The German registry for nephrogenic systemic fibrosis: findings from 23 patients.

BACKGROUND AND AIM: Nephrogenic systemic fibrosis (NSF) is a highly debilitating disorder primarily affecting the skin, but also other organ compartments. So far, it has only occurred in patients suffering from acute or chronic renal failure, with almost all of them having been exposed to gadolinium-based contrast agents (GBCA). The NSF registry was initiated on behalf of the German Society of Nephrology. The aim was to analyze the development, risk factors and clinical course of patients suffering from NSF. PATIENTS AND METHODS: Between July 2007 and July 2009, 23 patients were registered (12/23 (52,2%) male and 11/23 (47,8%) female). Onset of NSF symptoms was between 2002 and 2008, with a maximum of 8 cases in 2005. Since January 2008 no patient with a new onset of NSF has been reported. On all patients nuclear magnetic resonance procedures were performed between 1 day and 3 years (median 30 days) before the onset of symptoms ("index procedure"). At the time of the index procedure 21/23 (91,3%) patients required dialysis, 15/22 patients (68,2%) showed signs and symptoms of atherosclerosis and 17/20 (76,5%) of inflammation. 22/23 patients remained in chronic kidney disease stage 5D. Upper and lower extremities were affected in 18/23 (78,3%) patients; 20/23 (87%) developed joint contractures. RESULTS: Our data confirm previous observations that NSF is associated with impaired renal function and the application of GBCA. In individual cases the interval between the index procedure and the onset of symptoms lasted years. CONCLUSION: The incidence of NSF has decreased rapidly within the past 4 years. This could be due to general awareness within the medical community and the application of macrocyclic chelates.

Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte beta 2-adrenoceptor density (determined by (-)-125iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 microM (-)-isoprenaline) after desensitization by the beta 2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte beta 2-adrenoceptor density by approximately 40-50%; concomitantly, lymphocyte cAMP responses to 10 microM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline beta 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d. Prednisone (1 X 100 mg orally) accelerated beta 2-adrenoceptor recovery; only 8-10 h after administration of the steroid beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 X 1 mg/d for 4 d): 24 h after application of the drug beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte beta 2-adrenoceptor density and responsiveness. Prednisone (1 X 100 mg orally) or ketotifen (2 mg; thereafter 2 X 1 mg/d for 2 d) had no significant influence on lymphocyte beta 2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte beta 2-adrenoceptor toward high affinity state. We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte beta 2-adrenoceptors desensitized by long-term treatment with beta 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with beta 2-agonists.

Positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in the human heart: effects of long-term beta 1-adrenoceptor antagonist treatment.

OBJECTIVES: This study was conducted to determine whether activation of cardiac beta 2-adrenoceptors increases contractility in humans and whether this is affected by long-term beta 1-adrenoceptor antagonist treatment. BACKGROUND: Coexistence of beta 1- and beta 2-adrenoceptors in the human heart is generally accepted. The functional importance of cardiac beta 2-adrenoceptors for increases in contractility in humans, however, has not been completely established. METHODS: We studied 1) the beta-adrenoceptor subtype mediating positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in vitro (on right atrial and left ventricular preparations from nonfailing human hearts) and increases in contractility (by measurement of systolic time intervals) in vivo in seven healthy male volunteers; and 2) in vivo whether long-term treatment of volunteers with the beta 1-adrenoceptor antagonist bisoprolol affects terbutaline-induced increases in contractility. RESULTS: In vitro terbutaline caused a concentration-dependent increase in atrial and ventricular adenylate cyclase activity and force of contraction. Terbutaline effects were antagonized only by the beta 2-adrenoceptor antagonist ICI 118,551, indicating that they were mediated by beta 2-adrenoceptor stimulation. In vivo intravenous infusions of terbutaline (dose range 25 to 300 ng/kg body weight per min for 15 min) dose dependently increased heart rate and shortened the pre-ejection period and heart rate-corrected electromechanical systole (QS2) time. These effects are mediated predominantly by beta 2-adrenoceptor stimulation because they were only marginally affected by the beta 1-adrenoceptor antagonist bisoprolol (1 x 10 mg orally), either given 2 h before infusion or long term for 3 weeks. CONCLUSIONS: Stimulation of cardiac beta 2-adrenoceptors in humans causes not only in vitro but also in vivo positive inotropic effects. Long-term beta 1-adrenoceptor antagonist treatment does not considerably affect beta 2-adrenoceptor-mediated in vivo increases in contractility. Thus, it may be possible to treat patients with chronic heart failure and long-term beta 1-adrenoceptor antagonist therapy with beta 2-adrenoceptor agonists if immediate inotropic support is needed.

