uraemic WKY (16.2-20.3 g/dl) and SHR (16.4-20.5 g/dl) and uraemic animals (WKY 13.9-20.9; SHR 13.8-18.8 g/dl; p0.01 for all changes) following 4 weeks of r-HuEPO treatment. BP was unaffected by r-HuEPO in WKY but increased in nonuraemic SHR (210-250; p0.01) and in uraemic SHR (224-251 mm Hg; p0.001) at 4 weeks. VSMC [Ca2+]i was higher in SHR than WKY (121 vs. 83 nmol/l; MANOVA p0.05) but no effect of uraemia or r-HuEPO on [Ca2+]i was detected. In conclusion, the hypertensive effects of r-HuEPO are augmented both in a genetic model of hypertension and in uraemia. Although VSMC [Ca2+]i was elevated in SHR, the further increase in BP induced by r-HuEPO was not associated with alterations in VSMC cytosolic calcium.

1. Twelve patients receiving haemodialysis for end-stage renal failure were studied at a single dialysis session. Platelet cytosolic calcium concentration, plasma ionized calcium concentration and serum parathyroid hormone concentration were measured before dialysis, mid-dialysis and 30 min after dialysis. 2. Plasma ionized calcium concentration increased towards dialysate calcium concentrations, falling insignificantly after cessation of dialysis. Serum parathyroid hormone concentration fell by 39% during dialysis, with incomplete recovery afterwards. There was no overall change in platelet cytosolic calcium concentration. 3. Patients were divided into two subgroups: low parathyroid hormone (serum parathyroid hormone concentration < 10 pmol/l) and high parathyroid hormone (serum parathyroid hormone concentration > 10 pmol/l). Before dialysis, values of platelet cytosolic calcium concentration or plasma ionized calcium concentration were not statistically different between the subgroups, but the platelet cytosolic calcium concentration was higher in the high-parathyroid hormone subgroup during and after dialysis. 4. Before haemodialysis there was a linear correlation between plasma ionized calcium concentration and platelet cytosolic calcium concentration, which disappeared during dialysis. In contrast, there was no relationship between serum parathyroid hormone concentration and platelet cytosolic calcium concentration before dialysis, but after dialysis a hyperbolic relationship was evident. 5. These results suggest that uraemic toxins may interfere with cytosolic calcium homoeostasis, allowing passive diffusion of extracellular calcium to influence the resting concentration, and that this effect is reversible by haemodialysis.

Objectives Recovery from pediatric cardiac surgery is affected by ischemia–reperfusion injury, cardiac edema, and in some cases a low cardiac output syndrome. Although association has been made between the development of edema and dysfunction, modeling is confounded by intercurrent injurious stimuli that also cause cardiac edema and dysfunction. We tested whether a true causal relationship exists between edema and cardiac dysfunction. Methods We induced either ischemia or edema alone in isolated cardiomyocytes and whole Langendorff-perfused hearts. Function was measured as shortening dynamics and developed pressure, respectively. Results Ischemic injury impaired function in both cardiomyocytes and whole hearts. Isolated cells showed significant reduction in peak shortening and departure and relaxation velocities. Whole hearts displayed severely reduced developed pressures. Hyposmotic solution forced cardiomyocytes to swell to 7% greater than their normal size. No significant effect on shortening was seen. Similarly, Langendorff-perfused hearts were induced to take on 3% more water than control-perfused hearts and 9% more water than nonperfused hearts. This additional water was associated with mild dysfunction. Conclusions We demonstrate the capacity of the heart to tolerate edema greater than that seen in clinical settings without residual effect. Ischemia results in ongoing contractile dysfunction of both isolated cardiomyocytes and whole hearts. We conclude that dysfunction resulting from edema in ex vivo cardiac models is mild and suggest review of the importance given to edema-mediated dysfunction after cardiac surgery.