Th. Philipp

SYMPATHETIC NERVOUS SYSTEM AND BLOOD-PRESSURE CONTROL IN ESSENTIAL HYPERTENSION

In normotensive subjects an inverse correlation was observed between an index of sympathetic nervous activity (the plasma-noradrenaline concentration during physical exercise) and reactivity to exogenous noradrenaline. This relationship was invariably disturbed in age-matched patients with essential hypertension. Multiple-regression analysis revealed a highly significant correlation between the combination of both factors and the height of mean arterial blood-pressure (r=0.91). The findings suggest that sympathetic nervous activity and pressor response to noradrenaline together form an important determinant of the arterial blood-pressure level. An inverse relationship could be demonstrated between plasma-renin concentration and pressor response to angiotensin II in normotensives, and this relationship was unchanged in hypertensive patients. Therefore angiotensin II does not appear to contribute directly to high blood-pressure.

Wertigkeit moderner Verfahren zur Lokalisation von Phäochromocytomen

In six patients with adrenal pheochromocytoma the tumors were localized by ultrasonography, phlebography of the adrenal glands and by estimation of plasma catecholamines selectively obtained from the vena cava and the adrenal gland veins. All tumors were localized by selective catecholamine estimation, five by ultrasonography, and four by phlebography. The smallest pheochromocytoma of 1.5 g weight was only localized by selective catecholamine estimation but not by ultrasonography or phlebography. This tumor, however, had been visualized by computed tomography. To avoid diagnostic errors by selective catecholamine estimation, it is important to withdraw blood from the adrenal gland veins prior to the injection of any radiographic contrast media, since this may result in an extremely enhanced secretion of catecholamines from the adrenal medulla.SummaryIn six patients with adrenal pheochromocytoma the tumors were localized by ultrasonography, phlebography of the adrenal glands and by estimation of plasma catecholamines selectively obtained from the vena cava and the adrenal gland veins. All tumors were localized by selective catecholamine estimation, five by ultrasonography, and four by phlebography. The smallest pheochromocytoma of 1.5 g weight was only localized by selective catecholamine estimation but not by ultrasonography or phlebography. This tumor, however, had been visualized by computed tomography.To avoid diagnostic errors by selective catecholamine estimation, it is important to withdraw blood from the adrenal gland veins prior to the injection of any radiographic contrast media, since this may result in an extremely enhanced secretion of catecholamines from the adrenal medulla.ZusammenfassungBei sechs Patienten mit adrenalem Phäochromocytom erfolgte die Lokalisationsdiagnostik durch Ultraschalluntersuchung, Phlebographie der Nebennieren und selektiver Katecholaminbestimmung im Blut der Vena cava sowie der Nebennierenvenen. Durch die selektive Katecholaminbestimmung konnten alle Phäochromocytome lokalisiert werden, durch die Ultraschalluntersuchung fünf, durch die Phlebographie vier. Ein Phäochromocytom von 1,5 g Gewicht, das nur durch die selektive Katecholaminbe-stimmung, nicht aber durch Ultraschall oder Phlebographie lokalisiert wurde, konnte computertomographisch dargestellt werden.Um Fehldiagnosen bei der selektiven Katecholaminbestimmung zu vermeiden, darf vor der Blutentnahme aus den Nebennierenvenen kein Röntgenkontrastmittel injiziert werden, da dies zu einer erheblichen Adrenalin- oder Noradrenalinfreisetzung aus dem Nebennierenmark führen kann.

Different effects of furosemide on alpha-adrenoceptors and on platelet aggregation in man

SummaryThe effect of a long-term administration of furosemide (2×30 mg/day for 3 weeks) on platelet α2-adrenoceptor density and the fraction of high-affinity binding sites, as well as on platelet aggregation induced by adrenaline and ADP, was studied ex vivo in 8 normotensive volunteers. For comparison the in vitro effect of furosemide on platelet aggregation was also evaluated. Furosemide decreased α2-adrenoceptor-density (P<0.01) and the fraction of high-affinity binding sites (P<0.05). Adrenaline-induced platelet aggregation was not altered ex vivo and in vitro. Furosemide inhibited ADP-induced platelet aggregation ex vivo (P<0.05) and in parallel in vitro (P<0.01) in a dose-dependent manner. The reduction of the density of α2-adrenoceptors in the high affinity state may be of functional importance for the hemodynamic effects of furosemide. The inhibitory effect of furosemide on ADP-induced platelet aggregation ex vivo and in vitro, which is not related to the effects on adrenoceptors, seems to involve direct effects of furosemide on platelet function. It remains to be seen whether the latter effect is of clinical importance.

