Angiotensin-forming enzyme in brain tissue.

A renin-like enzyme is present in brain tissue and is independent of kidney and plasma renin. In the presence of homologous substrate it forms angiotensin. Administration of aldosterone significantly decreases this angiotensinforming enzyme activity, while administration of progesterone markedly enhances it.

Changing dopamine agonist treatment in Parkinson's disease: experiences with switching to pramipexole.

1202 patients suffering from Parkinson's disease switched from other dopamine agonists to pramipexole under open conditions either abruptly or in an overlapping, gradual manner. Mostly insufficient effectiveness motivated the switch. The investigators gave equal preference to either an abrupt or an overlapping switch to pramipexole in this observational study. There was a tendency in favour of the overlapping switch procedure in those patients who were on a relatively higher dose of a dopamine agonist before the switch. The switch was performed because the investigators expected the effect of pramipexole on tremor, motor functions and depression/anhedonia to be better compared with previous dopamine agonists. The main reasons for switching to pramipexole (anti-tremor effect, anti-depressive/anti-anhedonic effect) as given by the physicians at baseline came up to expectations. The switch to pramipexole mostly yielded further improvements irrespective of the mode of switching.

Safety, tolerability, and pharmacologic activity of multiple doses of the new platelet activating factor antagonist WEB 2086 in human subjects.

The safety, tolerability, and pharmacologic activity of WEB 2086, a novel, specific platelet activating factor antagonist, were examined in two double-blind, placebo-controlled, within-subject crossover studies. In each study, WEB 2086 (three times 40 mg/day or three times 100 mg/day) was administered for 7 days to 12 healthy volunteers. Pharmacologic activity of the compound was monitored with ex vivo platelet activating factor-induced platelet aggregation. Multiple administration of WEB 2086 resulted in a continuous, almost complete inhibition of this aggregation. Nevertheless, no clinically significant drug-related effects on vital and laboratory parameters or obvious drug-dependent adverse reactions were observed. In conclusion, the performed studies confirmed earlier findings that WEB 2086 was an effective platelet activating factor antagonist in human beings and, furthermore, showed no side effects that would provide objections against further clinical trials with this substance in patients.

The influence of sympathetic nervous activity on regression of cardiac hypertrophy.

Pharmacotherapeutical means of reversing cardiac hypertrophy (prazosin, clonidine and nifedipine) were analysed in concentrically, as well as eccentrically, hypertrophied left ventricles. Regression of cardiac hypertrophy, i.e. a therapeutic intervention on a critical precursor of hypertensive congestive heart failure, can be obtained by various antihypertensive agents. Prazosin, calcium channel blockers, clonidine and angiotensin converting enzyme inhibitors as well as a combined treatment regimen using alpha-receptor blockers together with diuretics and vasodilators can all induce regression of hypertrophy associated with an improvement in left ventricular function. Moreover, an improved coronary reserve may reduce the ischaemic risk of the hypertrophied myocardium. However, not all antihypertensive drugs seem equally effective in bringing about coronary regression of left ventricular hypertrophy (LVH). No regression or little regression has been found with diuretic monotherapy despite a satisfactory reduction in blood pressure. On the other hand, a trend towards a regression has been observed in patients in whom treatment with clonidine significantly reduced catecholamines.

Relation of plasma noradrenaline to blood pressure, age, sex and sodium balance in patients with stable essential hypertension and in normotensive subjects.

1. Plasma noradrenaline was measured in 125 patients with stable essential hypertension (WHO I-II) and in 107 normotensive control subjects lying and standing. 2. In normotensive subjects and in patients with essential hypertension no sex-related differences of plasma noradrenaline were found between age-matched groups. 3. Plasma noradrenaline was not related to sodium balance indexed by urinary sodium/creatinine ratio. 4. In patients with essential hypertension plasma noradrenaline increases with age. 5. Mean plasma noradrenaline concentrations are significantly higher in patients with essential hypertension compared with age-matched normotensive subjects both lying and standing. 6. In patients with essential hypertension diastolic blood pressure and heart rate correlated significantly with supine plasma noradrenaline concentrations.

Guanfacine in essential hypertension: effect on blood pressure, plasma noradrenaline concentration and plasma renin activity.

