Z. Glück

Sodium-volume factor, cardiovascular reactivity and hypotensive mechanism of diuretic therapy in mild hypertension associated with diabetes mellitus☆

Abstract Diabetes mellitus is often associated with excess body sodium and frequently accompanied by hypertension. Relationships among blood pressure and various regulatory factors were studied before and after six weeks of diuretic therapy with chlorthalidone, 100 mg/day, in 17 diabetic subjects (aged 32 to 75 years) with borderline to moderate hypertension. Following a four-week placebo phase, mean supine blood pressure was 165/93 ± 26/15 (±SD) mm Hg and exchangeable sodium was increased (49 ± 4 versus 45 ± 4 meq/kg lean body mass in 90 normal subjects; p

Increased serum low-density lipoprotein cholesterol in men treated short-term with the diuretic chlorthalidone☆☆☆

The effect of the diuretic chlorthalidone (100 mg/day for 6 weeks) on serum lipoproteins was evaluated in 37 subjects. In 19 men with essential hypertension (aged 41 +/- 3 yr), 8 normal men (26 +/- 3 yr), or all of these men considered together, chlorthalidone significantly increased serum low density lipoprotein--cholesterol (LDL-C) by 20% (p less than 0.05 to less than 0.01). There was also a tendency for increased LDL-C in seven postmenopausal women (+/- 15%) but not in three premenopausal women with essential hypertension. High density lipoprotein--cholesterol was not significantly changed in hypertensive women or normal men and decreased slightly (p less than 0.05) in hypertensive men. Apolipoproteins A-I, A-II, and B were not changed significantly in women or men. Diuretic-induced lipoprotein alterations were not associated with altered plasma volume and unrelated to variations in serum potassium, glucose, insulin levels, blood pressure, and body weight. Short-term diuretic therapy with chlorthalidone may increase serum LDL-C in young or middle-aged men with normal or high blood pressure.

Norepinephrine clearance and pressor effect in normal and hypertensive man

ZusammenfassungDie Bedeutung des sympathischen Nervensystems bei der Entwicklung einer essentiellen Hypertonie ist weiterhin unklar. Bei 28 Normalpersonen und 35 Patienten mit essentieller Hypertonie (bezüglich Alter und Geschlecht vergleichbar) wurden der Blutspiegel, die Clearance und die Blutdruckwirkung von exogen zugeführtem Noradrenalin untersucht. Die Schwellendosis der noradrenalin-induzierten Blutdrucksteigerung war bei den Hypertonikern niedriger als bei den Normalpersonen (20±10 versus 42±26 ng/kg·min;P<0.001). Die Steigerung der Dosis-Wirkungskurve und die basale endogene Plasmanoradrenalinkonzentration waren dagegen in beiden Gruppen vergleichbar. Die mittlere Gesamt-Plasmaclearance von Noradrenalin war ebenfalls gleich (5.3±2.5 gegenüber 5.4±2.3 l/min). Die Plasma-Noradrenalinclearance korrelierte bei den Normalpersonen invers mit der basalen Plasmanoradrenalinkonzentration (r=0.57;P<0.005). Die Halbwertszeit von Plasmanoradrenalin betrug etwa 2 min. Diese Ergebnisse weisen darauf hin, daß sowohl die basalen Blutspiegel und wie auch die Gesamt-Plasmaclearance von Noradrenalin während einer Noradrenalininfusion bei essentieller Hypertonie normal sind. Eine abnormal tiefe Schwelle der blutdrucksteigernden Wirkung von Noradrenalin könnte in Gegenwart von normalen Plasmanoradrenlinkonzentrationen zur Entwicklung und/oder Aufrechterhaltung einer essentiellen Hypertonie beitragen.SummaryWhether and to what extent the sympathetic nervous system participates in the development of essential hypertension has remained largely unclear. The role of the adrenergic effector — cardiovascular response axis in the pathogenesis of essential hypertension was investigated by combined analysis of blood levels, total plasma clearance and cardiovascular pressor effects of norepinephrine (NE). Measurements of plasma NE and blood pressure were performed before, during and after an intravenous infusion of NE at stepwise increasing rates in approximately age and sex-matched groups of 28 normal subjects and 35 patients with essential hypertension. The threshold of the pressor effect of NE was lower in hypertensive than in normal subjects (20±10 vs. 42±26 ng/kg min;P<0.001); but the slope of the dose — response curve and basal endogenous plasma NE were in the average similar. Total plasma NE clearance estimated under steady state conditions was similar in normal and hypertensive subjects (5.3±2.5 vs. 5.4±2.3 l/min). NE clearance correlated inversely with basal plasma NE in normal subjects (r=0.57;P<0.005). The plasma half-life of NE was about 2 min. These findings demonstrate that basal blood levels and total plasma clearance of NE during NE infusion are usually normal in essential hypertension. A low threshold of the pressor effect of NE in the presence of normal adrenergic activity may contribute to the development and/or maintenance of essential hypertension.

