Kilian Glänzer

The converting enzyme inhibitor captopril stimulates prostacyclin synthesis by isolated rat aorta

In the present study, pretreatment of rats with captopril significantly stimulated prostacyclin (PGI2) synthesis by their isolated aorta. This effect was maximal at captopril doses of 1.0 mumol/kg body weight. When added directly into the incubation buffer, captopril at final concentrations of 50 and 500 nM also increased the synthesis of PGI2 by isolated rat aorta. Our results show that captopril stimulates PGI2 synthesis in vascular tissue and that this effect may be due at least in part to a direct action of this substance.

Digoxin-Like Immunoreacting Substance(s) in the Serum of Patients with Chronic Uremia

In patients with chronic uremia we have previously demonstrated a significant inhibition of the Na-K-ATPase enzyme which represents the specific receptor protein for cardiac glycosides. Since an endogenous inhibitor of this enzyme was previously shown to react with a digoxin antibody, in the present study we determined digoxin-like immunoreacting activity(ies) (DLIA) by a radioimmunoassay in 15 nondialyzed patients with chronic renal failure. In native serum, DLIA ranged from 0 to 1.70 ng/ml and was unrelated to the degree of renal failure. After gel filtration of serum, DLIA exclusively eluted in the small molecular weight salt (FIII) and post-salt (FIV) fractions and averaged 0.22 +/- 0.04 and 0.20 +/- 0.05 ng/ml in fractions III and IV, respectively. Total activities ranged from 0.11 to 0.88 ng/ml with a mean of 0.42 +/- 0.06 ng/ml and closely correlated with the degree of renal impairment (p less than 0.001). The results confirm the presence of small molecular weight digoxin-like immunoreacting substance(s) in uremic serum. The variable activities in native serum and the lack of correlation between the degree of renal failure and DLIA in serum fraction IV previously shown to possess the Na-K-ATPase-inhibiting activity, however, indicate that DLIA may not reflect specifically the endogenous sodium pump inhibitor and that unspecific binding to this digoxin antibody of uremic toxins or other endogenous compounds, such as steroids other than aldosterone, may have occurred.

Baroreflex setting and sensitivity in normal subjects: Effects of pharmacologic inhibition of the angiotensin I converting enzyme

Arterial blood pressure, heart rate and the response of these hemodynamic parameters to exogenous norepinephrine were investigated in healthy volunteers (daily sodium intake of 150 mmol) during a control period and after a single oral dose of 5 mg of the angiotensin I converting enzyme (ACE) inhibitor ramipril (HOE 498). Norepinephrine was infused at doses of 0.1, 0.2 and 0.3 micrograms kg-1 min-1, each for 10 minutes, during control and 3 hours after ramipril administration. Exogenous norepinephrine induced a dose-dependent increase in mean arterial blood pressure from 76.4 +/- 0.9 mm Hg during control to 85.6 +/- 1.5, 92.2 +/- 1.8 and 98.4 +/- 2.4 mm Hg, respectively. Ramipril significantly affected the baroreceptor set point with a decrease in mean blood pressure (72.1 +/- 1.7 vs 76.4 +/- 0.9 mm Hg, p less than 0.01) in the presence of unchanged heart rate (71.7 +/- 0.9 vs 73.6 +/- 1.5 min-1). Baroreceptor sensitivity, estimated by the slope of the delta blood pressure versus delta heart rate relation, was not affected by ACE inhibition. Also, the pressor effect of exogenous norepinephrine was unchanged by converting enzyme inhibition. The present results show that ACE inhibition with ramipril in sodium-replete healthy volunteers induces a decrease in blood pressure that is not accompanied by changes in heart rate, pressor sensitivity to exogenous norepinephrine or baroreceptor sensitivity.

Hemodynamic and hormonal responses to 8-arginine-vasopressin in healthy man: effects of indomethacin.