Effects of insulin-induced hypoglycemia on beta 2-adrenoceptor density and proliferative responses of human lymphocytes.

We studied the effects of insulin (0.1 IU/kg BW, iv)-induced hypoglycemia on lymphocyte beta 2-adrenoceptor function, lymphocyte subset distribution, and proliferative response to mitogen stimulation in 10 healthy volunteers. Thirty minutes after insulin injection plasma glucose levels were markedly decreased; concomitantly, plasma epinephrine levels had increased about 10-fold; plasma norepinephrine levels, however, increased only moderately. Lymphocyte beta 2-adrenoceptor density and the cAMP response to 10 mumol/L isoproterenol stimulation were elevated; lymphocyte Ts/c-cells had increased, whereas Th-cells had decreased, resulting in a decrease in the Th-/Ts/c-cell ratio from 1.7 to 1.0. These changes were accompanied by a significantly reduced lymphocyte proliferative response (measured as [3H]thymidine uptake) to mitogen stimulation. Two hours after insulin injection plasma catecholamines, lymphocyte beta 2-adrenoceptor function, lymphocyte subset distribution, and proliferative responses had returned to nearly preinsulin levels. We conclude that acute vigorous increases in endogenous epinephrine evoked by insulin-induced hypoglycemia are associated with increases in lymphocyte beta 2-adrenoceptor function, redistribution of lymphocyte subsets, and an (at least transiently) attenuated in vitro immune responsiveness.

Dynamic exercise-induced increase in lymphocyte beta-2-adrenoceptors: abnormality in essential hypertension and its correction by antihypertensives.

We compared the effects of acute stimulation of sympathetic activity by dynamic exercise on a bicycle on lymphocyte beta 2-adrenoceptor density and 10 mumol/L (-)-isoprenaline-evoked lymphocyte cyclic adenosine monophosphate increases in normotensive volunteers with those in patients with essential hypertension. In normotensive subjects exercise increased lymphocyte beta 2-adrenoceptors by about 100%. This effect seems to be a beta 2-dependent process, since it is prevented by propranolol (5 mg administered intravenously) and the beta 2-selective antagonist ICI 118,551 (25 mg t.i.d. orally for 2 weeks) but not by the beta 1-selective antagonist bisoprolol (2.5 mg administered intravenously). In patients with essential hypertension who have elevated lymphocyte beta 2-adrenoceptors, dynamic exercise caused only marginal beta 2-adrenoceptor changes, suggesting an impairment of the acute beta-adrenoceptor regulation. Normalization of blood pressure by antihypertensive treatment resulted in a significant fall in lymphocyte beta 2-adrenoceptors and in a restoration of exercise-induced beta 2-adrenoceptor increases. It is concluded that in essential hypertension the impairment of beta-adrenoceptor regulation is directly linked to the elevated blood pressure.

Different mechanisms underlying reduced beta 2-adrenoceptor responsiveness in lymphocytes from neonates and old subjects.