Pressor factors and cardiovascular pressor responsiveness in borderline hypertension.

SUMMARY The role of various pressor factors and cardiovascular responsiveness to norepinephrine or angiotensin II in the pathogenesis of borderline hypertension was evaluated. Exchangeable body sodium, blood volume, plasma renin activity, norepinephrine or dopamine levels, and norepinephrine or epinephrine excretion rates were similar between 24 patients with borderline hypertension (mean age 34 ± 4 (SEM) years and 22 normal subjects matched for age; the patients had a slight increase in supine plasma epinephrine. Pressor doses of norepinephrine or angiotensin II were significantly lower (p < 0.01 and 0.001, respectively) in the borderline hypertensive group. These findings suggest that borderline hypertension may be maintained by inappropriately increased cardiovascular response to norepinephrine and angiotensin II in the presence of normal sympathetic and renin activity and a normal body sodium-volume state.

Plasma Catecholamines and Renin in Diabetes Mellitus * Relationships with Posture, Age, Sodium, and Blood Pressure

ZusammenfassungBei 90 Normalpersonen und 100 Patienten mit nicht-azotämischem Diabetes mellitus (18- bis 76jährig) wurden Plasmanoradrenalin (PNA), -adrenalin, Urinkatecholamine, Plasmareninaktivität (PRA) und Blutdruck, sowie ihre Beziehungen zu Körperlage, Alter und Körpernatrium-Volumen-Status untersucht. 46 Diabetiker hatten im Liegen einen normalen Blutdruck, 54 eine Hypertonie. Die Diabetiker hatten ein signifikant (p<0,01) erhöhtes austauschbares Körpernatrium (NaEx), das Blutvolumen war normal. Plasmaadrenalin war bei Diabetikern im Mittel normal und unabhängig von Körperlage oder Alter. Die orthostatische Stimulierbarkeit von PNA war bei Normalpersonen und Diabetikern vergleichbar, die PRA-Stimulierbarkeit war bei Diabetes im Mittel vermindert (p<0,001). In beiden Populationen korrelierte PNA positiv und PRA invers mit dem Alter (p<0,05), jedoch nicht mit dem Urinnatrium. Im Vergleich zu dynamischen Normbereichen für PNA und PRA in Beziehung zum Alter hatten 14% der Diabetiker im Stehen ein niedriges PNA, 12% hatten eine niedrige PRA und 6% eine erhöhte PRA. Die Niedrig-PNA-Subgruppe hatte ein höheres NaEx und niedrigere PRA-Werte als die Normal-PNA-Subgruppe (p<0,025); Niedrig-Renin-Patienten hatten ein höheres NaEx und niedrigeres Urinnoradrenalin als Normal- oder Hoch-Renin-Patienten. Ein orthostatischer Blutdruckabfall wurde bei Niedrig- oder Normal-Renin-Patienten, nicht aber bei Hoch-Renin-Patienten beobachtet. Diese Befunde weisen darauf hin, daß bei Diabetikern ohne wesentliche Nierenfunktionseinschränkung meist eine normale adrenerge Antwort auf Körperlagewechsel besteht und daß die physiologischen Beziehungen zwischen zirkulierendem Noradrenalin oder Renin und dem Alter weitgehend intakt sind. Der orthostatische Anstieg von Renin ist dagegen oft vermindert. Die beobachtete Körpernatriumretention könnte eine wichtige Rolle sowohl für die bei gewissen Patienten vorhandene Noradrenalin- und Reninsuppression als auch für das häufige Auftreten einer Hypertonie bei Diabetes mellitus spielen.SummaryPlasma and urinary norepinephrine (PNE, UNE) and epinephrine, plasma renin activity (PRA) and their interrelations with posture, age, the body sodium-volume state and blood pressure were analyzed in 90 normal and 100 non-azotemic diabetic subjects. Ages ranged from 18 to 76 yrs, urinary sodium from 51 to 249 mEq/24h. Fortysix patients had a normal supine blood pressure, 54 had hypertension. Diabetics had an increased (p<0.01) mean exchangeable sodium, while blood volume was normal. Upright posture caused a comparable increase in PNE in normal and diabetic subjects; but the response of PRA was blunted (p<0.001) in diabetics, with subnormal responsiveness in 32% of cases. Epinephrine levels in diabetics were normal and unchanged with posture or age. In both groups supine and upright PNE and PRA correlated (p<0.05) positively with age, but not with urinary sodium. Comparison with dynamic normal ranges relative to age revealed low upright PNE in 14% and low or high PRA in 12 and 6% of diabetics, respectively. The low-norepinephrine subgroup had a higher exchangeable sodium and lower PRA than the normal-norepinephrine patients (p<0.025). Low-renin patients had a higher exchangeable sodium and lower UNE than normal or high-renin patients. Orthostatic decrease in blood pressure was noted in low or normal-renin, but not in high-renin patients. These findings suggest that patients with non-azotemic diabetes mellitus have usually a normal adrenergic response to postural changes; and physiological variations of PNE and PRA with age are largely maintained. However, diminished renin-responsiveness is common. Distinct sodium retention could contribute to norepinephrine or renin suppression in some patients and possibly also to the frequent development of hypertension in diabetes mellitus.

