R. Kolloch

HYPERPROLACTINÆMIA AND ANTIHYPERTENSIVE EFFECT OF BROMOCRIPTINE IN ESSENTIAL HYPERTENSION: Identification of Abnormal Central Dopamine Control

Plasma-prolactin concentration was up to four times higher in male patients with essential hypertension than in normotensive controls. Oral administration of bromocriptine, a dopaminergic agonist, suppressed plasma-prolactin and lowered arterial pressure. It is proposed that in the hypertensive patients the raised prolactin levels reflect a defect in central dopamine control which is normalised by bromocriptine. The antihypertensive effect of bromocriptine suggests that the dopaminergic system is involved in blood-pressure regulation and that reduced central dopaminergic activity may be a factor in the maintenance of essential hypertension.

Decreased urinary kallikrein activity and elevated blood pressure normalized by orally applied kallikrein in essential hypertension

ZusammenfassungPatienten mit essentieller Hypertension schieden signifikant weniger Kallikrein im Urin (0,48±0,05 EU/24 h) aus als normotensive Kontrollpersonen (1,26±0,14 EU/24 h). Eine 8wöchige Therapie mit oralem Schweinepankreas-Kallikrein normalisierte die verminderte Kallikreinausscheidung und führte zu einer signifikanten Blutdrucksenkung. Der durch die Behandlung induzierte Anstieg der renalen Kallikreinexkretion war Folge einer vermehrten endogenen Freisetzung des Enzyms, wie mit Hilfe eines spezifischen Radioimmunoassays festgestellt werden konnte. Es ist denkbar, daß die bei den hypertensiven Patienten nachgewiesene verminderte Kallikreinausscheidung einen Defekt in der Bildung von endogenem renalen Kallikrein reflektiert, der durch die orale Kallikrein-Therapie behoben wurde. Die blutdrucksenkende Wirkung von oralem Kallikrein sowie der stimulierende Effekt des Enzyms auf die renale Kallikreinfreisetzung lassen vermuten, daß das Kallikrein-Kinin System an der Blutdruckregulation beteiligt ist, und daß eine verminderte renale Kallikrein-Aktivität ein Faktor bei der Aufrechterhaltung der essentiellen Hypertension darstellen könnte.SummaryUrinary kallikrein excretion was significantly lower in patients with essential hypertension (0.48±0.05 EU/24 h) than in normotensive controls (1.26±0.14 EU/24 h). Oral administration of hog pancreatic kallikrein normalized decreased urinary kallikrein and reduced arterial pressure. The treatment-induced rise in urinary kallikrein was due to an enhanced release of endogenous enzyme, as was determined by radioimmunoassay. It is proposed that in the hypertensive patients the low urinary kallikrein excretion reflects a defect in renal kallikrein formation which is normalized by oral kallikrein. The hypotensive action of oral kallikrein as well as its stimulating effects on renal kallikrein release suggest that the kallikrein-kinin system is involved in blood pressure regulation and that impaired renal kallikrein activity may be a factor in the maintenance of essential hypertension.

Effect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a randomised trial.

Objective. Angiotensin-converting enzyme (ACE) inhibitors have been shown to lower central augmentation index (cAI), an index of arterial wave reflection, more than β-blockers. We tested whether this is also true for long-term treatment with an angiotensin receptor blocker (ARB). Methods. One-hundred and fifty-six subjects with essential hypertension were randomised to treatment with either irbesartan or atenolol. cAI and central blood pressure (BP) were determined by pulse wave analysis from the radial and the carotid artery after six and after 18 months treatment. Results. Peripheral and central systolic and diastolic BP were reduced to a similar extent A in the two groups. cAI was reduced with irbesartan, but increased with atenolol (derived from the carotid artery: -6±10 vs. -4±12% after six months, p<0.001; —4±12 vs. +1±11% after 18 months; p=0.011). Furthermore, central to peripheral pulse pressure (PP) amplification was unaffected by treatment with irbesartan, but decreased with atenolol. Conclusions. Although treatment with irbesartan and atenolol similarly decreased peripheral and central BP, only treatment with irbesartan had beneficial effects on arterial wave reflection and preserved PP amplification. These haemodynamic effects may at least partly explain the reported differential effects of ARB versus β-blocker treatment on cardiovascular mortality in patients with essential hypertension.

