ABSTRACT
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.
Subject(s)
Nephrogenic Fibrosing Dermopathy/epidemiology , Adult , Aged , Aged, 80 and over , Contrast Media/adverse effects , Female , Gadolinium/adverse effects , Germany/epidemiology , Humans , Kidney Diseases/complications , Male , Middle Aged , Nephrogenic Fibrosing Dermopathy/etiology , Registries , Risk FactorsABSTRACT
Nephrogenic systemic fibrosis (NSF) - previously termed nephrogenic fibrosis dermopathy - is a newly recognized disorder occurring only in patients with renal failure. Exposure to gadolinium-containing contrast agents used for magnetic resonance imaging has been associated with subsequent development of NSF. This disease is characterised by swelling and tightening of the skin, mostly at the limbs. In addition, internal organs may be involved, which may ultimately cause death in rare cases. Skin biopsy showing fibrous tissue and spindle cells positive for CD34, and factor XIIIa as well as CD68-positive macrophages confirms the diagnosis. The main therapeutic goal is restoration of renal function by renal transplantation or recovery from acute renal failure, whenever possible. There are few data regarding other measures. The best available evidence for some therapeutic effect relates to physiotherapy and extracorporal photopheresis. Gadodiamide and gadopentetate-dimeglumin must not be used in stage 4 and 5 renal failure. Other gadolinium-containing contrast media must be used with extreme caution in patients with advanced renal failure.
Subject(s)
Contrast Media/adverse effects , Gadolinium/adverse effects , Renal Insufficiency/complications , Skin Diseases/chemically induced , Skin/pathology , Biopsy , Contraindications , Diagnosis, Differential , Fibrosis/chemically induced , Fibrosis/diagnosis , Fibrosis/pathology , Gadolinium DTPA/adverse effects , Germany , Glucocorticoids/therapeutic use , Humans , Kidney Transplantation , Magnetic Resonance Imaging/adverse effects , Magnetic Resonance Imaging/methods , Photopheresis , Plasmapheresis , Prednisone/therapeutic use , Registries , Renal Insufficiency/pathology , Renal Insufficiency/therapy , Risk Factors , Skin Diseases/diagnosis , Skin Diseases/pathology , Skin Diseases/therapyABSTRACT
HISTORY AND ADMISSION FINDINGS: A 59-year-old man was referred to the hospital for psychiatric reasons. To control hypertension and chronic heart failure he had been treated with 5 mg ramipril and 12.5 mg hydrochlorothiazide. In addition, he received 25 mg spironolactone. A prostate disease was diagnosed two months ago. INVESTIGATIONS: Laboratory analysis revealed a severe hyperkalemia (9.3 mmol/l) as well as an increase in creatinine (24.3 mg/dl) and urea nitrogen (349.0 mg/dl). The ECG showed a bradycardia with increased T-wave amplitudes. Abdominal sonography revealed a full urinary bladder. TREATMENT AND COURSE: Administration of terbutaline, sodium bicarbonate, and glucoseinfusion lowered potassium level to 6.3 mmol/l before hemodialysis was started. Hyperplasia of the prostate gland was found to be the reason for acute renal failure. Dialysis treatment was only temporarily necessary; afterwards, the patient was transferred to the urology department for subsequent therapy. CONCLUSION: Hyperkalemia is a life-threatening emergency that requires immediate therapy. Conservative treatment allows to partially correct water-electrolyte imbalance until hemodialysis can be performed. Hyperkalemia often results from the administration of combination therapy with ACE-inhibitors/AT (1)-antaganonists and antikaliuretic diuretics (spironolactone) in renal failure.
Subject(s)
Acute Kidney Injury/complications , Angiotensin II Type 1 Receptor Blockers/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Diuretics/adverse effects , Hyperkalemia/etiology , Acute Kidney Injury/drug therapy , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Adrenergic beta-Agonists/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Bradycardia/complications , Bradycardia/diagnosis , Diuretics/therapeutic use , Drug Therapy, Combination , Electrocardiography , Emergencies , Glucose/administration & dosage , Heart Failure/complications , Heart Failure/drug therapy , Humans , Hydrochlorothiazide/adverse effects , Hydrochlorothiazide/therapeutic use , Hyperkalemia/complications , Hyperkalemia/drug therapy , Hypertension/complications , Hypertension/drug therapy , Male , Mental Disorders/complications , Middle Aged , Prostatic Hyperplasia/complications , Ramipril/adverse effects , Ramipril/therapeutic use , Renal Dialysis , Sodium Bicarbonate/therapeutic use , Terbutaline/therapeutic useABSTRACT
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.