SummaryPrevious investigations suggest that in a normotensive organism the vasopressor effect of 8-arginine-vasopressin (AVP) is very effectively buffered by cardiovascular reflex mechanisms. Exogenous AVP administration shows only small, transient increases in blood pressure in spite of continued AVP-infusion and high plasma AVP concentrations. The present study aims to clarify the mechanism of the observed transient blood pressure elevations which are often referred to as “tachyphylaxis”.Our results in healthy subjects show a two phase response to exogenous AVP: an initial phase which is characterized by cardiac reflex mechanisms and a second phase during which a normalisation of the elevated total peripheral resistance occurs. Inhibition of prostaglandin synthesis with indomethacin almost completely attenuates this vascular counterregulation to exogenous AVP, thus providing evidence that a prostaglandin mediated vasodilation in response to AVP may be the underlying mechanism for “vasopressin tachyphylaxis”. The role of the renin-angiotensin-system and the importance of different regional hemodynamic effects of AVP are discussed.ZusammenfassungBisher vorliegende Untersuchungen lassen vermuten, daß in einem normotensiven Organismus der vasopressorische Effekt von 8-Arginin-Vasopressin (AVP) effektiv durch cardiovaskuläre Reflexe abgeschwächt wird. Die Gabe von exogenem AVP führt zu nur vorübergehenden Pressorreaktionen trotz fortgeführter ADH-Infusion und deutlich erhöhter Plasma-AVP-Konzentrationen. Die vorliegende Untersuchung versucht den Mechanismus der nur vorübergehenden Blutdruckerhöhungen, die oft als “Tachyphylaxie” bezeichnet werden, weiter zu charakterisieren.Unsere Ergebnisse bei gesunden Versuchspersonen zeigen einen zweiphasigen Verlauf nach i.v. Gabe von AVP: eine initiale Phase, die durch cardiovaskuläre Reflexe gekennzeichnet ist und eine zweite Phase, während der sich der periphere Gefäßwiderstand normalisiert. Hemmung der Prostaglandin-Synthese mit Indomethacin schwächt die vaskuläre Gegenregulation auf exogenes AVP ab und läßt so eine prostaglandinvermittelte Vasodilatation als Reaktion auf AVP als Ursache der „Vasopressintachyphylaxie“ vermuten. Die Bedeutung des Renin-Angiotensin-Systems und unterschiedlicher regionaler hämodynamischer Effekte von AVP werden diskutiert.

Renal Functional and Metabolic Studies on the Role of Preventive Measures in Experimental Acute Ischemic Renal Failure

In the present study 1 h of total occlusion of the left renal artery in conscious rats was chosen as experimental model of ischemic acute renal failure (ARF), while the contralateral kidney was left intact. Chronic high dietary sodium intake, acute isotonic saline infusion, or administration of saralasin did not protect from ARF. Furosemide, mannitol, and verapamil converted oliguric into non-oliguric ARF in 100%, 75%, and 60% of the animals, resp. Protection from oliguria and preservation of GFR inversely correlated with the depression of cortical ATP-concentration (control: 1.32 +/- 0.07 mumoles/g wet weight) 6 h after ischemia by 16%, 41%, and 58% in mannitol- and verapamil- treated rats and in untreated rats, resp. At this time, Na-K-ATPase enzyme activities in renal cortex and papilla were unaffected, while enzyme activity in outer medulla was suppressed from 15.4 +/- 1.4 to 9.4 +/- 1.0 mumoles Pi/mg protein h in all groups of animals. The results suggest that in this model of ARF renal ischemia not only affects cellular energy supply in renal cortex but also causes severe structural and functional impairment in the outer medulla, probably leading to tubular obstruction and depression of glomerular function. Pharmacological protection from ischemic oliguric ARF cannot be achieved by prior induction of high urine flow rates alone but depends on the degree of metabolic and functional reserve of the injured tubular epithelium.

Prostaglandins Participate in the Regulation of NaCl Absorption in the Diluting Segments of the Nephron in vivo: Effects of Furosemide