Evidence for Participation of Kinins in the Antihypertensive Effect of Converting Enzyme Inhibition

SummaryIn low- and normal- renin hypertensive patients, but not in high-renin patients, the acute antihypertensive response to the angiotensin-converting enzyme (ACE) inhibitor captopril was completely blocked by aprotinin-induced kallikrein inhibition. Blood pressure reduction with long-term ACE inhibition could be overcome only in part by aprotinin. It is proposed that in low- and normal-renin hypertension the vasodepressor effect of acute ACE inhibition is mainly due to kinin accumulation. Conversely, in high-renin patients a fall in angiotensin II concentration accounts for the hypotensive response to captopril. From the pressor effect of aprotinin in chronically captopril treated patients it appears that kinins are also involved in the blood pressure reduction with long-term ACE inhibition. The finding that ACE inhibition and kallikrein blockade produced predictable and opposite effects on blood pressure suggests broad participation of changes in depressor kinin production in the control of vascular tone in essential hypertension.ZusammenfassungBei essentiellen Hypertonikern mit niedriger und normaler Plasmareninaktivität, nicht dagegen bei Patienten mit hohen Reninwerten, konnte der akute antihypertensive Effekt einer Angiotensin-Converting-Enzym-(ACE) Blockade mit Captopril durch eine Aprotinin-induzierte Kallikreinblockade vollständig verhindert werden. Nach chronischer ACE-Hemmung ließ sich die Blutdrucksenkung nur zum Teil durch Aprotinin aufheben. Die Ergebnisse weisen darauf hin, daß bei essentieller Hypertension mit normaler und niedriger Reninaktivität der blutdrucksenkende Effekt einer akuten ACE-Hemmung im wesentlichen Folge einer Kinin-Akkumulation ist. Dagegen scheint bei Patienten mit hoher Reninaktivität eine Abnahme der Angiotensin II-Konzentration für die antihypertensive Wirkung von Captopril verantwortlich zu sein. Der pressorische Effekt von Aprotinin bei Patienten unter Langzeittherapie mit Captopril weist darauf hin, daß Kinine auch für die unter chronischer ACE-Hemmung auftretende Blutdrucksenkung mitverantwortlich sind. Die Beobachtung, daß ACE-Inhibition und Kallikrein-Blockade voraussagbare und gegensinnige Effekte auf den Blutdruck hervorrufen, läßt eine Beteiligung des Kallikrein-Kinin-Systems an der Kontrolle des Gefäßtonus bei essentieller Hypertension vermuten.

Hemodynamic, renal, and hormonal responses to changes in dietary potassium in normotensive and hypertensive man: Long-term antihypertensive effect of potassium supplementation in essential hypertension

SummaryThe hemodynamic, hormonal, and renal responses to alterations in dietary potassium were studied in normotensive and hypertensive subjects. In a short-term study, nine normotensive and nine hypertensive young men received a normal diet and low potassium, high potassium, and high potassium/low sodium diets for 1 week, each. The long-term effect of potassium supplementation (normal diet plus 96 mmol KCl/d for 8 weeks) was evaluated in 17 patients with essential hypertension. Blood pressure did not change significantly during short-term alterations of potassium intake but decreased during long-term supplementation (from 152.2±3.5/99.6±1.9 mm Hg to 137.4±2.9/89.1±1.4 mm Hg). High dietary potassium induced a significant but transient natriuresis. Plasma potassium concentration was increased during long- but not during short-term high potassium intake. In contrast to plasma renin activity (PRA) and aldosterone, urinary kallikrein was consistently stimulated during long-term potassium supplementation. The plasma concentrations of adrenaline and noradrenaline were significantly higher in hypertensive than in normotensive subjects and were not markedly altered by the dietary changes. It is concluded that long- but not short-term potassium supplementation lowers blood pressure in patients with essential hypertension. The antihypertensive effect may be mediated by potassium-induced natriuresis, by a stimulation of Na-K-ATPase secondary to increased plasma potassium levels, and/or by a modulation of the renin-angiotensin-aldosterone, kallikrein-kinin, and sympathetic nervous systems.