Effects of short-term norepinephrine infusion on plasma catecholamines, renin, and aldosterone in normal and hypertensive man.

SUMMARY The acute responsiveness of plasma catecbolamine, renln (PRA), and aldosterone levels to exogenous norepinephrine was studied under placebo conditions and following renin-angiotensin activation by diuretic pretreatment in 25 normal subjects and 34 patients with borderllne-to-moderate essential hypertension. Norepinephrine infusion caused increases in plasma norepinephrine (PNE) that correlated with the infused norepinephrine dose (p < 0.001); this relationship was similar in normal and hypertensive subjects and unaltered by diuretic therapy. Plasma eplnephrine and dopamine levels were unchanged during norepinephrine infusion. Norepinephrine infusion at pressor doses stimulated PRA (p < 0.01). The PRA responses correlated with the dose of infused norepinephrine [p < 0.0025), and norepinephrlne-stimolated PRA correlated with basal PRA (p < 0.001). These norepinephrine-PRA relationships were unaltered by diuretic treatment and similar in normal and hypertensive subjects. In both groups, norepinephrine also caused a similar Increase in plasma aldosterone (p < 0.05) under placebo conditions, but not following diuretic therapy. These findings demonstrate that an acute increase in the blood levels of the adrenergic neurotransmittor, norepinephrine, causes mild but distinct stimulation of plasma renin and aldosterone levels. Renin release in response to exogenous norepinephrine is not enhanced following renin-angiotensin activation by diuretic pretreatment. The responsiveness of the renin-angiotensin-aldosterone system to an acute norepinephrine input seems to be intact in essential hypertension.

Cardiovascular and renal profile of acute peripheral dopamine1-receptor agonism with fenoldopam.