Subject(s)
Exercise , Kidney Failure, Chronic/rehabilitation , Renal Dialysis , Humans , Kidney Failure, Chronic/physiopathology , Risk FactorsABSTRACT
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.
Subject(s)
Acute Kidney Injury/therapy , Anticoagulants/therapeutic use , Citric Acid/therapeutic use , Hemofiltration/methods , Adult , Aged , Anticoagulants/adverse effects , Calcium/administration & dosage , Calcium/therapeutic use , Citric Acid/adverse effects , Female , Hemofiltration/instrumentation , Humans , Hypocalcemia/drug therapy , Hypocalcemia/etiology , Intensive Care Units , Male , Middle Aged , Treatment OutcomeABSTRACT
The sympathetic nervous system (SNS) plays an important role in the regulation of blood pressure homeostasis and cardiac function. Furthermore, the increased SNS activity is a predictor of mortality in patients with hypertension, coronary artery disease and congestive heart failure. Experimental data and a few clinical trials suggest that there are important interactions between the main pressor systems, i.e. the SNS, the renin-angiotensin system and the vascular endothelium with the strongest vasoconstrictor, endothelin. The main methods for the assessment of SNS activity are described. Cardiovascular drugs of different classes interfere differently with the SNS and the other pressor systems. Pure vasodilators including nitrates, alpha-blockers and dihydropyridine (DHP)-calcium channel blockers increase SNS activity. Finally, central sympatholytics and possibly phenylalkylamine-type calcium channel blockers reduce SNS activity. The effects of angiotensin-II receptor antagonists on SNS activity in humans is not clear; experimental data are discussed in this review. There are important interactions between the pressor systems under experimental conditions. Recent studies in humans suggest that an activation of the SNS with pure vasodilators in parallel increases plasma endothelin. It can be assumed that, in cardiovascular diseases with already enhanced SNS activity, drugs which do not increase SNS activity or even lower it are preferable. Whether this reflects in lower mortality needs to be investigated in intervention trials.
Subject(s)
Antihypertensive Agents/pharmacology , Sympathetic Nervous System/drug effects , Animals , Endothelium, Vascular/drug effects , Endothelium, Vascular/innervation , HumansABSTRACT
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.
Subject(s)
Critical Illness/therapy , Liver Transplantation/methods , Renal Dialysis/adverse effects , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Biomarkers , Body Mass Index , Female , Graft Survival , Hemofiltration , Humans , Liver Transplantation/adverse effects , Liver Transplantation/immunology , Male , Middle Aged , Prognosis , Renal Dialysis/methods , Renal Dialysis/mortality , Retrospective Studies , Severity of Illness Index , Survival RateABSTRACT
In humans, prolonged administration of the beta 2-adrenoceptor agonist terbutaline leads to a desensitization of beta 2-adrenoceptor-mediated cardiovascular responses, which can be blunted by concomitant administration of the antianaphylactic drug ketotifen. This study investigated the effect of disodium cromoglycate, another antiallergic drug, on terbutaline-induced desensitization of beta-adrenoceptor-mediated cardiovascular and noncardiovascular responses. In a double-blind, placebo-controlled, randomized design, nine healthy male volunteers received disodium cromoglycate (4 x 200 mg/day, p.o.) or placebo for 3 weeks with terbutaline (3 x 5 mg/day, p.o.) administered concomitantly during the last 2 weeks. beta 2-Adrenoceptor cardiovascular function was assessed by the increase in heart rate and reduction of diastolic blood pressure induced by an incremental intravenous infusion of the unselective beta-adrenoceptor agonist isoprenaline; beta 1-adrenoceptor cardiovascular function was assessed by exercise-induced tachycardia. Tremulousness was monitored as a beta 2-adrenoceptor-mediated noncardiovascular effect. After 2 weeks' administration of terbutaline, there was a marked and significant (p < 0.001) attenuation of isoprenaline-induced tachycardia (mean percentage attenuation, 53.3%) and of the isoprenaline-induced decrease in diastolic blood pressure (mean percentage attenuation, 55.6%). Exercise-induced tachycardia also was significantly (p < 0.001) blunted, but the magnitude of this attenuation was only very small (mean attenuation, 5.6%). Disodium cromoglycate affected neither the rightward shift of beta 2-adrenoceptor-mediated responses nor the small rightward shift in beta 1-adrenoceptor-mediated exercise tachycardia after 2 weeks' administration of terbutaline. Tremulousness observed during the first few days of terbutaline administration disappeared after 4 to 8 days, indicating development of desensitization of beta 2-adrenoceptor-mediated noncardiovascular responses. This was not prevented by disodium cromoglycate. These results confirm that long-term beta 2-adrenoceptor agonist therapy leads to a desensitization of beta 2-adrenoceptor-mediated cardiovascular and noncardiovascular effects in humans in vivo. However, unlike ketotifen, cromolyn sodium is not able to attenuate this desensitization.