[Drug-drug interactions in urology]. / Arzneimittelinteraktionen in der Urologie.

Many patients concomitantly receive multiple urological and nonurological medications. This practice can lead to drug-drug interactions (DDIs). These interactions can be pharmacodynamic (acting on the same body function) or pharmacokinetic (affecting each other's concentrations) and are a frequent cause of adverse drug reactions. Examples of pharmacodynamic DDIs include the use of overactive bladder drugs together with those prescribed for psychiatric or neurological indications that also have anticholinergic properties, or the use of PDE5 inhibitors together with vasodilating drugs, particularly nitrates. Pharmacokinetic DDIs are mainly due to effects on drug metabolism, specifically that involving CYP3A4 and 2D6, or on drug transporters. Drugs can both inhibit and induce the activity of many of these enzymes and transporters. CYP3A4 inducers can lower levels of cyclosporine or tacrolimus so much that transplant rejection occurs, and CYP3A4 inhibitors can increase their levels, leading to nephrotoxicity. Levels of the anticholinergic darifenacin can be increased so much by potent CYP3A4 inhibitors that this combination is contraindicated. These examples show that knowledge of DDI can help patients avoid undesirable side effects of drugs.

The influence of continuous venovenous haemodialysis on the pharmacokinetics of multiple oral moxifloxacin administration to patients with severe renal dysfunction.

AIM: We investigated single dose and steady-state pharmacokinetics of moxifloxacin in eight venovenous haemodialysis patients. METHODS: Plasma, dialysate and urine pharmacokinetic parameters for moxifloxacin and its main metabolites were calculated after single and multiple (7 days) dosing with 400 mg day(-1). RESULTS: Moxifloxacin pharmacokinetics after a single dose and at steady state (multidose day 7) were comparable in patients with impaired renal function and healthy subjects (geometric mean/%CV AUC mg l(-1) h single dose 37.0/24.3 in haemodialysis patients vs. 29.8/22.6 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 99.34%, 154.60%; steady state 40.4/29.1 haemodialysis patients vs. 33.9/20.1 in healthy subjects, 95% CI for ratio of haemodialysis patients to healthy subjects 90/39%, 156.93%). In haemodialysis patients plasma concentrations of moxifloxacin at steady-state were elevated compared with those after a single 400 mg dose (AUC mg l(-1) h, geometric mean/%CV, 40.4/29.1) compared with 37.0/24.3; 95% CI for ratio of steady-state to single dose 87.29%, 136.52%, as were concentrations of metabolite M1 3.21/34.6 compared with 2.02/45.3, 95% CI for ratio of steady state to single dose 14.21%, 175.07%. Haemodialysis cleared about 9% of the dose as unchanged moxifloxacin. CONCLUSIONS: No dose adjustments are required for venovenous haemodialysis patients on oral moxifloxacin therapy.

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.

Terlipressin and gelafundin: safe therapy of hepatorenal syndrome.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) occurs in about 20 % of patients with liver cirrhosis and ascites and is characterized by intensive renal vasoconstriction, low glomerular filtration rate but preserved tubular function and normal renal histology. The potential of terlipressin and albumin to reverse HRS after a time period of 14 days has already been shown. However, intravenous albumin is expensive (approximately 25 per 50 ml 20% albumin in Germany) and has limited availability in some settings. Therefore we used an artificial plasma substitute, Gelatinepolysuccinat, which is less expensive (approximately 12 per 500 ml). The aim of our present study was to examine the effects of terlipressin and Gelatinepolysuccinat on renal function and hemodynamics in a time period of six days. METHODS AND PATIENTS: Seven consecutive patients with cirrhosis and hepatorenal syndrome were included in a pilot study of terlipressin (6 mg /24 h iv) therapy associated with i.v. Gelatinepolysuccinat (Gelafundin 4% Infusionslösung, Company Braun, Mw: 30 000 D). RESULTS: In five of the seven patients treatment was associated with a marked reduction of serum creatinine after six days (3.85 +/- 0.44 mg/dl vs.1.9 +/- 0.32 mg/dl; p< 0.018). Creatinine clearance improved (20 +/- 8.8 ml/min vs. 43 +/- 11.7 ml/min; p<0.12). There was a remarkable improvement in circulatory function in all patients, with an increase in mean arterial pressure (58+/-4.4 mmHg vs. 75 +/- 4.5 mmHg, p< 0.001). No patient developed signs of intestinal, myocardial or distal ischemia. CONCLUSIONS: Terlipressin and Gelatinepolysuccinat appear to be a safe and effective treatment of hepatorenal syndrome.