Various studies point to a role of the renal prostaglandin (PG) system in the regulation of renal NaCl excretion. In the present experiments, distal delivery of proximal tubular fluid (DD) [CH20 + CC1)/GFR x 100] and distal fractional chloride absorption (DFAC1) [CH20/(CH20 + CC1)] were studied in 6 healthy volunteers undergoing sustained water diuresis. Studies of renal function were performed during intravenous infusion of hypotonic (0.45%) saline and during additional treatment with indomethacin, furosemide and furosemide plus indomethacin. Hypotonic saline was infused at increasing rates of 0.09, 0.18, and 0.36 ml min-1 kg-1 body weight each for a 45-min period. DD over all three clearance periods averaged 8.27 +/- 0.71 ml min-1 100 ml-1 glomerular filtration rate (GFR) during saline infusion alone and was unchanged by indomethacin (8.09 +/- 0.63 ml min-1 100 ml-1 GFR). DFAC1 averaged 0.79 +/- 0.02 during saline and significantly increased to 0.87 +/- 0.01 (p less than 0.002) during concomitant indomethacin treatment. Increased NaCl absorption in the diluting segment during indomethacin was paralleled by a decrease in urinary excretion of chloride (UC1V) from 221 +/- 29 during control to 124 +/- 19 muEq/min (p less than 0.025) and in urinary excretion of PGE2 (UPGE2V) from 1.45 +/- 0.12 to 0.51 +/- 0.09 pmol/min (p less than 0.025). Furosemide increased UPGE2V to 2.94 +/- 0.34 pmol/min (p less than 0.05) and UC1V to 2,590 +/- 128 muEq/min (p less than 0.001). This effect was associated with an increase in DD to 26.70 +/- 1.33 ml min-1 100 ml-1 GFR (p less than 0.001) and a decrease in DFAC1 to 0.19 +/- 0.02 (p less than 0.001). Neither DD and DFAC1 nor UC1V were altered during furosemide+indomethacin as compared to furosemide in spite of a marked suppression of UPGE2V to 0.56 +/- 0.13 pmol/min. Our results support the concept that renal PG participate in the regulation of NaCl absorption in the diluting segments of the nephron. Furthermore, the tubular effects of furosemide appear not to be mediated by the PG system.

Effects of atrial natriuretic peptide on systemic and renal hemodynamics and renal excretory function in patients with chronic renal failure

SummaryWe examined the effects of 60 minα-hANP infusion (24 ng/min/kg) on glomerular filtration rate (GFR), renal blood flow (RBF), cardiac index (CI) and blood pressure (BP) in 8 patients with chronic renal failure (CRF) with GFR ranging from 18 to 80 ml/min/1.73 m2 and in 8 control (C) subjects with normal renal function. Basal plasma levels of ANP and cGMP were elevated in CRF (ANP: 60.6±9.1 vs 13.6±1.9 pmol/l,p<0.05; cGMP: 14.3±2.9 vs 6.6±1.1 pmol/ml,p<0.05). During ANP infusion, peak levels of cGMP were higher in CRF than in C (27.5±3.2 vs. 17.3±1.3 pmol/ml,p<0.05). During ANP infusion, GFR increased in CRF by 70.7±4.2% from 34.5±6.8 to 57.4±9.9 ml/min/1.73m2 (p<0.001) as compared to 16.2±1.4% in C (p<0.001 vs CRF). RBF increased in CRF by 43.6±6.4% and in C by 3.1±1.2% (p<0.01). Basal urinary sodium excretion (UNaV) was slightly lower in CRF than in C but rose to the same level in both groups during ANP infusion. In CRF, as opposed to C, UNaV remained elevated above baseline after the end of the infusion. The effect of ANP on fractional sodium excretion (FENa), however, was more pronounced in C. Basal FENa was higher in CRF (12.8±2.5% vs 2.4±1.5% in C,p<0.001), FENa remained elevated at 180% over baseline in C sixty minutes after cessation of ANP infusion, while it had returned to baseline in CRF. During ANP infusion, CI increased in CRF after 30 min from 2.91±0.08 to 3.12±0.091/min/m2 (p<0.001) and in C from 3.20±0.11 to 3.39±0.13 l/min/m2 (p< 0.05). Mean arterial BP was higher in CRF and its decrease was greater than in C (21.1±2.7% vs 9.1±1.0%,p<0.001). In patients with CRF GFR, RPF, and CI remained significantly elevated and BP was still significantly decreased 60 min after ANP infusion. Total peripheral vascular resistance (TPR) was elevated in CRF and declined during ANP infusion in both CRF and C. The decline of TPR was sustained and more pronounced in CRF than in C. Renal vascular resistance (RVR) was high in CRF and dropped by nearly 50% during ANP infusion, whereas only a moderate decline in RVR during ANP application was observed in C. Thus, exogenous ANP had greater and prolonged effects on systemic hemodynamics and renal function in CRF than in C. They may be due to higher levels of ANP following ANP infusion and appear to be mediated by a more sustained formation of the second messenger cGMP.

