G. Wambach

Evidence for a subgroup of essential hypertensives with non-suppressible excretion of aldosterone during sodium loading.

ZusammenfassungBei Patienten mit essentieller Hypertonie Grad I und II fand sich unter Salzbelastungsbedingungen (Natrium-Exkretion über 175 mval·d−1) eine bimodale Verteilung der Aldosteron-Exkretion, aufgrund welcher zwei Patientengruppen unterschieden wurden: Beim größeren Teil der Patienten mit essentieller Hypertonie führte die Salzbelastung zu einer Suppression der Aldosteron-Exkretion unter 6 µ·d−1, dem höchsten Kontrollwert unter Salzbelastung, im Durchschnitt zu 2,7±1,4 (SD) µg·d−1. Trotz ausgeprägter Salzbelastung über 6 Tage war die Aldosteron-Exkretion bei einer zweiten Gruppe nicht unter 6 µg·d−1 supprimierbar mit einer durchschnittlichen Aldosteron-Exkretion von 10,0±3,0 (SD) µg·d−1. Unter Salzentzug, freier Salzzufuhr oder Salzbelastung war die Aldosteron-Exkretion der ersten Gruppe der der Kontrollpersonen vergleichbar, während bei der zweiten Gruppe der essentiellen Hypertoniker die Korrelation zwischen Aldosteron-Exkretion und Log Natrium-Exkretion oder Log Natrium/Kalium-Quotient im 24 h-Urin (r=−0,59) deutlich unter der der Kontrollpersonen (r=−0.87) lag. Die Serum-Kalium-Konzentration unter Salzbelastung der zweiten Hypertonikergruppe mit nicht supprimierbarer Aldosteron-Exkretion war signifikant (p<0,001) niedriger (3,81±0,44 mval·l−1) als bei den übrigen Hypertonikern mit supprimierbarer Aldosteron-Exkretion (4,26±0,37 mval·l−1). Die Blutdrucksenkung unter 200 mg Spironolacton täglich war bei den Patienten mit nicht supprimierbarer Aldosteron-Exkretion signifikant (p<0,05) besser als beim Rest der Patienten. Die Plasmareninaktivität beider Gruppen war noch nicht signifikant unterschiedlich, zeigt jedoch eine Tendenz zu niedrigeren Werten in der Gruppe mit nicht supprimierbarer Aldosteron-Exkretion.SummaryIn patients with grade I and II essential hypertension studied during sodium loading (Na+ excretion above 175 meq·d−1) we found a bimodal behaviour of aldosterone excretion and could distinguish two groups of patients: In the major part of essential hypertensives sodium loading led to a suppression of aldosterone excretion below 6 µg·d−1, which is the highest control value during sodium loading, with an average of 2.7±1.4 (SD) µg·d−1. Aldosterone excretion in a second group of patients was not suppressible below 6 µg·d−1 despite forced sodium loading; it resulted in an average value of 10.0±3.0 (SD) µg·d−1. During sodium deprivation or free sodium intake, aldosterone excretion in the first group of patients followed exactly the behaviour of normotensive controls, while in the second group of essential hypertensives the correlation of aldosterone excretion and log. Na excretion or log. Na+/K+ ratio in 24 h urine (r=−0.59) was far below the control value ofr=−0.87. Serum potassium concentration during sodium loading was significantly (p<0.001) lower (3.81±0.44 meq·l−1) in the essential hypertensives with non-suppressible aldosterone excretion compared to those with suppressible aldosterone excretion (4.26±0.37 meq·l−1). The blood pressure response to treatment with 200 mg spironolactone·d−1 was better (p<0.05) in patients with non-suppressible aldosterone excretion compared to the essential hypertensives with normal aldosterone regulation. The plasma renin activity of both groups of patients was not significantly different, however, a tendency prevailed towards lower PRA-values in the patient group with non-suppressible aldosterone excretion during sodium loading.

Insulin Attenuates Vasoconstriction by Noradrenaline, Serotonin and Potassium Chloride in Rat Mesenteric Arterioles

We investigated the effect of insulin on the vascular reactivity to noradrenaline, serotonin and potassium chloride in rat mesenteric resistance arterioles in vitro. Mesenteric artery segments were placed in a myograph system. Sensitivity to noradrenaline, serotonin and KCl was tested after an equilibration at 37 degrees C. Thereafter, arteries were incubated with buffer alone or with insulin (40, 100, 250 and 400 mU/ml) for one hour at 37 degrees C. Sensitivity to the three vasoconstrictors was retested. Incubation with noradrenaline, serotonin and KCl resulted in a dose dependent increase in wall force. Exposure with buffer did not change the shape of the dose-response-curve. The same was true for the lowest dose of insulin (40 mU/ml). However, incubation with insulin at concentrations of 100, 250 and 400 mU/ml led to a reduction in wall force by 37-77%. The reduction in the slope of the curve and the maximal response suggest a non-competitive inhibition. Supraphysiological doses of insulin attenuate the vasoconstriction by noradrenaline, serotonin and KCl in rat mesenteric arteries in vitro.