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Anti-Allergic Agents/pharmacology , Cromolyn Sodium/pharmacology , Heart/drug effects , Receptors, Adrenergic, beta-2/physiology , Terbutaline/pharmacology , Adrenergic beta-2 Receptor Agonists , Adrenergic beta-Agonists/adverse effects , Adult , Blood Pressure/drug effects , Drug Interactions , Exercise Test , Heart/physiology , Heart Rate/drug effects , Humans , Isoproterenol/pharmacology , Male , Receptors, Adrenergic, beta-1/physiology , Terbutaline/adverse effects , Tremor/chemically induced , Tremor/physiopathologyABSTRACT
AIMS: To study whether desensitization occurs after long-term administration of the 1-adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen. METHODS: In a double-blind, randomized design 10 young, healthy males received ketotifen (2 x 1 mg day(-1) p.o.) or placebo for 3 weeks with xamoterol (2 x 200 mg day(-1) p.o.) administered concomitantly during the last 2 weeks. 'l1-adrenoceptor mediated responses were assessed as exercise-induced tachycardia and isoprenaline-induced shortening of heart rate corrected electromechanical systole (QS2c); isoprenaline-induced tachycardia was measured as a mixed beta1-/beta2-adrenoceptor-mediated effect. RESULTS: The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS2c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise- and isoprenaline-induced tachycardia (mean dose ratios+/-s.e.mean: 1.20+/-0.05 and 2.46+/-0.23) and the isoprenaline-evoked shortening of QS2c (dose ratio 3.59+/-0.68). This rightward shift was even more pronounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference (95% CI) of log transformed dose ratios between placebo and ketotifen: exercise tachycardia 0.001 (-0.03; 0.04); isoprenaline tachycardia 0.03 (-0.15; 0.21); isoprenaline induced shortening of QS2c 0.13 (-0.22; 0.48)). CONCLUSIONS: In humans xamoterol is a partial beta1-adrenoceptor agonist with positive chrono- and inotropic effects at rest and antagonistic properties under conditions of beta-adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of beta1-adrenoceptor desensitization. Ketotifen does not change the beta-adrenoceptor mediated responses of xamoterol after chronic dosing.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Anti-Allergic Agents/pharmacology , Hemodynamics/drug effects , Ketotifen/pharmacology , Xamoterol/pharmacology , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Drug Interactions , Electrocardiography/drug effects , Humans , Isoproterenol/adverse effects , Male , Placebos , Reproducibility of Results , Tachycardia/chemically induced , Xamoterol/administration & dosage , Xamoterol/bloodABSTRACT
Genetic susceptibility contributes significantly to the risk of developing nephropathy in insulin-dependent diabetes mellitus (IDDM). The cellular substrate for this has remained enigmatic. We investigated whether afflicted IDDM patients display an enhanced activation of pertussis toxin (PTX)-sensitive G proteins, a phenomenon which has been demonstrated in patients with essential hypertension. We established immortalised B lymphoblast cell lines from 10 IDDM patients without nephropathy (DC) and 15 IDDM patients with nephropathy (DN). Nephropathy was defined as a persistent albumin excretion rate of more than 20 microg/min (DC 3.9 +/- 5.8, DN 562.3 +/- 539.0 microg/min, respectively). Subjects were matched with regard to age (DC 28.9 +/- 6.5, DN 35.9 +/- 9.9 years), diabetes duration (DC 19.3 +/- 6.9, DN 22.7 +/- 5.8 years) and HbA1c values (DC 8.5 +/- 1.4, DN 8.8 +/- 1.6%). Reactivity of PTX-sensitive G proteins was quantified by measuring platelet-activating factor (PAF)-induced Ca2+ mobilisation (fura 2 method) and by mastoparan-stimulated [35S]GTPgammaS binding. Expression of Galphai proteins was quantified by Western blot analysis. PAF-evoked Ca2+ increases above baseline averaged 77.0 +/- 52.5 nmol/l in DC and 150.7 +/- 61.5 nmol/l in DN (p = 0.005). PAF-evoked Ca2+ increases correlated with stimulated [35S]GTPgammaS binding (r2 = 0.42, p = 0.012). From Western blot analysis an overexpression of Galphai proteins could be excluded in DN. A consequence of the altered metabolic milieu in diabetes is the increased release of vasoactive and proliferative agonists which promote glomerular hyperfiltration, hypertrophy, enhanced matrix deposition, and, finally, glomerulosclerosis. Many of these auto- and paracrine agonists bind to G protein-coupled receptors. Therefore, their cellular effects are reinforced by the enhanced G protein reactivity and increase the propensity to nephropathy in IDDM.