1. The acute and chronic effects of guanfacine on blood pressure, plasma noradrenaline concentration and plasma renin activity were investigated in 23 patients (15 males, 8 females) with essential hypertension (WHO grade I-II). 2. Guanfacine induced a decrease in plasma noradrenaline concentration and plasma renin activity concomitant with a fall in blood pressure and heart rate in both the acute and the chronic study. 3. The adrenergic response to upright posture, reflected by an increase in plasma noradrenaline concentration and plasma renin activity, was not abolished after chronic guanfacine therapy. 4. The decrease in blood pressure 15 min after intravenous administration of guanfacine was inversely correlated with the basal sympathetic activity before treatment and with the decrease in plasma noradrenaline. 5. After chronic treatment with guanfacine no significant correlation existed between blood pressure reduction and the concomitant changes in peripheral sympathetic and/or plasma renin activity. 6. Despite the lack of a close correlation it is suggested that the antihypertensive effect of guanfacine in patients with essential hypertension is at least partially mediated by an inhibition of the sympathetic nervous and plasma renin activity.

Increased plasma noradrenaline concentrations in essential hypertension and their decrease after long-term treatment with a beta-receptor-blocking agent (prindolol).

1. Plasma noradrenaline was measured in fifty-nine patients with mild to severe essential hypertension and in fifteen normotensive control subjects under basal and orthostatic conditions. 2. In patients with essential hypertension mean plasma noradrenaline concentrations were significantly higher than in control subjects under basal and orthostatic conditions. 3. In patients with essential hypertension basal diastolic blood pressure correlated closely with the corresponding plasma noradrenaline concentrations. 4. Long-term treatment with prindolol of patients with essential hypertension led to a significant fall in diastolic and systolic blood pressure and heart rate and to a significant decrease in plasma noradrenaline concentrations under basal and orthostatic conditions. 5. The adrenergic response to upright posture, reflected by an increase in plasma noradrenaline, was not abolished by prindolol. 6. It is concluded that the anti-hypertensive effect of prindolol in patients with essential hypertension is at least partially mediated by a decrease of sympathetic nervous activity.

Increase of total body potassium and decrease of exchangeable sodium after long-term treatment with a beta-receptor-blocking agent (prindolol) in essential hypertension.

1. The effect of long-term treatment with prindolol on blood pressure, total body potassium (Kt), exchangeable sodium (Nae) and plasma renin activity was investigated in twelve patients with essential hypertension. 2. Systolic and diastolic pressures were significantly reduced from 164/112 to 127/90 mmHg under basal conditions. 3. Before treatment Nae in patients with essential hypertension was significantly higher than in normotensive individuals. After an average of 16 weeks on prindolol Nae in patients with essential hypertension was significantly decreased, despite an average increased in body weight of 2 kg in the patients. 4. In contrast to the decrease in Nae, Kt was found to be significantly increased after long-term treatment with prindolol. Kt values of patients before and after prindolol, however, did not differ significantly from the corresponding sex- and age-dependent normal values. 5. Plasma renin activity was slightly diminished under basal and orthostatic conditions; the stimulatory effect orthostatis was not abolished but reduced by prindolol. 6. It is suggested that the changes in sodium balance contribute to the anti-hypertensive effect of prindolol in patients with essential hypertension.

Plasma noradrenaline levels in regular haemodialysis patients.

Plasma concentrations of noradrenaline (NA), adrenaline (A) and renin (R) were measured in 29 regular haemodialysis patients (RHP) [13 normotensive, 10 hypertensive, 6 binephrectomised] and in 15 healthy control subjects (C) under various physiological conditions: supine-standing-walking. RHP had significant higher plasma levels of noradrenaline and adrenaline in the mean than C. All RHP responded to passive orthostasis with a significant increase in diastolic blood pressure, heart rate and plasma NA. In contrast to C, plasma NA did not drop after two hours of active orthostasis. Hypertensive RHP had significant higher plasma concentrations of R and A than normotensives. It is concluded that the sympathetic nervous system (SNS) plays a minor role in hypertensive blood pressure regulation of RHP. The adequate response to passive orthostasis in RHP with regard to diastolic blood pressure, heart rate and plasma NA indicates and intact function of the SNS under this condition. Hypertension in RHP not controllable by salt and volume depletion can be attributed to elevated levels of R, which in turn may stimulate adrenaline release from the adrenals. The mechanisms responsible for the elevated levels of circulating catecholamines remain unclear: an inhibition of re-uptake, disturbances in enzymatic metabolism or/and abolished renal clearance are suggested.

The effect of prindolol on plasma noradrenaline, plasma renin and sodium-potassium metabolism in patients with essential hypertension.

