[Significance of dietary sodium restriction in hypertension. Effects and status of diuretic therapy].
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Combined Modality Therapy↗
Biomedical subjects
R Düsing
Publications and source records attributed to R Düsing.
[Severe periodic hypokalemic paralysis. Prevention using beta-receptor blockade].
For ten years, severe physical exercise in a 24 year old male patient had been an almost constant trigger of frequent attacks of pareses which were mostly accompanied by complete tetraplegia and once by the occurrence of cardiac arrest with atrial fibrillation. During the attack, the serum potassium concentration fell to 1.2 mmol/l, whereas the intraleukocytic potassium concentration rose from 136 mmol/l to 149 mmol/l. The catecholamine excretion in the urine was raised during the first 24 hours after admission as an emergency (189 micrograms noradrenalin and 54 micrograms adrenalin). After intravenous adrenalin infusion (0.01-0.1 microgram/kg X min) during the symptom-free interval, there was a major fall of the serum potassium concentration from 3.9 mmol/l to 3.1 mmol/l. This was not accompanied by a raised insulin excretion and could be prevented by prior administration of the nonselective beta blocker propranolol. On the basis of these results, the patient was treated prophylactically with three times 40 mg/d p.o. propranolol. Pareses requiring treatment no longer occurred under this therapy.
Adrenergic beta-Antagonists↗
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.
Adult↗
Combined treatment of severe essential hypertension with the new angiotensin converting enzyme inhibitor ramipril.
Ramipril is a newly synthesized angiotensin converting enzyme inhibitor without a sulfhydryl group in the molecule but with a prolonged duration of action. Efficacy, tolerance and safety of this drug were evaluated in 10 patients with severe essential hypertension. After a treatment period of at least 4 weeks with the conventional antihypertensive drug combination of a diuretic and a beta-blocking agent with the vasodilator dihydralazine, their systolic and diastolic blood pressures averaged 161 +/- 6 and 111 +/- 2 mm Hg, respectively. Because diastolic blood pressure during this drug regimen was still greater than 105 mm Hg in all patients, the patients received ramipril initially at single daily doses of 5 mg in addition to their previous medication. The first dose of 5 mg ramipril resulted in a moderate but significant decrease in systolic and diastolic blood pressure in 9 of the 10 patients to 142 +/- 5 and 104 +/- 4 mm Hg (p less than 0.01), respectively, between 3 and 6 hours after drug administration. In 1 patient blood pressure was unresponsive to ramipril and 1 patient complained of nausea and vomiting within the first week of treatment with ramipril. Within the following 8-week treatment period with a once-daily intake of 5 or, if necessary, 10 mg of ramipril, diastolic blood pressure normalized in the remaining 8 patients to less than 90 mm Hg. Systolic and diastolic blood pressure averaged 130 +/- 5 and 83 +/- 2 mm Hg, respectively, at the end of the 8-week treatment period with ramipril. Severe hypotension and reflex tachycardia were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The role of renal prostaglandins in the regulation of renal sodium excretion.
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Adult↗
The kidney and cardiovascular system in obstructive jaundice: functional and metabolic studies in conscious rats.
1. The effects of jaundice on renal and circulatory function were investigated in chronic bile duct ligated (CBDL) rats 6 days after surgery. Sham operated (SO) animals served as controls. 2. Body weight was significantly reduced, whereas blood pressure remained unaltered, 6 days after bile duct ligation when serum bilirubin had risen to 169 +/- 18 (SEM) as compared with 2.8 +/- 0.3 mumol/l in SO rats. When compared with control values before surgery, urinary volume had significantly increased and absolute excretion of sodium, potassium, chloride and phosphate had decreased on day 6 after CBDL. Endogenous creatinine clearance was markedly depressed when compared with SO rats. Whereas fractional excretion of potassium remained unaltered, fractional excretion of sodium and of phosphate was significantly increased. 3. Except for a significant increase in urinary thromboxane B2 (TXB2) excretion in CBDL rats, no significant changes were observed in urinary excretion of prostaglandin (PG) E2, in the synthesis of PGE2, 6-keto-PGF1 alpha and TXB2 by isolated aortic tissue in vitro, nor in renal and cardiac adenosine triphosphatase activities or renal cortical mitochondrial function. 4. The adenosine triphosphate content of kidney cortex and cardiac mitochondrial function were significantly depressed in CBDL rats. 5. The results demonstrate that jaundice in CBDL rats is associated with functional and metabolic disturbances of the kidney and cardiac muscle, which may contribute to the renal and haemodynamic characteristics observed in jaundiced animals and humans.