Converting enzyme activity and essential hypertension

SummarySerum ACE-activity was studied in 27 young patients with uncomplicated essential hypertension. The possible importance of an increase in ACE for the pathogenesis of essential hypertension was evaluated by comparing the ACE levels to PRA, the plasma concentrations of angiotensin II and to the blood pressure lowering effect of captopril. Mean ACE-activity was slightly but significantly elevated in the hypertensive patients when compared to 28 normotensive control subjects. ACE-activity was not correlated to PRA, angiotensin II or the decrease in blood pressure following captopril. It is concluded that the increase in ACE-activity in essential hypertension is not of pathophysiological or clinical significance.

Interactions of diuretics with the renal kallikrein-kinin and prostaglandin systems

SummaryThe renal kallikrein-kinin system may participate in the diuretic, natriuretic and antihypertensive effect of diuretics. This possibility was investigated by studying the influence of hydrochlorothiazide on blood pressure and urinary kallikrein excretion in patients with essential hypertension. Furthermore, the effect of kallikrein-blockade and prostaglandin-synthesis inhibition on the acute furosemide-induced changes of diuresis, natriuresis, GFR and renal plasma flow were studied in normotensive subjects. Thiazide treatment normalized the reduced kallikrein excretion of the hypertensive patients. The fall in mean arterial blood pressure was significantly correlated with the increase in urinary kallikrein excretion. In the normotensive subjects aprotinin-induced kallikrein inhibition failed to alter the acute response to furosemide, whereas indomethacin attenuated the diuretic and natriuretic effect of furosemide. The combination of indomethacin and aprotinin had a greater suppressive effect on plasma renin activity than indomethacin alone, suggesting a participation of kallikrein in renin release. An increase in the activity of the renal kallikreinkinin system may contribute to the long-term antihypertensive effect of thiazide diuretics but it does not seem to be involved in the acute renal responses to furosemide.ZusammenfassungDas renale Kallikrein-Kinin System ist möglicherweise am diuretischen, natriuretischen und antihypertensiven Effekt von Diuretika beteiligt. In der vorliegenden Studie wurde deshalb an Patienten mit essentieller Hypertension der Einfluß von Hydrochlorothiazid auf das Blutdruckverhalten und die renale Kallikreinaktivität untersucht. Zusätzlich wurde bei Normalpersonen die Beeinflußbarkeit der renalen Furosemidwirkung durch Kallikreinblockade und Hemmung der Prostaglandinsynthese gemessen.Hydrochlorothiazidbehandlung normalisierte die erniedrigte Kallikreinausscheidung hypertensiver Patienten. Der Abfall des mittleren arteriellen Drucks korrelierte mit dem Anstieg der Kallikreinausscheidung. Bei den normotensiven Probanden wurden die akuten Furosemid-induzierten Änderungen von Diurese, Natriurese, glomerulärer Filtration und renalem Plasmafluß durch Kallikreinhemmung mit Aprotinin nicht beeinflußt. Indomethacin hingegen verminderte den diuretischen und natriuretischen Effekt von Furosemid. Die Plasmareninaktivität wurde durch die Kombination von Indomethacin und Aprotinin deutlicher supprimiert als durch Indomethacin allein. Dies könnte auf eine Beteiligung von Kallikrein an der Reninfreisetzung hinweisen. Eine Aktivitätszunahme des renalen Kallikrein-Kinin Systems könnte zum antihypertensiven Effekt der Thiaziddiuretika beitragen. Andererseits scheint dieses System an den akuten renalen Wirkungen von Furosemid nicht beteiligt zu sein.