Intrazelluläres freies Kalzium und Plasma-Kalzium bei Patienten mit essentieller Hypertonie

Alterations in intracellular free calcium regulation as well as disturbances of extracellular calcium homeostasis have been observed in patients with essential hypertension. It has been hypothesized that a generalized defect of calcium regulation might be of importance in the pathogenesis of essential hypertension. In one hypothesis a primary calcium-deficiency in essential hypertension has been linked to subsequent membrane instability and altered intracellular free calcium concentrations. We therefore investigated the relationship between intracellular free calcium concentrations in platelets and ionized as well as total plasma calcium in patients (n = 38) with essential hypertension and in age-matched normotensive subjects (n = 35). Intracellular free calcium in hypertensive patients was elevated by 13% (p less than 0.05) although there was a wide overlap between the values of the two groups. However, no difference with regard to the ionized or total plasma calcium concentrations could be observed. Total plasma calcium concentration, ionized plasma levels as well as intracellular free calcium were positively correlated (p less than 0.05) with mean arterial blood pressure. No correlation however was found between the extracellular and intracellular calcium compartments. We therefore could not observe a generalized defect of calcium regulation in essential hypertension, and extracellular calcium concentrations do not seem to be related to intracellular calcium derangement in this disease.(ABSTRACT TRUNCATED AT 250 WORDS)SummaryAlterations in intracellular free calcium regulation as well as disturbances of extracellular calcium homeostasis have been observed in patients with essential hypertension. It has been hypothesized that a generalized defect of calcium regulation might be of importance in the pathogenesis of essential hypertension. In one hypothesis a primary calcium-deficiency in essential hypertension has been linked to subsequent membrane instability and altered intracellular free calcium concentrations.We therefore investigated the relationship between intracellular free calcium concentrations in platelets and ionized as well as total plasma calcium in patients (n=38) with essential hypertension and in age-matched normotensive subjects (n=35). Intracellular free calcium in hypertensive patients was elevated by 13% (p<0.05) although there was a wide overlap between the values of the two groups. However, no difference with regard to the ionized or total plasma calcium concentrations could be observed. Total plasma calcium concentration, ionized plasma levels as well as intracellular free calcium were positively correlated (p<0.05) with mean arterial blood pressure. No correlation however was found between the extracellular and intracellular calcium compartments.We therefore could not observe a generalized defect of calcium regulation in essential hypertension, and extracellular calcium concentrations do not seem to be related to intracellular calcium derangement in this disease. Furthermore, we can conclude from our data that there is no evidence for the so-called calcium deficiency hypothesis in patients with essential hypertension.

Sympathetic nervous activity and the pressor effect of noradrenaline under chronicα-β-adrenoceptor blockade with labetalol in hypertension

SummaryIn 14 patients with essential hypertension, the influence of theα- andβ-adrenoceptor blocking drug labetalol on blood pressure, heart rate, plasma renin, plasma noradrenaline and pressor effect of exogenous noradrenaline was investigated during long-term treatment. During the initial four weeks of treatment, labetalol at a dose of 400 mg/day showed a slight effect only on supine blood pressure, whereas upright blood pressure was already lowered effectively after the second week of treatment (p<0.01). An increase in the mean dose to 850 mg/day had an additional blood pressure-lowering effect (p<0.001), whereby a preferential decrease of the orthostatic blood pressure was no longer apparent. Further increase in the mean dose to 1,000 mg/day at the end of the 12th week did not have an additional blood pressure-lowering effect. Body weight, plasma renin and plasma noradrenaline remained unchanged on labetalol treatment in the lowest and the highest dose. There was, however, an increased pressor effect of exogenous noradrenaline, i.e. anα-adrenoceptor antagonistic effect of labetalol was not detectable under these conditions. The cause of the increased pressor effect was a reduced climination of noradrenaline from plasma, which is probably the consequence of an inhibition of the uptake1 process by labetalol. During long-term treatment with the doses administered, the blood pressure-lowering effect of labetalol appears essentially to be the expression of theβ-adrenoceptor blocking properties of the drug.