Subject(s)
B-Lymphocytes/metabolism , Diabetes Mellitus, Type 1/metabolism , Diabetic Nephropathies/metabolism , GTP-Binding Proteins/metabolism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Adult , Aged , B-Lymphocytes/drug effects , Blood Pressure , Body Mass Index , Calcium/metabolism , Cell Line , Cells, Cultured , Diabetes Mellitus, Type 1/physiopathology , Diabetic Nephropathies/physiopathology , Female , Humans , Kinetics , Male , Middle Aged , Pertussis Toxin , Virulence Factors, Bordetella/pharmacologyABSTRACT
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.
Subject(s)
Hemofiltration , Interleukin-6/blood , Systemic Inflammatory Response Syndrome/therapy , Tumor Necrosis Factor-alpha/metabolism , Adult , Aged , Female , Hemodynamics , Humans , Interleukin-6/urine , Linear Models , Male , Middle Aged , Statistics, Nonparametric , Systemic Inflammatory Response Syndrome/bloodABSTRACT
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.
Subject(s)
Atropine/pharmacology , Hemodynamics/drug effects , Muscarinic Antagonists/pharmacology , Norepinephrine/pharmacology , Tyramine/pharmacology , Aged , Blood Pressure/drug effects , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Single-Blind Method , Systole/drug effectsABSTRACT
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.
Subject(s)
Adrenergic Antagonists/pharmacology , Heart/drug effects , Muscarinic Antagonists/pharmacology , Norepinephrine/pharmacology , Tyramine/pharmacology , Adult , Blood Pressure/drug effects , Cross-Over Studies , Heart/physiology , Heart Rate/drug effects , Humans , Male , Myocardium/metabolism , Norepinephrine/blood , Vasoconstriction/drug effectsABSTRACT
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.
Subject(s)
Deoxyepinephrine/pharmacology , Dopamine Agonists/pharmacology , Receptors, Adrenergic/drug effects , Receptors, Dopamine/drug effects , Sympathomimetics/pharmacology , Adult , Bisoprolol/pharmacology , Blood Pressure/drug effects , Domperidone/pharmacology , Dose-Response Relationship, Drug , Heart Rate/drug effects , Humans , Male , Norepinephrine/blood , Prolactin/blood , Propranolol/pharmacologyABSTRACT
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)
Subject(s)
Bisoprolol/pharmacology , Blood Pressure/drug effects , Dobutamine/pharmacology , Epinephrine/pharmacology , Heart Rate/drug effects , Propranolol/pharmacology , Tachycardia/chemically induced , Adult , Bisoprolol/blood , Dobutamine/antagonists & inhibitors , Dose-Response Relationship, Drug , Epinephrine/antagonists & inhibitors , Humans , Infusions, Intravenous , Male , Propranolol/blood , Receptors, Adrenergic, beta/drug effects , Tachycardia/drug therapyABSTRACT
A retrospective study was undertaken of 14 patients (eleven men, three women; mean age 52 [33-68] years in whom haemolysis had occurred during chronic haemodialysis (n = 12) or haemofiltration (n = 2). The haemolysis was of mechanical cause in eight patients, by an osmotic mechanism in one, and of unknown cause in five. Cardinal symptoms were nausea in 14 patients, abdominal pain in nine, vomiting in eight and raised blood pressure in ten. The plasma was discoloured in all patients and there was also an increase in free haemoglobin (110-2400 mg/dl) and (or) lactate dehydrogenase (311-7403 U/l). In all of eleven patients in whom it was measured the activity of serum amylase and (or) lipase was more than doubled (to 73-2400 U/l and 473-16,740 U/l, respectively). All patients were treated symptomatically, three had a blood exchange, two others plasma separation. Eight patients recovered within a few days, but necrotizing pancreatitis developed in six, three of whom died while two had permanent sequelae. This series shows that dialysis-induced acute haemolysis can cause life-threatening pancreatitis. Narrowings within the extracorporeal circuit, not always recognized in current dialysis equipment, are the most frequent cause of the mechanical haemolysis.
Subject(s)
Hemolysis , Pancreatitis/etiology , Renal Dialysis/adverse effects , Renal Dialysis/instrumentation , Acute Disease , Adult , Aged , Combined Modality Therapy , Female , Germany, West/epidemiology , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/therapy , Male , Middle Aged , Necrosis , Pancreas/pathology , Pancreatitis/diagnosis , Pancreatitis/epidemiology , Pancreatitis/prevention & control , Pancreatitis/therapy , Renal Dialysis/statistics & numerical data , Retrospective StudiesABSTRACT
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.