The T-allele of the C825T polymorphism is associated with higher arterial stiffness in young healthy males.

Arterial stiffening is the major cause of increasing systolic blood pressure in arterial hypertension. Increased arterial stiffness is one major mechanism responsible for morbidity and mortality in hypertension. A C825T polymorphism was identified in the gene encoding the G-protein beta3 subunit (GNB3), and an association of the T-allele with hypertension was demonstrated in several studies. In order to identify a pathogenetic link between hypertension and arterial stiffness, we compared two indices of arterial stiffness, pulse wave velocity (PWV) and augmentation index, in young, healthy men with and without the 825T-allele under resting conditions. PWV was determined from pressure tracing over carotid and femoral arteries in 99 subjects (CC: n=43; CT&TT: n=56). Augmentation index was derived in 72 subjects (CC: n=30; CT&TT: n=42) by pulse wave analysis using radial applanation tonometry. Carriers of the 825T-allele exhibited a significantly higher PWV compared to subjects with the CC genotype (6.0+/-0.1 m/s (TC&TT) vs 5.7+/-0.1 m/s (CC); P=0.0251). There was also a significant difference (P = 0.0448) in augmentation index between carriers of the T-allele (CT&TT: 3.4+/-2.9%) and controls with the CC -genotype (-5.0+/-4.1 %). There was no difference in any other anthropometric (age, height, weight, body mass index) or haemodynamic (heart rate, peripheral and central blood pressure). In summary, the C825T polymorphism is associated with higher arterial stiffness in young, healthy males. Arterial stiffening may pathogenetically contribute to the development of hypertension in carriers of the T-allele.

Do effects on blood pressure contribute to improved clinical outcomes with metformin?

Hyperinsulinaemia and hypertension commonly coexist, and a large body of evidence points to a common pathogenesis based on the presence of underlying insulin resistance (the "insulin hypothesis" of hypertension). Metformin improves insulin sensitivity in liver and muscle as its primary antihyperglycaemic mechanism of action, and intensive glycaemic management with metformin significantly reduced the risk of macrovascular diabetic complications in the UK Prospective Diabetes Study. The clinical outcome benefits in the metformin group included a significant reduction in the risk of stroke (- 41% vs + 14% with sulphonylurea or insulin treatment, p=0.032), which is well known to be highly sensitive to changes in blood pressure. Furthermore, a placebo-controlled study has shown that metformin significantly improved endothelial function, a key regulator of vascular tone and blood pressure, in type 2 diabetic patients. However, clinical studies have shown that metformin treatment is not associated with clinically relevant reductions in blood pressure in man. These apparently conflicting observations are difficult to reconcile. Either the beneficial vascular actions of metformin involve physiological systems not involved in the control of blood pressure, or counter-regulatory mechanisms prevent beneficial effects of metformin on the vasculature being translated into a clinically meaningful antihypertensive effect. Further research will be required to resolve this paradox.

Diastolic blood pressure is an important determinant of augmentation index and pulse wave velocity in young, healthy males.

Pulse wave velocity (PWV) and augmentation index are widely used measures of arterial stiffness. The purpose of this study was to evaluate the role of blood pressure as a determinant of both indices independent of potentially confounding factors including gender, age and cardiovascular disorders. A total of 77 young, healthy subjects were investigated under resting conditions. Augmentation index was derived by pulse wave analysis using carotid applanation tonometry. PWV was determined from pressure tracing over the carotid and femoral artery. The relations between stiffness markers and haemodynamic parameters were analysed by simple (r) and multiple (beta) regression analysis. Using simple regression analysis, augmentation index was correlated to age (r=0.292, P=0.0105), diastolic blood pressure (DBP, r=0.483, P<0.0001), mean arterial blood pressure (MAP, r=0.381, P=0.0007), pulse pressure (r=-0.414, P=0.0002) and total peripheral resistance (r=0.266, P=0.0204). After multiple regression analysis, augmentation index remained significantly correlated only to DBP (beta=0.347, P=0.0051). Using simple regression analysis, PWV was correlated to age (r=0.304, P=0.0067), systolic blood pressure (r=0.280, P=0.0129). DBP (r=0.455, P<0.0001), MAP (r=0.446, P&<0.0001) and heart rate (r=0.348, P=0.0018). After multiple regression analysis, PWV remained correlated only to age (beta=0.218, P=0.0422) and DBP (beta=0.4105, P=0.0316). In summary, DBP is an important determinant of augmentation index and PWV in young, healthy males. Further studies are needed to characterize the impact of blood pressure on arterial stiffness in other populations including females and older subjects.