Kreislaufreaktionen bei Patienten mit primärem Aldosteronismus

Summary1. In 7 patients with hypertension, aldosteronism, and low plasma renin (6 patients with a solitary adrenal adenoma, 1 patient with bilateral adrenal hyperplasia) circulatory reflexes (Valsalvas maneuver, head-up tilt and cold pressure test) were examined. Furthermore, the reactivity to the pressor action of tyramine and norepinephrine was determined. For comparison 10 patients with essential hypertension were studied.2. In 4 of the 7 patients with primary aldosteronism no overshoot following Valsalvas maneuver could be observed. Compared to the patients with essential hypertension the mean overshoot in the patients with primary aldosteronism was significantly reduced. The decrease in blood pressure during head-up tilt was significantly more pronounced in the patients with primary aldosteronism. However, both groups did not differ in their reaction to the cold pressure test. In the patients with primary aldosteronism responsiveness to tyramine was significantly reduced compared to the patients with essential hypertension. No significant difference was observed in the reactivity to norepinephrine between both groups studied.3. The results point towards a disturbance of the sympathetic nervous system in patients with primary aldosteronism.Zusammenfassung1. Bei 7 Patienten mit arterieller Hypertonie, Aldosteronismus und niedrigem Plasmarenin (6 Patienten mit solitärem Nebennierenrindenadenom, 1 Patient mit mikronodulärer Nebennierenrindenhyperplasie) wurden die Kreislaufreaktionen auf den Valsalva-Versuch, auf passive Orthostase und auf den Eiswasserversuch geprüft. Darüber hinaus wurde die Reaktion des Blutdruckes auf Tyramin und Noradrenalin bestimmt. Als Vergleichsgruppe dienten 10 Patienten mit essentieller Hypertonie.2. Bei 4 der 7 Patienten mit primärem Aldosteronismus war kein overshoot nach Valsalva-Versuch nachweisbar. Im Durchschnitt war das Ausmaß des postpressorischen overshoot bei Patienten mit primärem Aldosteronismus signifikant geringer als bei Patienten mit essentieller Hypertonie. Der Abfall des mittleren arteriellen Druckes während der 15 minütigen passiven Orthostase war bei den Patienten mit primärem Aldosteronismus signifikant stärker als bei den Patienten mit essentieller Hypertonie. Ein Unterschied in der Blutdruck reaktion auf den Eiswasserversuch konnte dagegen zwischen beiden Gruppen nicht festgestellt werden. Die pressorische Wirkung von Tyramin war bei den Patienten mit primärem Aldosteronismus im Vergleich zu den Patienten mit essentieller Hypertonie signifikant geringer. In der Empfindlichkeit gegenüber Noradrenalin unterschieden sich beide Gruppen nicht signifikant.3. Die Befunde sprechen für eine nicht näher zu lokalisierende Störung der Sympathikusfunktion bei Patienten mit primärem Aldosteronismus.

[Haemodynamic studies on the blood pressure-raising effect of mineralocorticoids (author's transl)].