The chronic administration of prindolol in patients with essential hypertension resulted in the following: 1) a significant decrease in blood pressure and heart rate (with only the exception of the unchanged diastolic blood pressure after the stimulus of the seven-minute standing period), 2) a significant decrease of plasma noradrenaline concentrativn at rest and under orthostatic conditions, 3) a significant decrease of PRC at rest and an even more pronounced suppression of PRA after the stimulus of upright posture, 4)a significant decrease in total exchangeable sodium and 5) a concomitant significant increase in total body potassium even with an increase in body weight. These findings are not subject to easy interpretation. In particular, we cannot conclude which of the changed parameters plays the initial role in lowering blood pressure. A working hypothesis might presume that beta blocking agents inhibit central and/or peripheral sympathetic nervous activity. The results reduction in plasma renin concentration would in turn lead to a drop in aldosterone secretion rate indicated by the increase in potassium and decrease in sodiummour data would support such a sequence of events.

Decrease in plasma noradrenaline levels following long-term treatment with prindolol in patients with essential hypertension.

15 patients (4 females, 11 males, 21 to 55-year old) with mild to moderate essential hypertension (EH) were treated with placebo for two weeks and thereafter with increasing doses of prindolol (15 to 38 mg/day in the mean) and kept on a mean maintenance dosage of 32 mg/day for an average of 16 weeks in all. Blood pressure (BP), heart rate und plasma noradrenaline (PNA) concentrations were measured under standardized conditions (supine, standing, walking) at the end of two weeks on placebo and after the experimental treatment period. The results were compared to those of a group of 15 normotensive untreated control subjects (NS): after an average of 16 weeks on prindolol BP fell from 163/113 mm Hg to 129/91 mm Hg in the mean. PNA levels in EH before prindolol were significantly higher than in NS (supine: 272 +/- 22.0 ng/l (mean +/- SEM) vs. 135 +/- 15.1 ng/l, standing: 448 +/- 31.9 ng/l vs. 359 +/- 18.4 ng/l, walking: 388 +/- 22.5 ng/l vs. 234 +/- 22.1 ng/l). In EH chronic administration of prindolol led to a significant decrease in PNA concentrations under all the three test conditions to levels which did not differ significantly any more from those derived from NS. The adrenergic response to upright posture reflected in the percentage increase in PNA was significantly less in EH before prindolol when compared to the percentage increase in NS. On prindolol the adrenergic response was not abolidhed, yet it tended to approach the values found in NS. Before prindolol under resting conditions diastolic BP correlated closely with the corresponding PNA levels (p less than 0.01, r = 0.66, n = 15). This correlation could not be reestablished after prindolol treatment. The decrease in PNA after long-term treatment with prindolol was not correlated to the fall in blood pressure. The decrease in PNA indicates a lower activity of the sympathetic nervous system which may contribute to the antihypertensive effect of prindolol.

Plasma catecholamines in exercise induced bronchoconstriction.

Plasma nor-epinephrine (NE) and epinephrine (E) levels at rest and immediately after exercise were estimated in 8 patients with asymptomatic extrinsic allergic bronchial asthma. The patients had a normal airway resistance at rest and developed a marked bronchoconstriction (EIB) during exercise, which could be prevented by previous alpha-adrenergic blockade with phentolamine. In 7 control persons NE and E levels were measured also after beta-adrenergic blockade with propranolol. The following results were obtained: 1. At rest NE levels showed no significant differences between the groups. After exercise an increase of NE was observed in all groups, but in patients, even after phentolamine, and in normals after propranolol the increase was significantly higher than in the normal group within the control test. 2. No significant differences between the groups were found in E levels at rest and after exercise. Exercise caused no significant increase of E levels, except in the normals after propranolol application. 3. No significant correlation existed between NE levels and the increase of airway resistance after exercise. It is concluded that during exercise in asthmatics the sympathetic activity is enhanced, but the provocation of an EIB does not seem to be mediated by enhanced plasma NE levels.

Inhibitory effect of oral WEB 2086, a novel selective PAF-acether antagonist, on ex vivo platelet aggregation.

WEB 2086 is a novel PAF-acether antagonist, whose pharmacological action in man has only been preliminarily defined. Twelve healthy male volunteers received oral doses of 5, 30 and 90 mg and over the following 24 h inhibition of 5 x 10(-8) M PAF-acether-induced platelet aggregation ex vivo was studied as an indicator of pharmacological activity. WEB 2086 inhibited PAF-acether-induced platelet aggregation in all the doses tested, with the maximum effect 1 to 2 h after administration. After 2 h 5- 30- and 90-mg doses caused, respectively, 87, 98 and 100% inhibition. The magnitude and duration of the inhibitory effect was dose-dependent, with a significant action still detectable 10 h after administration of all three doses, and 12 h after administration of the two highest doses (30 and 90 mg). The subjects did not complain of any significant adverse effect and all completed the study.