Effects of a high-cholesterol diet on arterial wall thickness and vascular reactivity in young rabbits

SummaryCholesterol enrichment of arteries may induce biochemical and structural abnormalities in vascular smooth muscle resulting in increased arterial contractile sensitivity. We studied the effects of a high-cholesterol diet on arterial structural properties and vascular reactivity in young rabbits. In vivo measurements of aortic intimal-plus-medial thickness using high resolution ultrasound imaging were obtained before and after 3 weeks of a high-cholesterol diet in 12 rabbits (group 2) and compared to data from 12 animals a cholesterol-free diet fed (group 1). Six rabbits (group 3) were studied before and after a 3-week, high-cholesterol diet and after a subsequent 13-week, cholesterol-free recovery diet. Blood pressure responsiveness to noradrenaline was evaluated before and at the end of each diet period. In groups 2 and 3, high dietary cholesterol caused an increase in intimal-plus-medial thickness from 0.31 mm and 0.33 mm to 0.88 mm and 0.89 mm, respectively (p<0.001). Plasma cholesterol concentration rose from 0.9 ±0.26 mmol/l to 36.7 ± 8.56 mmol/l. There was no change in group 1. In group 3, intimal-plus-medial thickness remained increased (1.01 mm) following the cholesterol-free recovery diet despite normal plasma cholesterol. Blood pressure responsiveness to noradrenaline was markedly increased after the high-cholesterol diet (p<0.001) in groups 2 and 3 and after the cholesterol-free recovery diet in group 3 (p<0.001), and was directly related to intimal-plus-medial thickness (r=0.84;p<0.001). The data indicate that short-term high dietary cholesterol in the early life of rabbits causes long-lasting biochemical and structural arterial wall abnormalities, which might not only explain the observed increase in blood pressure responsiveness to noradrenaline, but could also lead to persistent functional vascular smooth muscle alterations. The result may be a predisposition to increased vascular smooth muscle response to high dietary cholesterol in adult life and development of high blood pressure and atherosclerosis.

Vascular wall thickness in hypertension: the Perindopril Regression of Vascular Thickening European Community Trial (PROTECT).

A high prevalence of increased intima/media thickness of the arterial wall has been documented in hypertension. These alterations in vascular wall structure may be potent determinants for the promotion of the development of atherosclerosis. Direct histologic data from animal models of hypertension, and indirect data from hypertensive patients, have demonstrated a marked regression of increased intima/media thickness by angiotensin-converting enzyme (ACE) inhibition. Long-term effects of ACE inhibition on structural wall changes in humans have not been examined. Therefore, a multicenter, randomized, double-blind European trial was designed to compare the effects of the ACE inhibitor perindopril and the diuretic hydrochlorothiazide in slowing or reversing progression of increased intima/media thickness of carotid and femoral arteries in hypertensive patients. A total of 800 patients at 17 clinical centers in 7 European countries, aged 35-65 years, with hypertension and ultrasonographically proven intima/media thickness > or = 0.8 mm of the common carotid artery will be randomly assigned to receive in a double-blind fashion either perindopril or hydrochlorothiazide and will be followed for 24 months. High resolution duplex sonography will be used to quantify intima/media thickness at baseline and twice a year during follow-up. A change of 0.1 mm of intima/media thickness from baseline is considered to be detectable, and the standard deviations of the changes from baseline are expected not to be higher than 0.2 mm. The primary endpoint of the study is the comparison of changes in intima/media thickness of the common carotid artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Erhöhte Plasma-Prolactin-Konzentration bei essentieller Hypertension: Index einer verminderten hypothalamischen dopaminergen Aktivität