Plasma levels of atrial natriuretic peptide are raised in essential hypertension during low and high sodium intake.

SummaryPlasma levels of α-human atrial natriuretic peptide (hANP) were measured in 17 patients with primary hypertension (11 females, 6 males, aged 22–61; blood pressure systolic 154±7 mmHg, diastolic 92±4 mmHg) and in 9 normotensive controls (4 males, 5 females, aged 20–71; blood pressure systolic 117±4 mmHg, diastolic 76±2 mmHg) during unrestricted sodium diet, at the 4th day of a low sodium intake (40–60 mEq/day) and at the 6th day of sodium loading (280–320 mEq/day) both after an overnight rest and after 4 h of upright posture. In the controls, plasma levels of hANP at 8:00 a.m. were lowered from 73±11 to 49±7 pg/ml during low sodium diet and increased to 128±37 pg/ml after high salt intake. Plasma ANP levels were significantly lower after 4 h of upright posture during unrestricted, low and high sodium intake. In the hypertensive group, plasma ANP levels were elevated during unrestricted diet (203±43 pg/ml), during the low sodium period (139±31 pg/ml), and after high sodium intake (267±63 pg/ml) compared to the controls. All levels were lowered by upright posture. The absolute decrease was more pronounced compared to the normotensives, the relative decline was similar in both groups. In the hypertensives, plasma ANP levels significantly correlate with systolic and diastolic blood pressure (r=0.468,r=0.448,P<0.05) and with urinary aldosterone during unrestricted diet (r=0.536,P<0.05). There was an inverse correlation between plasma ANP levels and plasma renin concentration during low and high sodium intake (r=−0.469,r=−0.496,P<0.05).These studies demonstrate raised circulating plasma ANP levels in patients with essential hypertension. The modulation of ANP by different sodium intake and by upright posture is maintained similar to the changes in plasma ANP in normotensive controls. Raised ANP levels in the hypertensives are correlated with low renin secretion and high aldosterone excretion. High ANP levels, therefore, might indicate sodium retention in essential hypertension.

Interference of different ACE-inhibitors with the diuretic action of furosemide and hydrochlorothiazide

SummaryIn healthy volunteers the acute effect of furosemide (40 mg i.v.) and hydrochlorothiazide (100 mg p.o.) on diuresis, natriuresis and renal kallikrein and kinin excretion was investigated. Furosemide stimulated markedly diuresis and natriuresis as well as urinary kallikrein and kinin excretion. Pretreatment by captopril (C) reduced the diuretic and natriuretic effect of furosemide significantly probably due to a diminished (about 50%) proximal-tubular secretion of furosemide. Captopril did not alter significantly the furosemide induced changes in urinary kallikrein and kinin excretion. After captopril there was a clear dissociation between aldosterone, which was diminished by captopril continuously, and renal kallikrein and kinins, which were still stimulated by furosemide. These results suggest that renal kallikrein-kinin system is stimulated by furosemide directly and independently of aldosterone secretion. Other ACE-inhibitors like ramipril (5 mg) or enalapril (20 mg) did not influence the stimulatory effects of furosemide on diuresis or kallikrein-kinin excretion. Ramipril at a dose of 10 mg, however, enhanced the initial diuretic effect of furosemide by increased furosemide secretion and increased relative sodium excretion. Hydrochlorothiazide induced a prolonged diuresis which was not changed by either captopril or ramipril. Urinary kallikrein excretion was not stimulated by hydrochlorothiazide. Our results show an important drug interference between captopril and furosemide, which is independent of ACE-inhibition and probably only due to an interference in proximal-tubular secretion of both drugs. Between captopril and hydrochlorothiazide no such interaction could be observed.

Na-K-atpase in Erythrocyte Ghosts is not a Marker for Primary Hypertension

In search for a diagnostic marker for essential hypertension, we investigated the activity of the ouabain sensitive Na-K-ATPase and the ouabain insensitive ATPase in erythrocyte ghosts of 57 patients with essential hypertension, 12 patients with renal hypertension, 6 patients with Cushings syndrome and 4 patients with primary hyperaldosteronism. Na-K-ATPase-activity was increased in patients with essential hypertension and in patients with renal hypertension compared with controls with a considerable overlap. Na-K-ATPase-activity was increased in all patients with Cushings syndrome but was not different from the control group in patients with Conns syndrome. Ouabain-insensitive ATPase-activity was similar in all patients and in normotensive controls. The serum of patients with essential hypertension did not exhibit an ouabain-like ATPase-inhibiting activity when incubated with erythrocyte ghosts of normotensive controls. In our hands, determination of the Na-K-ATPase-activity in erythrocyte ghosts cannot be used as a diagnostic marker for essential hypertension.