Age- and sex-related differences in plasma aldosterone in essential hypertension. Relationship to plasma renin activity.

ZusammenfassungBei Patienten mit essentieller Hypertonie fiel sowohl die basale als auch die stimulierte Plasmareninaktivität (2 h aktive Orthostase +40 mg Furosemid intravenös) mit zunehmendem Lebensalter kontinuierlich ab. Signifikante Unterschiede zwischen Männern und Frauen fanden sich nicht.Die mittlere basale Plasmaaldosteronkonzentration zeigte bei weiblichen Patienten keine altersabhängigen Veränderungen, während bei männlichen Patienten ein leichter Anstieg festgestellt werden konnte. Allerdings ergaben sich hier keine signifikanten Geschlechtsunterschiede in den vergleichbaren Altersgruppen. Die mittlere stimulierte Plasmaaldosteronkonzentration zeigte bei Frauen mit zunehmendem Alter ein der Plasmareninaktivität paralleles Verhalten, während dies bei Männern weit weniger ausgeprägt war; so fand sich bei männlichen Patienten nur ein geringer Abfall der mittleren stimulierten Plasmaaldosteronkonzentration mit dem Alter und die Aldosteronspiegel waren in den jüngeren Altersgruppen (<40 Jahre) signifikant niedriger als bei weiblichen Patienten.Die Ergebnisse zeigen, daß bei Patienten mit essentieller Hypertonie mit zunehmendem Lebensalter eine Dissoziation zwischen Plasmaaldosteron und Plasmareninaktivität auftritt, wobei dieser Befund bei Männern deutlicher ausgeprägt ist als bei Frauen.SummaryIn essential hypertension mean basal (supine) and stimulated plasma renin activity (2 h upright posture +40 mg furosemide intraveneously) decreased progressively with age. No significant differences were observed in renin levels between male and female patients.With increasing age mean basal (supine) plasma aldosterone remained almost unchanged in females, whereas in males a slight increase was found. However, in the comparable age-groups no significant sexrelated differences were obtained. In female patients changes in mean stimulated plasma aldosterone with increasing age paralleled those of plasma renin activity, whereas in males this relationship was less obvious: only a slight age-related decline in stimulated aldosterone levels was observed and significantly lower plasma aldosterone concentrations in male than in female hypertensives of the younger age-groups (<40 years) were found.The results indicate that in essential hypertension with increasing age dissociation between plasma aldosterone and plasma renin activity occurred. Furthermore, the described alterations in adrenal aldosterone release are more pronounced in male than in female patients.

Contrast enhanced color Doppler — basics and potential clinical value

Ten years ago Goldberg and coworkers [1] already used ultrasound contrast agents for enhancement of pulsed wave Doppler signals. The combination of Doppler echocardiography was then neglected, probably because the introduction of more sensitive Doppler equipment promised a sufficient display of intracardiac blood flow. Today Doppler techniques are used for routine diagnostic procedures. Extensive experimental and clinical advantages and limitations of these methods have thus been obtained.

Atrial Natriuretic Peptide in Patients with Essential Hypertension: Effects on Systemic and Renal Hemodynamics and Renal Excretory Function

Human atrial natriuretic peptide 1–28 (α-hANP) processed and secreted by myoendocrine cells located in the heart atria have been demonstrated to possess strong diuretic, natriuretic and vasodilatory properties [3, 17]. Furthermore, ANP modulates the activity of neural and hormonal systems involved in the regulation of arterial blood pressure (BP) and extracellular fluid volume (ECFV), e.g. of the adrenergic nervous and the renin-angiotensin aldosterone systems [15, 19]. This profile of biological actions suggests that ANP may play a role in at least some forms of essential hypertension in which chronic retention of sodium with subsequent ECFV expansion and an increase in total peripheral vascular resistance (TPR) are frequently observed.