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.

Haemodynamic characterization of young normotensive men carrying the 825T-allele of the G-protein beta3 subunit.

A C825T polymorphism was recently identified in the gene for the G-protein beta3 subunit, the T-allele being associated with hypertension. To better understand the underlying pathophysiological mechanisms, we compared the haemodynamics of young healthy males with and without the T-allele. In three studies, subjects were investigated with regard to cardiac and vascular function at rest and following intravenous administration of the beta-adrenoceptor antagonist, propranolol, and the alpha2-adrenoceptor agonist, alpha-methylnoradrenaline, and with regard to local venous vasoconstriction in the dorsal hand vein in situ following infusion of the alpha2-adrenoceptor agonist, azepexol. alpha2-Adrenoceptor agonists were chosen as vasoconstrictor drugs since alpha2-adrenoceptors couple to pertussis toxin (PTX)-sensitive G-proteins and since in-vitro studies have demonstrated enhanced signal transduction of PTX-dependent pathways in the presence of the T-allele. Total peripheral resistance was determined as a parameter of vasoconstrictor tone and heart rate, stroke volume and systolic time intervals for cardiac function. T-allele carriers had a significantly elevated stroke volume and lower total peripheral resistance at baseline. After propranolol, their fall in stroke volume was significantly greater. During alpha-methylnoradrenaline infusion, elevation of total peripheral resistance was not increased relative to controls. Similarly, the constriction response of the dorsal hand vein to azepexol was not different. Our study does not support the idea of increased vasoconstrictor tone in T-allele carriers either at rest or during stimulation of alpha2-adrenoceptors. However, this allele may be associated with elevated cardiac stroke volume.

Endothelin-A receptor antagonist inhibits angiotensin II and noradrenaline in man.

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. The interactions of ET with the mediators of the sympathetic nervous system and the renin-angiotensin-system in humans are unclear. METHODS: We studied the effects of the ETA-selective antagonist BQ-123 and the ETB-selective antagonist BQ-788 (both 10(-10)-10(-8) M) on ET-1 (10(-16)-10(-10) M), angiotensin II (AT, 10(-16)-10(-10) M) and noradrenaline (NA, 10(-16)-10(-10) M) induced vasoconstriction in the human skin microcirculation in vivo in 25 healthy male volunteers using laser Doppler flowmetry and double injection technique. RESULTS: BQ-123 caused a dose-dependent vasodilatation (maximum effect: + 949 +/- 84 AUC-PU, P < 0.001), whereas BQ-788 induced mild vasoconstriction (maximum effect: -388 +/- 96 AUC-PU, P < 0.01). In the presence of BQ-123, but not BQ-788, ET-1, AT and NA caused markedly less vasoconstriction at any tested agonist dose; the effect was most pronounced on ET-1 (maximum effect at 10(-14) M: + 814 +/- 93 AUC-PU vs ET alone, P < 0.001), followed by noradrenaline (maximum effect at 10(-16) M: +580 +/- 107 AUC-PU vs NA alone, P < 0.01) and angiotensin II (maximum effect at 10(-14) M: + 493 +/- 111 AUC-PU vs AT alone, P < 0.001). CONCLUSIONS: ETA-selective antagonism inhibits vasoconstriction to AT and NA in vivo in healthy subjects. This beneficial effect may be useful for the treatment of patients with cardiovascular disease including hypertension especially in combination therapy with sympatholytic agents and inhibitors of the renin-angiotensin system.