SummaryThe effects on systemic haemodynamics of long-term administration of high mineralocorticoid doses were studied in six healthy volunteers. The subjects received the synthetic steroid fludrocortisone in a daily oral dose of 0.8 mg. Central venous and arterial pressures were recorded directly, and cardiac output was determined by dye dilution method before as well as after 1 and 6 weeks of steroid application.Within the first week of steroid administration, mean arterial pressure rose by 5.6±4.6 (±S.D.) mm Hg (p<0.025). Body weight increased by 2.5±1.1 kg (p<0.01), and central venous pressure by 1.3±1.4 mm Hg (p<0.05). An increase in cardiac index was observed in all subjects, the average increase was 0.72±0.47 l/min·m2 (p<0.01). Heart rate decreased.After the 6th week of steroid administration, blood pressure had risen in all subjects, the average increase in mean arterial pressure was 17.8±6.0 mm Hg (p<0.001). This pressure rise was the consequence of an increase in total peripheral resistance by 267±125 dyn·cm−5·s (p<0.01) on the average. At that time cardiac index was even lower than at the first study in five of the six subjects. Compared to the second study, heart rate had decreased further, central venous pressure had increased further, and body weight had not changed significantly.The data show that the mineralocorticoid-induced blood pressure rise is initially due to an increase in cardiac output and in its chronic phase due to an elevated peripheral resistance. The mechanism of the increase in peripheral resistance remains unclear.ZusammenfassungBei 6 gesunden freiwilligen Probanden wurde der Einfluß einer längerfristigen hochdosierten Mineralocorticoid-Applikation auf die Hämodynamik untersucht. Die Versuchspersonen erhielten das synthetische Mineralocorticoid 9α-Fluorhydrocortison in einer Dosierung von 0,8 mg p.o. täglich. Vor der Gabe des Steroids sowie nach 1- und 6wöchiger Steroidbehandlung wurden der zentrale Venendruck und der arterielle Blutdruck direkt gemessen, das Herzzeitvolumen wurde mittels Farbstoffverdünnungsmethode bestimmt.Innerhalb der 1. Woche der Mineralocorticoid-Einnahme stieg der arterielle Mitteldruck um durchschnittlich 5,6±4,6 mm Hg (±S.D.) (p<0,025) an. Das Körpergewicht stieg um durchschnittlich 2,5±1,1 kg (p<0,01), der zentrale Venendruck um 1,3±1,4 mm Hg (p<0,05). Bei allen Versuchspersonen kam es zu einer Zunahme des Herzzeitvolumens, die im Durchschnitt 0,72±0,47 l/min×m2 (p<0,01) betrug. Die Herzfrequenz nahm ab.Nach der 6. Woche der Steroidgabe war der Blutdruck bei allen Probanden deutlich angestiegen, der durchschnittliche Anstieg des arteriellen Mitteldrucks betrug 17,8±6,0 mm Hg (p<0,001). Dieser Druckanstieg war die Folge einer Erhöhung des peripheren Gesamtwiderstands um durchschnittlich 267±125 dyn·cm−5·s (p<0,01). Das Herzzeitvolumen lag zu diesem Zeitpunkt bei 5 der 6 Probanden sogar niedriger als bei der ersten Untersuchung. Gegenüber der 1. Woche zeigte die Herzfrequenz eine weitere Abnahme, der zentrale Venendruck einen weiteren Anstieg, das Körpergewicht dagegen keine sichere Veränderung.Die Untersuchungen zeigen, daß der mineralocorticoid-induzierte Blutdruckanstieg initial Folge eines erhöhten Herzzeitvolumens, in der chronischen Phase Folge einer Erhöhung des peripheren Widerstands ist. Der Mechanismus des Widerstandsanstiegs bleibt unklar.

Einfluß des Angiotensin II-Antagonisten Saralasin auf die Hämodynamik bei Patienten mit renovaskulärer Hypertonie

SummaryIn 7 hypertensive patients with renal artery stenosis and in 1 patient with hypertension and unilateral pyelonephritic nephrophthisis the influence of the angiotensin II antagonist, saralasin on systemic hemodynamics was studied. In the patients with normal renin infusion of saralasin produced an increase in total peripheral resistance, in patients with elevated renin a decrease in peripheral resistance was observed. In 3 patients who had extremely high renin levels while under sodium depletion saralasin produced a dangerous drop in blood pressure concomitant with a marked decrease in cardiac output and in central venous pressure, heart rate remained unchanged or increased just slightly. The findings suggest that in patients with high plasma renin peripheral resistance, venous tone, venous return, and cardiac output are to a large extent controlled by circulating angiotensin II.ZusammenfassungBei 7 Patienten mit Hypertonie bei einseitiger Nierenarterienstenose sowie einem Patienten mit Hypertonie bei einseitiger pyelonephritischer Schrumpfniere wurde der Einfluß des Angiotensin II-Antagonisten Saralasin auf die Hämodynamik untersucht. Die Infusion von Saralasin führte bei Patienten mit normalem Plasmarenin zu einer Erhöhung des peripheren Gesamtwiderstands, bei erhöhtem Renin zu einer Widerstandsabnahme. Bei extrem erhöhten Reninwerten, die bei 3 Patienten unter forcierter Kochsalzverarmung beobachtet wurden, führte Saralasin zu einem bedrohlichen Blutdruckabfall mit zusätzlicher starker Verminderung des Herzminutenvolumens und des zentralvenösen Drucks; die Herzfrequenz stieg dabei entweder nicht oder nur geringfügig an. Die Befunde sprechen dafür, daß bei Patienten mit hohem Plasmareninspiegel der periphere Gesamtwiderstand, der Venentonus und damit der venöse Rückstrom zum Herzen und das Herzzeitvolumen wesentlich vom zirkulierenden Angiotensin II reguliert wird.In 7 hypertensive patients with renal artery stenosis and in 1 patient with hypertension and unilateral pyelonephritic nephrophthisi the influence of the angiotensin II antagonist, saralasin on systemic hemodynamics was studied. In the patients with normal renin infusion of saralasin produced an increase in total peripheral resistance, in patients with elevated renin a decrease in peripheral resistance was observed. In 3 patients who had extremely high renin levels while under sodium saralasin produced a dangerous drop in blood pressure concomitant with a marked decrease in cardiac output and in central venous pressure, heart rate remained unchanged or increased just slightly. The findings suggest that in patients with high plasma renin peripheral resistance, venous tone, venous retrun, and cardiac output are to a large extent controlled by circulating angiotensin II.