To investigate the mechanism underlying age-dependent changes in beta-adrenoceptor function we have determined beta 2-adrenoceptor density (by (+/-)-125iodocyanopindolol (ICYP) binding) and beta 2-responsiveness (cyclic AMP responses to isoprenaline stimulation) in lymphocytes derived from 20 neonates, 54 young adults (19-30 years) and 15 old subjects (60-86 years). In young adults the mean number of lymphocyte beta 2-adrenoceptors amounted to 862 +/- 36 (range 500-1560) ICYP binding sites/cell (N = 54); it was slightly higher in old subjects with 1230 +/- 94 (698-1980) ICYP binding sites/cell (N = 15). In contrast, lymphocytes derived from neonatal blood had a significantly lower mean beta 2-adrenoceptor number (385 +/- 35 (130-608) ICYP binding sites/cell, N = 20, P less than 0.01). (-)-Isoprenaline (0.01-100 microM)-induced increases in lymphocyte cyclic AMP content were significantly lower in neonates and old subjects than in young adults. While for neonates and young adults significant positive correlations between beta 2-adrenoceptor density and 10 microM (-)-isoprenaline-induced cyclic AMP increases exist, in old subjects cyclic AMP increases were much lower than could be expected from the beta 2-adrenoceptor number. It is concluded that the mechanism underlying reduced beta 2-adrenoceptor responsiveness in neonates and old subjects is different: while in neonates it seems to be due to the reduced beta-adrenoceptor number, in old subjects it is caused by a post-receptor defect--presumably by a decreased activity of the adenylate cyclase.

Effects of antihypertensive therapy on human alpha- and beta-adrenoceptors.

The present study was designed to investigate the role of plasma catecholamines in the regulation of adrenoceptors in human hypertension. Thirty-three patients with newly detected essential hypertension were treated for 4 weeks with either nifedipine (2 x 20 mg/day), hydergine (2 x 2 mg/day), or both (20 and 2 mg/day, respectively, twice daily each), which lowered blood pressure equally well. Plasma noradrenaline increased during nifedipine, decreased during hydergine and was unaltered during the combination therapy. Lymphocyte beta 2-adrenoceptor density decreased by similar amounts, independent of whether blood pressure was normalized by treatment with nifedipine or hydergine. Platelet alpha 2-adrenoceptor density, however, decreased during nifedipine, slightly increased during hydergine and was unchanged during the combination treatment. We conclude that lymphocyte beta 2-adrenoceptors of hypertensive patients are not regulated primarily by plasma catecholamines but rather by a distinct factor associated with the extent of blood pressure elevation. The density of platelet alpha 2-adrenoceptors, however, appears to be dynamically regulated by catecholamines.

Hemofiltration increases IL-6 clearance in early systemic inflammatory response syndrome but does not alter IL-6 and TNF alpha plasma concentrations.

OBJECTIVE: To test the hypothesis that continuous hemofiltration increases interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) clearances and results in decreased cytokine plasma concentrations independent of renal function in patients with early SIRS. DESIGN: Prospective, controlled, randomized study. SETTING: Intensive care units at a university hospital. PATIENTS: 28 consecutive patients who fulfilled the criteria of the systemic inflammatory response syndrome (SIRS). INTERVENTIONS: Patients with SIRS were randomly assigned to either a hemofiltration or a control group irrespective of renal function. In patients of the hemofiltration group an isovolemic hemofiltration was initiated directly after the diagnosis of SIRS and maintained for at least 48 h. MEASUREMENTS AND RESULTS: A significant (p < 0.001) increase in total IL-6 clearance (hemofiltrate + urine), but not in TNF alpha clearance, was observed with hemofiltration. However, the plasma concentrations of both cytokines remained unchanged. Hemodynamic variables did not change significantly. CONCLUSIONS: Continuous hemofiltration increases IL-6 plasma clearance but not TNF alpha clearance. However, hemofiltration failed to decrease plasma concentrations of TNF alpha and IL-6 and, therefore, cannot be used effectively for cytokine elimination in SIRS. Accordingly, beneficial effects occasionally reported with hemofiltration are unlikely to be expected due to elimination of IL-6 or TNF alpha.

Continuous venovenous hemodialysis treatment in critically ill patients after liver transplantation.