SummarySerial measurements of plasma-prolactin concentration (HPr) and plasma-renin activity (PRA) at 30-min intervals were made in 19 male patients with essential hypertension and in 8 normotensive subjects.HPr was markedly higher in the hypertensive patients than in the normotensive controls. Patients with reduced plasma-renin activity and only slightly elevated HPr-levels showed lower urinary sodium excretion, but a more pronounced 24-h natriuretic response to i.v. furosemide than patients with normal renin and very high HPr-levels.Six patients were treated with the dopaminergic agonist bromocriptine. The drug induced a significant blood pressure reduction in five patients and normalised pressure in two patients.The data do not indicate a role for prolactin in sustaining hypertension via renal salt retaining mechanisms. It is suggested that the raised HPr-levels represent an index of altered central nervous function, characterized by reduced hypothalamic activity. The blood pressure-lowering effect of the dopaminergic agonist bromocriptine fits with the hypothesis that reduced hypothalamic dopaminergic activity might be a factor in the pathogenesis of essential hypertension.ZusammenfassungBei 19 männlichen Patienten mit essentieller Hypertonie und 8 normotensiven Probanden wurde die Plasma-Prolactin-Konzentration halbstündlich zwischen 22.00 und 6.00 Uhr bestimmt. Die hypertensiven Patienten wiesen signifikant höhere Plasma-Prolactin-Konzentrationen auf als die normotensiven Kontrollen. Patienten mit niedriger Plasma-Renin-Aktivität und nur geringgradig erhöhten Plasma-Prolactin-Konzentrationen hatten eine geringere Natriumausscheidung, aber eine stärkere 24 h-Natriurese nach Furosemid, als die Patienten mit normalem Renin und sehr hohen Plasma-Prolactinwerten. 6 Patienten wurden mit dem dopaminergen Agonisten Bromocriptine über einen Zeitraum von 3–6 Wochen behandelt. Es kam in 5 Fällen zu einer signifikanten Senkung des systolischen und diastolischen Blutdrucks, bei 2 Patienten zu einer Blutdrucknormalisierung.Die Ergebnisse weisen darauf hin, daß der beschriebenen Natrium- und Wasser-retinierenden Wirkung von Prolactin für die Aufrechterhaltung einer chronischen Blutdrucksteigerung wahrscheinlich keine entscheidende Bedeutung zukommt. Es ist denkbar, daß die erhöhte Plasma-Prolactin-Konzentration bei den hypertensiven Patienten einen Index für eine veränderte zentralnervöse Funktion darstellt, die durch eine verminderte hypothalamische dopaminerge Aktivität charakterisiert ist. Die blutdrucksenkende Wirkung des dopaminergen Agonisten Bromocriptine könnte darauf hinweisen, daß eine Abnahme des dopaminergen Tonus im Hypothalamus einen Faktor in der Pathogenese der essentiellen Hypertension darstellt.Serial measurements of plasma-prolactin concentration (HPr) and plasma-renin activity (PRA) at 30-min intervals were made in 19 male patients with essential hypertension and in 8 normotensive subjects. HPr was markedly higher in the hypertensive patients than in the normotensive controls. Patients with reduced plasma-renin activity and only slightly elevated HPr-levels showed lower urinary sodium excretion, but a more pronouced 24-h natriuretic response to i.v. furosemide than patients with normal renin and very high HPr-levels. Six patients were treated with the dopaminergic agonist bromocriptine. The drug induced a significant blood pressure reduction in five patients and normalised pressure in two patients. The data do not indicate a role for prolactin in sustaining hypertension via renal salt retaining mechanisms. It is suggested that the raised HPr-levels represent an index of altered central nervous function, characterized by reduced hypothalamic activity. The blood pressure-lowering effect of the dopaminergic agonist bromocriptine fits with the hypothesis that reduced hypothalamic dopaminergic activity might be a factor in the pathogenesis of essential hypertension.