Hormonal and metabolic parameters following insulin-induced hypoglycemia.

The present study was conducted in 12 healthy volunteers to determine the effect of porcine insulin (0.15 U/kg i.v.) on a number of different metabolic and hormonal parameters measured simultaneously. The nadir of blood glucose (19.0 +/- 2.7 ng/100 ml) is detected 30 min following insulin application, paralleled by suppressed levels of FFA and beta-hydroxybutyrate. The lowest level of potassium (3.39 +/- 0.09 mval/l) is observed 45 min following insulin application. The hormones of counterregulation show an uniform pattern of response. Peak levels of norepinephrine (228.9 +/- 36.0 ng/l) and epinephrine (720.6 +/- 125.6 ng/l) are observed at 30 and 45 min, those of cAMP (33.4 +/- 2.5 pmol/ml), glucagon (0.209 +/- 0.024 ng/ml), ACTH (166.0 +/- 40.1 ng/ml), and prolactin (28.1 +/- 7.8 ng/ml) at 45 min and finally those of cortisol (26.1 +/- 3.3 micrograms/100 ml) and growth hormone (21.6 +/- 3.1 ng/ml) at 60 min following insulin injection. As the blood glucose level is already rising after 30 min it is concluded that the catecholamines and glucagon play a major part in the restitution of normal blood glucose levels. At the end of the test, blood glucose and hormone levels have almost normalized, but FFA and beta-hydroxybutyrate levels are doubled and almost triplicated as compared to the starting point levels.

Differences in psychic performance with guanfacine and clonidine in normotensive subjects.

1. Doses of clonidine 0.15 mg or guanfacine 1.0 mg, respectively, and 2 h later additional doses of clonidine 0.3 mg or guanfacine 2.0 mg, respectively, were given to 24 healthy students. 2. Blood pressure was reduced by the same amount by both drugs. 3. Plasma noradrenaline concentrations decreased with both drugs, but the reduction was significantly greater following the administration of clonidine. 4. Mental activity in the EEG was less suppressed in the guanfacine group than in the clonidine group. The differences were statistically significant. 5. Self-estimations for well-being and mood showed only small changes due to guanfacine but significant changes due to clonidine. 6. The decrease of information processing and the increase in reaction time, measured by performance in different psychometric tests, were significantly more pronounced after clonidine treatment than guanfacine. 7. A dose-response relationship could only be observed in vigilosomnograms, in the tests of self-estimation related to well-being and mood and in the decrease in plasma noradrenaline in the clonidine group. 8. It was concluded that guanfacine had a lesser CNS depressant action than clonidine, when administered in equipotent hypotensive doses.

[Pramipexole in Parkinson disease. Results of a treatment observation]. / Pramipexol bei der Parkinson-Krankheit. Ergebnisse einer Anwendungsbeobachtung.

Pramipexole is a novel, internationally available selective nonergot D2 dopamine agonist. The effectiveness, tolerability, and safety of pramipexole have been extensively proven in controlled trials in patients in the early and advanced stage of Parkinson's disease as monotherapy and in combination with L dopa. These trials indicated specific activity against tremor, anhedonia, and depression. Therefore, the present prospective, multicenter postmarketing surveillance study evaluated for the first time to what extent the results from the controlled pramipexole trials could be replicated under routine conditions in neurological practice and clinics. Modern scales were applied for the assessment of tremor and mood, i.e., the Short Parkinson's Evaluation Scale (SPES), the Tremor Impact Scale (TIS), and the German version of the Snaith-Hamilton Pleasure Scale (SHAPS-D). In 298 German Centers, 657 Parkinson's patients (365 men, 292 women) in advanced disease stages were treated with pramipexole in combination with levodopa. The average ages (+/- SD) were 67 (+/- 8.9) years for men and 69 (+/- 9.4) years for females. Motor functioning, especially tremor, motor complications, depression, and activities of daily living improved highly significantly (P < 0.0005), including self-rating by the patients. The dosage of levodopa could be reduced on average by 8% (P < 0.0001). This might contribute to a slowing of the disease progression in the long run. Dropouts due to side effects were observed only in 3.5% of the patients. Using new assessment scales suitable for routine application allowed confirmation of the results from controlled clinical trials with regard to tremor, anhedonia, and depression. The average daily dosage of pramipexole prescribed was 1.05 mg and thus was definitely lower than the average daily dosages of 2.35-2.66 mg used in controlled trials. This signifies that the option to adjust dosage according to effectiveness and tolerability under routine conditions yields a considerably lower incidence of adverse effects.