BACKGROUND: Acute renal failure (ARF) in critically ill patients is associated with a high mortality rate. Continuous renal replacement therapy (CRRT) is now widely used for the treatment of ARF in these critically ill patients. We retrospectively analyzed the role of CRRT as a prognostic parameter in patients receiving a cadaveric liver graft in 1998. METHODS: We reviewed the patient records of all adult recipients of a cadaveric liver graft (N = 54) in 1998 and compared those who underwent CRRT treatment (N = 19) to those without CRRT treatment (N = 35). RESULTS: Mortality was high in the continuous venovenous hemodialysis (CVVHD) group (58%). At the time of transplantation, creatinine (1.7+/-0.4 vs. 1.0+/-0.1 mg/dl), blood urea nitrogen (40+/-13 vs. 22+/-3 mg/dl), aspartate aminotransferase (ASAT; 585+/-420 vs. 242+/-97 U/liter), and bilirubin (11.6+/-4.1 vs. 6.5+/-1.9 mg/dl) were higher in the CVVHD group than in controls, whereas hemoglobin (10.3+/-0.6 vs. 10.8+/-0.4 g/dl), white blood cells (6.3+/-0.6 vs. 7.0+/-0.8/nl), and thrombocytes (110+/-18 vs. 90+/-10/nl) were similar. After transplantation, liver graft function was impaired in the CVVHD group as compared with controls. CONCLUSIONS: The necessity for CRRT in patients after liver transplantation correlates with a high risk of death. Thus, more efforts have to be made to prevent renal failure in patients after liver transplantation.

Beta-adrenoceptor changes in human lymphocytes, induced by dynamic exercise.

In 10 healthy volunteers the effects of acute increases in concentrations of catecholamines in plasma induced by dynamic exercise (on a bicycle for 15 min at 80% of maximum heart rate) on lymphocyte beta 2-adrenoceptor density (determined by (+/-)-125iodocyanopindolol binding) and -responsiveness (determined by cyclic AMP responses to 10 mumol/l isoprenaline) were investigated. Immediately after exercise plasma catecholamines were increased about 4-fold; concomitantly receptor density and cyclic AMP production increased 55% and 65%, respectively. One hour after exercise beta-adrenoceptor density and plasma catecholamines had reached values, which were not significantly different from pre-exercise values, while cyclic AMP production was significantly diminished. It is concluded, that acute increases in concentrations of catecholamines in plasma may increase beta-adrenoceptor density and - responsiveness in human lymphocytes.

Beta-adrenoceptor antagonists (non-selective as well as beta 1-selective) with partial agonistic activity decrease beta 2-adrenoceptor density in human lymphocytes. Evidence for a beta 2-agonistic component of the partial agonistic activity.

In the present study the effects of pindolol [non-selective beta-adrenoceptor antagonist with strong partial agonistic activity (PAA)] on beta 2-adrenoceptor density in lymphocytes (assessed by (-)-[125I]iodocyanopindolol (ICYP) binding) were compared with those of the beta 1-selective antagonists celiprolol (with PAA) and bisoprolol (no PAA) in normotensive young volunteers to get further insights into the nature of PAA. Administration of pindolol (2 X 5 mg/day) caused an about 25% decrease in lymphocyte beta 2-adrenoceptor density after 2 days; during treatment beta 2-adrenoceptor density declined further (maximum decrease after 7 days: 50%). After withdrawal of pindolol lymphocyte beta 2-adrenoceptor density recovered very slowly being still after 4 days significantly reduced, although no pindolol was detectable in plasma after 36 h. The KD-values for ICYP, however, did not change during or after pindolol treatment. The decrease in lymphocyte beta 2-adrenoceptor density induced by pindolol could be completely prevented by simultaneous administration of propranolol (3 X 40 mg/day) indicating that the PAA of pindolol is the cause of its beta-adrenoceptor decreasing effect. Administration of the non-selective beta-adrenoceptor antagonist bopindolol (1 X 2 mg/day) with PAA caused decreases in lymphocyte beta 2-adrenoceptor density (maximum decrease after 7 days: 40%); concomitantly the 10 mumol/l (-)-isoprenaline evoked increases in the intracellular level of lymphocyte cyclic AMP were attenuated to a similar extent indicating that the beta-adrenoceptor antagonist-induced decrease in beta-adrenoceptor density is accompanied by a loss in beta-adrenoceptor function.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of beta-adrenoceptor antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity".

Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent separation of dopaminergic and adrenergic effects of epinine in healthy volunteers.

Epinine (N-methyl-dopamine, the active metabolite of ibopamine), is a full agonist at dopamine (DA)-receptors and alpha- and beta-adrenoceptors. To study whether in vivo DA-receptors mediated effects can be separated from alpha- and beta-adrenoceptor effects we compared in 10 male volunteers the effects of i.v. epinine (0.5; 1; 2; 4 micrograms/kg/min for 15 min each) on DA-receptor (changes in serum prolactin)- and alpha- and beta-adrenoceptor (changes in systolic [Psyst] and diastolic blood pressure [Pdiast] and heart rate)-mediated effects with those of dopamine before and after propranolol (5 mg i.v. 45 min pre-infusion), bisoprolol (15 mg p.o. 2 h pre-infusion) and domperidone (10 mg p.o. 1 h pre-infusion). At the 0.5 and 1 microgram doses of dopamine and epinine did not effect Psyst, Pdiast and heart rate but significantly decreased prolactin levels. At the higher dose both dopamine and epinine significantly increased Psyst and heart rate, while only epinine significantly increased Pdiast. In addition, both dopamine and epinine significantly increased diuresis and natriuresis; in contrast, only dopamine, but not epinine dose-dependently increased plasma noradrenaline levels. Domperidone did not affect dopamine- and epinine-evoked blood pressure- and heart rate-changes, but antagonized their prolactin-effects (at least at the lower doses). Bisoprolol and propranolol significantly reduced dopamine-induced Psyst- and heart rate-increases to about the same extent. Propranolol enhanced epinine-induced Psyst- and Pdiast-increases while bisoprolol reduced epinine-evoked Psyst-increase but not Pdiast-increase. Epinine-induced heart rate-increase was abolished by bisoprolol and was converted into heart rate-decrease by propranolol. We concluded that in 0.5 and 1 microgram doses (plasma levels of 20-80 nmol/l)epinine acts only at DA-receptors. Thus, ibopamine in therapeutically recommended doses (3 x 100 mg/day with peak plasma epinine-levels of 50-80 nmol/l) very likely activates only DA-receptors. In higher doses, however, epinine-like dopamine-activates alpha- and beta-adrenoceptors whereby epinine has a stronger alpha-adrenoceptor agonistic activity than dopamine. Moreover, part of the dopamine-effects are indirect via release of endogenous noradrenaline whereas epinine-effects do not appear to include an indirect component.

Influence of atropine on the cardiovascular effects of noradrenaline and tyramine in elder volunteers.