Whether the dopaminergic system may be involved in essential hypertension is of pathogenetic as well as therapeutic interest. Therefore, we investigated in eight hypertensive and 12 normal subjects cardiovascular, endocrine, and renal responses to fenoldopam, which has been characterized experimentally as an agonist of peripheral postsynaptic dopamine1 receptors. A single oral dose of fenoldopam, 100 mg, changed blood pressure (BP) in hypertensive subjects (from 163/103 to 147/76 mm Hg; p less than 0.01 for systolic and p less than 0.001 for diastolic BP) and normal subjects (from 121/81 to 123/65 mm Hg; p less than 0.001 for diastolic BP); percentage decreases in diastolic BP averaged -20 +/- 6 and -16 +/- 7%, respectively. Fenoldopam-induced effects on other variables were similar in the two groups. Heart rate rose (p less than 0.001) on average from 69 to 92 beats/min in hypertensive and from 64 to 84 beats/min in normal subjects. Effective renal plasma flow increased (from 552 to 765 and 634 to 937 ml/min/1.73 m2; p less than 0.01), while glomerular filtration rate tended to decrease (from 121 to 99 ml/min/1.73 m2 in the hypertensive and from 119 to 97 ml/min/1.73 m2; p less than 0.001 in the normal group). Fractional sodium clearance was elevated (from 2.8 to 5.2 and 1.7 to 3.8%; p less than 0.01), as was free water clearance (from -1.7 to 0.6 and -1.7 to 0.1 ml/min/1.73 m2; p less than 0.01). Potassium clearance was largely unchanged. Plasma renin activity increased about twofold (p less than 0.01 in normal subjects), and plasma aldosterone by 40% (NS). Plasma norepinephrine levels increased twofold to 2.5-fold (p less than 0.001), and urinary norepinephrine excretion fivefold to 10-fold (p less than 0.01). Fenoldopam-induced changes were not significantly modified by intravenous and/or oral pretreatment with the dopamine-receptor antagonist metoclopramide or the cyclooxygenase inhibitor indomethacin. These findings suggest that in humans, fenoldopam may acutely override the dopaminergic antagonism of metoclopramide given in clinical dosage and that its cardiovascular and renal effects are not prostaglandin-mediated. Although acute sympathetic stimulation may be partially antagonistic, the concomitant BP-lowering, renal vasodilating, and natriuretic actions of fenoldopam represent a desirable profile of a potential antihypertensive agent.

Evaluation of autonomic neuropathy in diabetes mellitus. Comparison of clinical, functional and biochemical parameters.

ZusammenfassungBei 23 Diabetikern und 10 Normalpersonen wurden die klinischen Symptome und Befunde einer Neuropathie quantitativ analysiert, und der Beat-to-Beat-Variations-Test, der Valsalva-Versuch, die Orthostase-, Handdruck- und Kälte-Pressor-Tests sowie Bestimmungen von Plasmarenin und Katecholaminexkretionsraten durchgeführt.Die klinische Punktzahl korrelierte invers mit der Beat-to-Beat-Variation (Test der efferenten Vagusfunktion) (rΞ-0,72,P<0,0005), mit der Blutdruckreaktion während manuellem Pressen (möglicher Test des efferenten Sympathicus) (r=-0,55,P<0,005), sowie noch besser mit beiden Tests zusammen (r=-0,79,P«0,0005). Mit den übrigen Parametern korrelierte die klinische Punktzahl nicht. Die Beat-to-Beat-Variation war bei allen 9 Diabetikern mit erhöhter und bei 9 von 14 mit normaler klinischer Punktzahl abnormal, die Valsalva-Ratio bei 7 bzw. 1 Patient dieser Subgruppen. Die pressorische Antwort auf manuelles Pressen war bei den Diabetikern nur gering abgeschwächt, etwas ausgeprägter bei der Subgruppe mit erhöhter klinischer Punktzahl. Weitere mögliche Parameter der sympathischen Funktion wie Kälte-Pressoreffekt, Plasmarenin- und Urin-Adrenalin-und Noradrenalin-Werte unterschieden sich zwischen Normalpersonen und Diabetikern nicht signifikant.Diese Befunde weisen auf eine größere Prävalenz von parasympathischen gegenüber sympathischen Ausfällen bei autonomer diabetischer Neuropathie hin. Dabei war die Beat-to-Beat-Variation in dieser Serie der empfindlichste Test. Eine klinische Analyse kombiniert mit nicht-invasiven Funktionstests wie Beat-to-Beat-Variation und Handdruck-Test, sind nützliche und auch in der Praxis anwendbare Hilfsmittel bei der Untersuchung einer diabetischen Neuropathie.SummaryQuantitative assessment of signs or symptoms of neuropathy, and the beat-to-beat variation, valsalva, orthostasis, handgrip and cold pressor tests, and measurements of plasma renin and catecholamine excretion rate were performed in 23 diabetic patients and 10 age-matched normal subjects.Significant inverse correlations were found between the clinical score and the beat-to-beat variation (a test of efferent vagus function) (r=-0.72,P<0.0005) or the pressor response to handgrip (possible test of efferent sympathetic integrity (r=-0.55,P<0.005) or the values of both tests combined (r=-0.79,P«0.0005); but not with the other measured parameters. Beat-to-beat variation was abnormal in all 9 diabetics with increased and in 9 of 14 with normal clinical score, whereas only seven and one patient from these subgroups, respectively, had an abnormal Valsalva ratio. The pressor response to handgrip was only slightly reduced in the diabetic patients, with greater tendency in those with abnormal clincal score. Additional possible indices of adrenergic dysfunction such as the pressor response to cold stimulus, plasma renin levels and noradrenaline or adrenaline excretion rates did not differ significantly between normal subjects and diabetics.These findings demonstrate a greater prevalence of parasympathetic as compared to sympathetic impairment in diabetic autonomic neuropathy; the beat-to-beat variation was the most sensitive among the tests used. An assessment of clinical evidence combined with non-invasive functional procedures such as the beat-to-beat variation and handgrip tests provide a valuable and easy to perform tool in the evaluation of diabetic neuropathy.