Increased activity of the Na-K-ATPase in red cell-ghosts of patients with Cushing's Syndrome: Possible significance for the pathogenesis of glucocorticoid-induced hypertension

ZusammenfassungBei 6 Patienten mit Cushing-Syndrom fand sich eine 3–4fach gesteigerte Aktivität der Na-K-ATPase in Erythrocytenmembranen im Vergleich zu 28 Kontrollpersonen (0.986±0.291 gegenüber 0.259±0.1 µM Pi·h−1·mg−1,p<0.001). Die Strophan-thininsensible Mg-ATPase war bei beiden Gruppen gleich. Der Befund spricht für eine Aktivierung der Natriumpumpe an den Zellmembranen von Patienten mit Glukokortikoidexceß.SummaryThe Na-K-ATPase activity of erythrocyte ghosts was increased in 6 patients with Cushings syndrome compared with 28 control subjects (0.986±0.291 versus 0.259±0.1 µM Pi·h−1·mg−1,p<0.001). Ouabain insensitive Mg-ATPase activity was similar in both groups. These data support the concept of an activation of the Na-pump in patients with glucocorticoid excess.

Acid- and cryoactivation of renin in human plasma.

ZusammenfassungInaktives Renin in Normalplasmen wurde durch Kälte- (Inkubation bei 0° C/−5°C bis zu drei Monaten) oder Säureeinwirkung (Dialyse gegen pH 3,0 über 48 h, Rückdialyse gegen pH 7,5 über 24 h) aktiviert. Es fand sich kein signifikanter Unterschied der Plasma-Renin-Konzentration (PRC) nach beiden Aktivierungsverfahren. Maximal kälteaktiviertes Renin zeigte keinen weiteren signifikanten Anstieg durch Säureaktivierung. Die Ergebnisse zeigen, daß eine vollständige Reninaktivierung durch Optimierung der Methodik erreicht werden kann. Der Begriff „total renin“ für die Ergebnisse der PRC-Bestimmung nach Aktivierung scheint unter den hier gegebenen Bedingungen berechtigt.SummaryInactive renin in normal human plasma was activated in vitro either by cryoactivation (incubation at 0° C/−5° C up to 3 months) or acid-activation (dialysis to pH 3.0 for 48 h followed by dialysis to pH 7.5). Plasma-renin-concentration was similar after either activation procedure (96±50µU/ml vs 100±43µU/ml). There was no further significant acid-activable renin after cryoactivation. These data suggest that conversion of inactive to active renin by optimized procedures is complete. The term „total renin“ for activation results under these conditions seems to be valid.

Aldosteronexkretion von Patienten mit essentieller Hypertonie nach unterschiedlicher Natriumbelastung

SummaryIn patients with benign essential hypertension we could demonstrate a defect in aldosterone regulation: In 55% of the hypertensive patients studied the stimulation of aldosterone excretion by sodium deficiency was less marked and in 45% of the patients, the suppressibility of aldosterone excretion by sodium loading was incomplete compared with controls. The regulatory defect of the hypertensive patients is less pronounced in patients with first grade hypertension than in those with second grade hypertension and can be best demonstrated in patients with suppressed plasma-renin activity. In the latter, considerable changes of sodium intake did induce only minor changes of aldosterone excretion. Patients with incomplete suppression of aldosterone excretion had a significantly lower serum potassium concentration during sodium loading compared with the rest of the hypertensive subjects. All patients with suppressed plasma renin activity, except one, also belonged to this group of essential hypertensives.ZusammenfassungBei Patienten mit benigner essentieller Hypertonie konnte eine Regulationsstörung der Aldosteronexkretion nachgewiesen werden: 55% der Patienten zeigten im Vergleich mit Kontrollpersonen eine eingeschränkte Stimulationsfähigkeit der Aldosteronexkretion nach Natriumverarmung und 45% eine unvollständige Supprimierbarkeit der Aldosteronexkretion nach Natriumbelastung. Die Regulationsstörung der Aldosteronexkretion in Abhängigkeit von der Natriumzufuhr ist bei Hypertonikern 2. Grades deutlicher ausgeprägt als bei Hypertonikern 1. Grades und ist am stärksten bei Patienten mit supprimierter Plasmareninaktivität zu beobachten. Große Änderungen der Natriumzufuhr bedingen bei diesen Patienten in der Regel nur geringe Schwankungen der Aldosteronexkretion. Die mangelhafte Supprimierbarkeit der Aldosteronexkretion scheint Auswirkungen im Sinne eines Hyperaldosteronismus zu haben: Patienten mit unvollständiger Suppression der Aldosteronexkretion wiesen nach Natriumbelastung eine signifikant niedrigere Serumkaliumkonzentration auf. Außerdem gehören zu dieser Gruppe mit einer Ausnahme alle Patienten mit supprimierter Plasmareninaktivität.