The aim of this study, carried out in six elder healthy volunteers (mean age: 61 years), was to determine the influence of muscarinic receptor blockade with atropine (15 microg/kg i.v. loading dose followed by 0.15 microg/kg/min by i.v. infusion) on the effects of i.v. infusions of noradrenaline (5 incremental doses of 10-120 ng/kg/min) or tyramine, that releases endogenous noradrenaline (4 incremental doses of 5-20 microg/kg/min), on blood pressure, heart rate and systolic time intervals (STI's, as a measure of positive inotropism). These results were compared with those recently published for young healthy volunteers (mean age: 26 years; Schäfers et al. 1997). Noradrenaline caused increases in systolic and diastolic blood pressure, decreases in heart rate and a shortening of STI's that were not different from those in young volunteers. Atropine did not significantly affect these hemodynamic responses to noradrenaline, while in young volunteers it significantly enhanced noradrenaline-induced blood pressure increases and converted the heart rate decrease into an increase. In the present study in elder volunteers, tyramine caused a smaller increase in systolic blood pressure than in the previous study in young volunteers; in addition, it slightly increased diastolic blood pressure while it decreased diastolic blood pressure in young volunteers. Atropine did not significantly affect the hemodynamic effects of tyramine in the elder volunteers, while in the young volunteers it enhanced the increase in systolic blood pressure and converted the decreases in diastolic blood pressure and heart rate into increases. These results indicate a) that ageing is accompanied by a blunted baroreflex-mediated parasympathetic activation resulting in reduced cholinergic vasodilation and decreases in heart rate, and b) that ageing is associated with a decreased responsiveness of (cardiac) beta-adrenoceptors and (vascular) alpha1-adrenoceptors which is only unmasked when the counterregulatory action of parasympathetic activation is removed.

Influence of adrenoceptor and muscarinic receptor blockade on the cardiovascular effects of exogenous noradrenaline and of endogenous noradrenaline released by infused tyramine.

This study aimed firstly to compare the in vivo cardiovascular effects of exogenously administered and of endogenously released noradrenaline; secondly to characterize the adrenoceptors mediating these responses; thirdly to assess the influence of parasympathetic tone on the cardiovascular effects of noradrenaline. In two randomised placebo-controlled studies, healthy, young, male volunteers received intravenous (i.v.) infusions of noradrenaline at six incremental doses of 10-160 ng/kg/min and-in order to release endogenous noradrenaline-tyramine at four incremental doses of 5-20 micrograms/kg/min. Noradrenaline and tyramine were administered in the absence and presence of alpha 1-adrenoceptor blockade with doxazosin (2 mg p.o.), alpha 2-adrenoceptor blockade with yohimbine (15 mg p.o.), selective beta 1-adrenoceptor blockade with bisoprolol (15 mg p.o.) and muscarinic receptor blockade with atropine (1.5 micrograms/kg i.v. loading dose followed by 0.15 microgram/kg/min by i.v. infusion). Vasoconstrictor effects were assessed by measurement of diastolic blood pressure (Pdiast) and myocardial effects by measurement of systolic time intervals, namely the duration of electromechanical systole corrected for heart rate (QS2c). I.v. noradrenaline increased Pdiast (delta max 17 mmHg) and this was nearly completely suppressed by doxazosin but only slightly blunted by yohimbine. Noradrenaline also slightly shortened QS2c (delta max -22 ms), and this was potentiated by both doxazosin and yohimbine and completely blocked by biosprolol. I.v. tyramine reduced Pdiast (delta max -7 mmHg), which was not affected by alpha 1-adrenoceptor blockade, and profoundly shortened QS2c (delta max -104 ms) which was significantly correlated with a marked increase in systolic blood pressure (Psyst) (delta max 57 mmHg). The shortening of QS2c and the rise in Psyst were not influenced by alpha-adrenoceptor blockade but were antagonized by bisoprolol. Atropine potentiated the blood pressure rise and the shortening of QS2c induced by i.v. noradrenaline and converted the fall in Pdiast induced by i.v. tyramine into an increase. Thus the cardiovascular effects of exogenous noradrenaline are mainly characterized by alpha 1-adrenoceptor-mediated vasoconstriction and the actions of endogenous noradrenaline (released by i.v. tyramine) by beta 1-adrenoceptor-mediated positive inotropic effects. The rise in Psyst with i.v. tyramine most likely reflects positive inotropism and not a vascular "pressor' response.

Exercise during hemodialysis.