Cardiovascular and endocrine profile of adrenergic neurone blockade in normal and hypertensive man

Abstract Some cardiovascular and endocrine effects of adrenergic blockade were assessed in six normal subjects, six patients with mild hypertension (diastolic pressure

Age-related profile of cardiovascular reactivity to norepinephrine and angiotensin II in normal and hypertensive man

ZusammenfassungBei 31 Normalpersonen und 37 Patienten mit essentieller Hypertonie wurden die Beziehungen zwischen Alter, der kardiovaskulären Reaktivität gegenüber intravenös infundiertem Noradrenalin (NA) und Angiotensin II, sowie den Plasmaspiegeln von NA und Renin (PRA) untersucht. Bei den Normalpersonen nahmen sowohl die Angiotensin II-Pressor-Dosis als auch PRA mit zunehmendem Alter ab. Die Angiotensin II-Pressor-Dosis korrelierte positiv mit PRA (r=0.41,P<0.025) und negativ mit dem Alter (r=−0.46,P<0.02). Die NA-Pressor-Dosis und der basale NA-Blutspiegel korrelierten ebenfalls positiv miteinander (r=0.53,P<0.005), doch zeigten diese beiden Faktoren keine wesentliche Altersabhängigkeit. Bei der essentiellen Hypertonie ergaben sich zum Teil andere Befunde. Die Angiotensin II-Pressor-Dosis korrelierte weder mit der basalen PRA noch mit dem Alter; und die Pressor-Dosen sowohl von NA wie auch von Angiotensin II waren bei den Hypertonikern eher niedriger als bei Normalpersonen. Unsere Befunde zeigen, daß der Altersprozeß von einer physiologischen Abnahme der kardiovaskulären Reaktivität gegenüber Angiotensin II begleitet ist, wahrscheinlich als Folge einer parallelen Abnahme der PRA. Die Dissoziation zwischen Angiotensin II-Pressor-Dosis und PRA bei der essentiellen Hypertonie weist auf einen wichtigen Einfluß eines zusätzlichen Faktors auf dieses System hin.SummaryThe interrelationships among age, cardiovascular pressor reactivity to intravenously infused norepinephrine (NE) or angiotensin II, and endogenous plasma NE or renin (PRA) levels were evaluated in 31 normal subjects and 37 patients with essential hypertension. In normal subjects both angiotensin II pressor dose and PRA decreased progressively with aging. Angiotensin pressor dose correlated positively with PRA (r=0.41,P<0.025) and inversely with age (r=−0.46,P<0.02). NE pressor dose and basal plasma NE were also positively correlated (r=0.53,P<0.005), but the two factors remained largely unchanged with aging. Findings in essential hypertension differed in certain aspects. Angiotensin II pressor dose did not correlate with either basal PRA or age; and pressor doses of NE and angiotensin II tended to be lower in some patients than in normal subjects. These findings indicate that aging is accompanied by a physiologic increase in cardiovascular reactivity to angiotensin II, probably due to a concomitant decrease in circulating renin. The dissociation between angiotensin pressor dose and PRA in essential hypertension suggests an interference from an other factor.