Untersuchungen zur Pathogenese des Hochdrucks bei primärem Aldosteronismus

Bisher liegen nur vereinzelte Mitteilungen uber hamodynamische Untersuchungen bei Patienten mit primarem Aldosteronismus vor [1, 2]. Bei den beschriebenen Fallen war der Hochdruck durch eine Erhohung des peripheren Gesamtwiderstands bedingt, wahrend Schlag- und Herzzeitvolumen im Normbereich lagen.

Sekretion, Verteilung und Abbau von Aldosteron bei verschiedenen Hochdruckformen

SummaryThe secretion rate (SR) and metabolic clearance rate (MCR) of aldosterone were assessed in 11 normotensive control subjects, in 11 patients with mild essential hypertension, in 5 showing advanced essential hypertension, in 5 with primary aldosteronism, and in 13 with hypertension associated with renal artery stenosis. The following determinants of the metabolic clearance rate were computed together with MCR fromA,B, α, andβ, the constants of the3H-aldosterone plasma concentration—time—function resulting after i.v. injection of3H-aldosterone: The rate constantsK1 andK2 for distribution and turnover of aldosterone, the apparent volumes of distributionV1 andV2, the equilibrium timeteq, and the biological half-timet1/2. In addition, mean plasma concentration of aldosterone (mPC) and mean body pool of miscible aldosterone (mmP) were calculated.SR, mPC and mmP were slightly increased in most cases with mild essential hypertension, and significantly increased in advanced essential hypertension, in primary aldosteronism and in hypertension associated with renal artery stenosis. None of the groups of hypertensive patients differed significantly from the control group with regard toA,B, α,β,K1,K2,V1,V2,teq,t1/2, and MCR.These results suggest that hyperaldosteronaemia and increased quantities of miscible aldosterone in the types of hypertension studied are due to increased aldosterone secretion, while distribution and turnover of the hormone remain unchanged.ZusammenfassungBei 11 normotensiven Kontrollpersonen, 11 Patienten mit milder essentieller Hypertonie, 5 Patienten mit fortgeschrittener essentieller Hypertonie, 5 Patienten mit primärem Aldosteronismus und 13 Patienten mit Hypertonie in Verbindung mit Nierenarterienstenose wurde die Sekretionsrate (SR) und die metabolische Clearancerate (MCR) von Aldosteron bestimmt. Folgende Determinanten der metabolischen Clearancerate wurden zusammen mit MCR ausA,B, α, undβ, den Konstanten der3H-Aldosteronplasmakonzentration-Zeit-Funktion nach i.v. Injektion von3H-Aldosteron, berechnet: Die GeschwindigkeitskonstantenK1 undK2 für die Verteilung und den Abbau des Aldosterons, die virtuellen VerteilungsvoluminaV1 undV2, die Äquilibriumzeitteq und die biologische Halbwertszeitt1/2. Zusätzlich wurden die mittlere Aldosteronplasmakonzentration (mPC) und die mittlere Gesamtmenge austauschbaren Aldosterons (mmP) berechnet.SR, mPC und mmP waren leicht erhöht in den meisten Fällen von milder essentieller Hypertonie und signifikant erhöht bei fortgeschrittener essentieller Hypertonie, bei primärem Aldosteronismus und bei Hypertonie mit Nierenarterienstenose. HinsichtlichA,B,α,β,K1,K2,V1,V2,teq,t1/2 und MCR war für keine der vier Gruppen von Hochdruckpatienten ein signifikanter Unterschied zur Kontrollgruppe nachzuweisen.Die Ergebnisse erlauben die Schlußfolgerung, daß die Hyperaldosteronämie mit erhöhter Gesamtmenge austauschbaren Aldosterons bei den untersuchten Hochdruckformen aus der erhöhten Aldosteronsekretion resultiert, während Verteilung und Abbau des Hormones unverändert bleiben.