In patients with end-stage renal failure physical exercise has beneficial effects on functional capacity, anemia, cardiovascular risks factors and on psychosocial problems. However, only few patients are able or willing to participate in an exercise training which is organised on an outpatient basis. As a consequence, an exercise program was developed which can be performed during hemodialysis. This program consists of a low intensity endurance training with a bed bicycle ergometer, gymnastics to increase muscular strength, flexibility and co-ordination and of relaxation techniques. An increasing number of studies show that this type of exercise training has comparable beneficial effects as an outpatient exercise rehabilitation program. In addition, exercise during hemodialysis increases the solute removal and thereby the efficiency of dialysis probably by an increased perfusion of skeletal muscles. Since 1995 this type of exercise training was implemented in about 200 German dialysis centers. The participation rate is much higher than in supervised outpatient rehabilitation programs as also elderly patients and patients with severe additional medical problems participate. Even in very old patients functional capacity is improved by exercise during dialysis. As a consequence, some patients do not need any longer professional help for the activity of daily living. Up to now no serious adverse effects or complications were induced by exercise during dialysis. This could be achieved as the patients are instructed and supervised by physiotherapists who have special knowledge and skills in renal exercise rehabilitation. Almost all patients can do some exercise during dialysis and therefore this is the most favourable type of exercise training for hemodialysis patients today.

A new system for regional citrate anticoagulation in continuous venovenous hemodialysis (CVVHD).

BACKGROUND: CVVHD is an established renal replacement therapy in hemodynamically unstable ICU patients. Various methods for regional citrate anticoagulation have been developed to minimize bleeding complications. Metabolic alkalosis, the risk of severe hypocalcemia and need for continuous calcium substitution as well as treatment-associated hypernatremia have limited the success of systems employed so far. We have developed a new technique for regional citrate anticoagulation in CVVHD to overcome these deficiencies and have performed a validation study. METHODS: One hundred and thirty-three filters with an overall treatment duration of 3,324 hours were used in 19 critically ill patients with bleeding complications. We used a calcium-containing dialysate (1.81 mmol/l Ca) to avoid mandatory systemic calcium supplementation. Sodium bicarbonate was added to the dialysate in variable concentrations (13 - 34 mmol/l) to control acid-base status and prevent hypernatremia. The resulting dialysate sodium concentrations were between 121 and 140 mmol/l. Blood flow was set at 75 ml /min. Infusion of a solution containing trisodium citrate and citric acid with an overall citrate concentration of 113 mmol/l was started at 250 ml/h. Primary endpoints were pre- and post-filter ionized calcium (Ca(i)) concentrations, base excess and serum sodium. Filter life was assessed as a secondary end-point. RESULTS: Control of electrolyte balance and azotemia was excellent (prefilter serum Ca(i) 1.06 +/- 0.012 mmol/l (+/- SEM), post-filter Ca(i) 0.23 +/- 0.01 mmol/l, base excess -0.39 +/- 0.4 mmol/l, serum sodium 137 +/- 4 mmol/l, mean serum creatinine 1.8 +/- 0.07 mg/dl). Normal base excess was achieved with a mean dialysate bicarbonate concentration of 26 mmol/l at a mean citrate infusion rate of 266 +/- 4 ml/h. After 48 hours, 25% of filters were still patent, mean filter life was 26 +/- 1.6 hours. No patient developed serious CVVHD-related adverse events. CONCLUSION: The new regional citrate anticoagulation system for CVVHD is safe, feasible and can avoid major complications of previously described methods, especially hypocalcemia, alkalosis and hypernatremia.

Plasma exchange and immunosuppression in rapidly progressive glomerulonephritis: a controlled, multi-center study.

In a randomized study of 26 patients with histologically confirmed rapidly progressive crescentic glomerulonephritis, 12 patients were treated with immunosuppressants alone (corticosteroids, cyclophosphamide and azathioprine) while the other 14 patients received not only the identical immunosuppressive treatment but also plasma exchange therapy for four weeks. No statistically significant difference was found between the two groups. After 8 weeks, 73% and 69% of the patients in each respective group showed recompensation of renal function; serum creatinine fell from initially 7.0 and 6.2 mg/dl mean to 2.7 and 2.3 mg/dl mean, and under continued immunosuppression did not rise in the following months. Thus, in non-autoantibody induced rapidly progressive glomerulonephritis, kidney function could be improved substantially by immunosuppressive therapy, but an advantage of supplementary plasma exchange could not be shown.