The nitric oxide synthase inhibitor L-NMMA potentiates noradrenaline-induced vasoconstriction: effects of the alpha2-receptor antagonist yohimbine.

OBJECTIVE: Alpha2-adrenoceptors can be found both on vascular smooth muscle cells and on the endothelium, where they exert opposing effects on vascular tone. In vitro, the stimulation of alpha2-adrenoceptors on endothelial cells leads to the release of vasodilating substances like nitric oxide (NO) and prostanoids. Little is known of this mechanism in vivo. DESIGN AND METHODS: We investigated the effects of the NO-synthase inhibitor L-NMMA (10(-6) mol) and the alpha2-adrenoceptor antagonist yohimbine (YO, 10(-10)-10(-6) mol) on noradrenaline (NA, 10(-12)-10(-8) mol)-induced vasoconstriction in the forearm skin microcirculation of 16 healthy volunteers using double injection technique and laser Doppler flowmetry. Results are expressed in perfusion units (PU) as differences from baseline and control in mean +/- SEM; the area under the time-response-curve was calculated (AUC). RESULTS: NA (10(-8)- 10(-12) mol) caused a marked, dose-dependent reduction in blood flow (mean effect -745 +/- 84 AUC PU; P< 0.001 versus saline). NA-induced vasoconstriction was enhanced by L-NMMA (mean effect -916 +/- 72 AUC PU; P< 0.001 versus NA). YO (10(-6)-10(-10) mol) induced a significant, dose-dependent vasodilation (mean effect +/- 446 +/- 110 AUC PU; P < 0.05 versus control); high doses of YO (10(-6) mol) inhibited NA constriction (P < 0.001 versus NA), whereas lower doses of YO (10(-8)/10(-10) mol) had no effect or even increased NA-induced constriction. In the presence of L-NMMA, YO (10(-8) and 10(-10) mol) further potentiated NA-induced vasoconstriction (mean effect -1165 +/- 108 AUC PU; NS versus NA). CONCLUSION: These data demonstrate, that in humans in vivo, endogenous NO attenuates noradrenergic constriction. The effects of YO suggest that endothelial alpha2-adrenoceptors are involved in the release of NO and other vasodilating substances. Furthermore, there is an additive NO-independent vasodilation, which can be unmasked by L-NMMA.

Modulation of noradrenaline-induced microvascular constriction by protein kinase inhibitors.

We have tested the role of various protein kinases in noradrenaline-induced, alpha1A-adrenoceptor-mediated constriction of mesenteric and intrarenal rat microvessels. The protein kinase C inhibitors, H7 and staurosporine, inhibited constriction in both vessel types in concentrations which also inhibit myosin light chain kinase. The more selective protein kinase C inhibitors, bisindolylmaleimide I and Gö 6976, did not inhibit microvessel constriction in concentrations selective for protein kinase C. Moreover, the protein kinase C-activating phorbol ester, phorbol-12-myristate-13-acetate, did not cause constriction. The tyrosine kinase inhibitors, genistein and tyrphostin 23, inhibited constriction in concentrations compatible with tyrosine kinase inhibition. An inhibitor of the extracellular signal-regulated kinase cascade, PD 98059, also caused concentration-dependent inhibition. While chelation of extracellular Ca2+ abolished noradrenaline-induced constrictions, the Ca2+-ATPase inhibitor, thapsigargin, had no effects. We conclude that tyrosine kinases and extracellular signal-regulated kinase (but not protein kinase C) may be involved in noradrenaline-induced rat mesenteric and intrarenal microvessel constriction but this appears to occur independently of an effect on sarcoplasmic Ca2+ storage.

Do saw palmetto extracts block human alpha1-adrenoceptor subtypes in vivo?

BACKGROUND: To test whether saw palmetto extracts, which act as alpha1-adrenoceptor antagonists in vitro, also do so in vivo in man. METHODS: In a placebo-controlled, double-blind, four-way cross-over study 12 healthy young men were treated with three different saw palmetto extract preparations (320 mg o.d.) for 8 days each. On the last day, before and 2, 4 and 6 hr after drug intake blood pressure and heart rate were determined and blood samples obtained, which were used in an ex vivo radioreceptor assay with cloned human alpha1-adrenoceptor subtypes. RESULTS: Saw palmetto extract treatment did not result in alpha1-adrenoceptor subtype occupancy in the radioreceptor assay. Although the saw palmetto extracts caused minor reductions of supine blood pressure, they did not affect blood pressure during orthostatic stress testing and did not alter heart rate under either condition. Moreover, plasma catecholamines remained largely unaltered. CONCLUSIONS: Despite their alpha1-adrenoceptor antagonist effects in vitro, therapeutically used doses of saw palmetto extracts do not cause alpha1-adrenoceptor antagonism in man in vivo.