Effect of bradykinin on systemic and pulmonary hemodynamics in the human

SummaryIn our studies we investigated the vasodepressor effects of bradykinin in vivo in normotensive and hypertensive subjects. Bradykinin was injected intravenously and intraarterially (40–6050 pM/kg) respectively was infused intraarterially (40–6050 pM/kg/min). The investigations were performed in 21 normotensives and 15 hypertensives. Bradykinin injections were performed after the following pharmacological interventions: salt restriction (10 mmol Na/d), salt loading (300 mmol Na/d), captopril (50 mg), ramipril (5 mg), lisinopril (20 mg), ketotifen (2×1 mg), indomethacin (2×50 mg), and propranolol (80 mg).The results show that bradykinin lowers blood pressure dose related by marked reduction in peripheral vascular resistance. The blood pressure reduction was strongly correlated with the increase in kinin concentration. This effect of bradykinin appears to be independent of changes in sodium metabolism, of betaadrenoceptors, of histamin-1 receptors, and of prostaglandins. ACE-inhibitors potentiate the blood pressure lowering effect of bradykinin about 20- to 50-fold. In case of an intraarterial injection of bradykin in only 2–5% of the intravenously used dose of bradykinin are needed to produce an identical fall in blood pressure. From this experiments a pulmonary clearance rate of bradykinin over 95% can be calculated. In the pulmonary arteries bradykinin has no effect on the vascular resistance.In patients suffering from primary or renovascular hypertension the blood pressure response to bradykinin was enhanced. The bradykinin potentiating effect of the ACE-inhibitors was not altered in the hypertensives. In patients suffering from borderline hypertension or primary hyperaldosteronism bradykinin developed the same blood pressure lowering effect as in the normotensives.In our studies we investigated the vasodepressor effects of bradykinin in vivo in normotensive and hypertensive subjects. Bradykinin was injected intravenously and intraarterially (40-6050 pM/kg) respectively was infused intraarterially (40-6050 pM/kg/min). The investigations were performed in 21 normotensives and 15 hypertensives. Bradykinin injections were performed after the following pharmacological interventions: salt restriction (10 mmol Na/d), salt loading (300 mmol Na/d), captopril (50 mg), ramipril (5 mg), lisinopril (20 mg), ketotifen (2 x 1 mg), indomethacin (2 x 50 mg), and propranolol (80 mg). The results show that bradykinin lowers blood pressure dose related by marked reduction in peripheral vascular resistance. The blood pressure reduction was strongly correlated with the increase in kinin concentration. This effect of bradykinin appears to be independent of changes in sodium metabolism, of beta adrenoceptors, of histamine-1 receptors, and of prostaglandins. ACE-inhibitors potentiate the blood pressure lowering effect of bradykinin about 20- to 50-fold. In case of an intraarterial injection of bradykinin in only 2-5% o the intravenously used dose of bradykinin are needed to produce an identical fall in blood pressure. From this experiments a pulmonary clearance rate of bradykinin over 95% can be calculated. In the pulmonary arteries bradykinin has no effect on the vascular resistance. In patients suffering from primary or renovascular hypertension the blood pressure response to bradykinin was enhanced. The bradykinin potentiating effect of the ACE-inhibitors was not altered in the hypertensives. In patients suffering from bradykinin hypertension or primary hyperaldosteronism bradykinin developed the same blood pressure lowering effect as in the normotensives.

Characterization of a group of essential hypertensives with impaired regulation of aldosterone.

The pattern of aldosterone excretion during high sodium intake in 100 patients with essential hypertension allowed the differentiation of two groups: in the majority of patients (group A, n = 64) aldosterone excretion was suppressed below 6 micrograms/day similar to the normotensive control group. In a second group (group B, n = 36), aldosterone remained above the control range despite forced sodium loading. In group B, serum potassium was significantly lower than in patients of group A (3.81 +/- 0.44 meq/l vs. 4.26 +/- 0.57 meq/l, p less than 0.001). The blood pressure lowering effect of spironolactone (200 mg/d) was more pronounced among patients in group B. Plasma renin values tended to be lower in group B compared to patients with suppressed aldosterone. Infusion of Angiotensin II (0.1 - 2 micrograms/kg/min) led to a similar relative rise of plasma aldosterone levels in both groups despite higher baseline values in group B. The exact mechanism of the impaired regulation of aldosterone in a subgroup of patients with essential hypertension remains to be elucidated.