The beta-adrenoceptor subtype(s) mediating adrenaline- and dobutamine-induced blood pressure and heart rate changes in healthy volunteers.

In order to characterize the beta-adrenoceptor subtype(s) mediating blood pressure and heart rate changes induced by adrenaline and dobutamine, we compared the effects in healthy male volunteers of propranolol (5 mg i.v.) and of the beta 1-adrenoceptor selective antagonist bisoprolol (15 mg p.o.) on adrenaline- and dobutamine-infusion induced changes in systolic (P(syst)) and diastolic blood pressure (P(diast)) and heart rate with those on blood pressure and heart rate (HR) changes induced by "pure" alpha- or beta-adrenoceptor agonists (phenylephrine, selective alpha, terbutaline, selective beta 2, isoprenaline, non-selective beta 1 and beta 2). Both beta-adrenoceptor antagonists did not affect phenylephrine (0.25 -1.0 microgram/kg/min for 10 min) infusion induced P(syst)- and P(diast)-increases and HR-decreases. On the other hand, propranolol completely suppressed terbutaline (25-150 ng/kg/min for 15 min) and isoprenaline (3.5-35 ng/kg/min for 8 min) infusion induced P(syst)- and HR-increases and P(diast)-decreases while bisoprolol significantly attenuated only isoprenaline-effects but had nearly no effect on terbutaline effects. Thus, in these doses bisoprolol antagonized only beta 1-adrenoceptor mediated effects, propranolol both beta 1- and beta 2-adrenoceptor mediated effects, but both antagonists had no alpha-adrenoceptor antagonistic effects. Dobutamine (1.0-6.0 micrograms/kg/min for 15 min) infusion significantly increased P(syst), but did not significantly affect P(diast) and HR; bisoprolol markedly reduced dobutamine-induced P(syst)-increase. In the presence of propranolol, however, dobutamine caused P(syst)- and P(diast)-increases and HR-decreases. Adrenaline (20-120 ng/kg/min for 15 min) infusion increased P(syst) and HR and decreased P(diast). Bisoprolol did not affect P(syst)- and HR-increases, but significantly attenuated P(diast)-decreases.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential haemodynamic effects induced by beta 1-(bisoprolol) or beta 2-(ICI 118,551) adrenoceptor blockade in man.

To characterize beta 1- and beta 2-adrenoceptor mediated effects in man the influence of the selective beta 1-adrenoceptor antagonist bisoprolol and the selective beta 2-adrenoceptor antagonist ICI 118,551 on changes in blood pressure, heart rate and lymphocyte beta 2-adrenoceptor density evoked by dynamic exercise or isoprenaline infusion was studied in 12 male normotensive volunteers. Bisoprolol administration (1 X 10 mg/day) did not affect lymphocyte beta 2-adrenoceptor density, while ICI 118,551 (3 X 25 mg/day) increased it by about 40%. Exercise as well as isoprenaline infusion caused 100% increases in lymphocyte beta 2-adrenoceptor density; these increases were completely abolished by ICI 118,551, but not affected by bisoprolol. ICI 118,551 markedly attenuated isoprenaline-induced decrease in diastolic blood pressure, but did not affect increase in systolic blood pressure; on the contrary, bisoprolol inhibited the isoprenaline-evoked increase in systolic blood pressure, but did not affect the decrease in diastolic blood pressure. ICI 118,551 antagonized the isoprenaline-induced tachycardia much more potently than bisoprolol, while bisoprolol, but not ICI 118,551, suppressed exercise-induced tachycardia. It is concluded that exercise-induced tachycardia is mediated by cardiac beta 1-adrenoceptor stimulation, whereas isoprenaline-induced tachycardia is mediated by both beta 1- and beta 2-adrenoceptor stimulation.