[Diuretic therapy of hypertensives with Type 2 diabetes; rational therapy or malpractice?]. / Diuretikatherapie beim Hypertoniker mit Typ-II-Diabetes--rationale Therapie oder Kunstfehler?

There is overwhelming evidence that effective antihypertensive therapy with diuretics reduces total mortality and cardiovascular morbidity. Therefore, diuretics have a well established place in the pharmacotherapy of hypertension. However, their role in the treatment of hypertensives with type-II-diabetes is a matter of controversy due to their potentially adverse effects on glucose-, lipid- and electrolyte metabolism which--in type-II-diabetics--may potentially offset the beneficial effects of blood pressure lowering. However, results of large-scale, prospective, randomised intervention trials demonstrate that in type-II-diabetics the beneficial effects of blood pressure reduction per se are more important than any potentially adverse effects on metabolic surrogate parameters. The reduction in total mortality and cardiovascular morbidity as a result of effective antihypertensive therapy is more pronounced in type-II-diabetics than in non-diabetics. This holds also true for a diuretic based antihypertensive therapy in type-II-diabetics. Clearly their effects on glucose-, lipid- and electrolyte metabolism are of minor, if any, clinical relevance. The hypertensive type-II-diabetic benefits from diuretics--they prolong life and improve its quality. Therefore, antihypertensive therapy with diuretics constitutes a rational pharmacotherapy founded on the principles of evidence based medicine and must not be considered as malpractice.

[Heart failure as a cardiac symptom of sarcoidosis. Successful treatment of heart failure with steroids, digitalis and an angiotensin-1-receptor antagonist in sarcoidosis]. / Herzinsuffizienz als kardiale Manifestation einer Sarkoidose. Erfolgreiche Therapie der Herzinsuffizienz mit Steroiden, Digitalis und einem Angiotensin-1-Rezeptor-Antagonisten bei Sarkoidose.

BACKGROUND: Sarcoidosis is a multisystemic disorder that may involve every organ. A symptomatic manifestation of the myocardium is possible, in these cases arrhythmias are the most common symptoms. CASE REPORT: This case report presents a 26-year-old female with the recurrence of Boeck's sarcoid. Fever, chill and a severe reduction in stress tolerance were the first symptoms. At the time of admission she complained of Grade III dyspnea according to the NYHA classification. The echocardiogram showed a severe impairment of the global and left ventricular function. The left ventricular ejection fraction was reduced to 30% and the Tei index was elevated to 1.0. A specimen taken from a mediastinal tumor confirmed the hypothesis of the recurrence of the sarcoidosis. Myocardial perfusion scintigraphy showed typical lesions for myocardial sarcoidosis. There were signs of an old anteroseptal infarction in the resting ECG without evidence of myocardial ischemia during a stress test. Repeated Holter-ECGs were without signs of severe arrhythmias whereas ventricular late potentials were positive. After the combined therapy with steroids, digitalis and an angiotensin-1 receptor antagonist, mediastinal mass and Tei index were reduced and the ejection fraction moved to 56%. Dyspnoea was classified with Grade II according to the NYHA classification. CONCLUSION: Treatment of asymptomatic sarcoidosis is still controversial, whereas the treatment of life-threatening sarcoidosis, eye involvement or severe hypercalcemia is accepted. This case report presents the successful treatment of severe heart failure with prednisone, glycosides and an angiotensin-1 receptor antagonist. With this combined therapy an improvement of subjective and objective parameters was possible.

Antihypertensive drugs and the sympathetic nervous system.

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.

Disodium cromoglycate does not prevent terbutaline-induced desensitization of beta 2-adrenoceptor-mediated cardiovascular in vivo functions in human volunteers.

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.