Adenosine Triphosphate↗
Sodium balance as a determinant of prostacyclin production by isolated rat aorta.
The present study investigates whether the synthesis of prostacyclin (PGI2) in isolated rat aorta is dependent on the state of sodium balance of the animals. Three groups of ten rats each were included into the study. Two of them were fed a diet low in NaCl for 10 days with group I receiving 0.9% saline and group II distilled water as drinking fluid. Group III received a regular rat chow containing approximately 0.8 mmol day-1 of sodium, also for 10 days. At the end of the dietary protocol, systolic arterial blood pressure was significantly higher in group I (109.9 +/- 2.4 mmHg) as compared to group II (101.0 +/- 2.4 mm Hg; P less than 0.05) and group III animals (102.2 +/- 1.6 mm Hg; P less than 0.05). Generation of PGI2-like activity was determined in portions of the animals' isolated aorta using a platelet aggregation bioassay following incubation in 0.05 M Tris buffer (pH 9.3) for 12, 15, and 30 min, respectively. During these incubation times, generation of PGI2-like activity averaged 48.6 +/- 3.5, 57.8 +/- 4.3 and 68.3 +/- 3.2 pmol mg-1 in group III animals, which had received the regular rat chow, with similar values in the low salt group II (50.2 +/- 2.5, 57.7 +/- 2.7 and 72.9 +/- 3.7 pmol mg-1). Aortic generation of PGI2-like material was significantly suppressed in the high salt group I (37.5 +/- 2.8, 46.2 +/- 3.2 and 61.3 +/- 4.0 pmol mg-1; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Acid-Base Equilibrium↗
Relationship of plasma concentrations of human atrial natriuretic peptide to renal function and blood pressure in patients with progressive chronic renal failure.
Recent experimental and clinical findings indicate that immunoreactive human Atrial Natriuretic Peptide (alpha-hANP) is involved in the regulation of blood volume and arterial blood pressure (BP). Whereas the potential regulatory role of alpha-hANP in acute changes of extracellular fluid volume (ECFV) and in the modulation of BP has been demonstrated in various studies, their involvement in the chronic maintenance of sodium and water homeostasis is still equivocal. Moreover the role of alpha-hANP is of particular interest in chronic renal failure, since in this pathological condition increased sodium and water retention plays a major pathogenetic role in the development of hypertension and altered secretion and/or metabolism of alpha-hANP may contribute to fluid volume and BP regulation. To evaluate the relationship between the degree of renal insufficiency, BP and circulating alpha hANP we determined plasma alpha-hANP concentrations in 16 nondialyzed patients with progressive chronic renal failure (CRF) of various degree. Serum creatinine concentrations ranged from 127 to 1187 (435 +/- 76) mumol/l, systolic BP from 135 to 200 (158 +/- 4) and diastolic BP from 80 to 110 (94 +/- 2) mm Hg respectively. Plasma alpha-hANP concentrations ranged from 49 to 753 with a mean of 228 +/- 42 pg/ml which was thus significantly higher as compared to 90.0 +/- 16.2 pg/ml found in healthy volunteers (p less than 0.05). A highly significant linear correlation between plasma alpha-hANP and serum creatinine concentrations (r = 0.92) was observed; a weaker correlation was found between mean arterial pressure and alpha-hANP (r = 0.66) and serum creatinine concentration (r = 0.59), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Kidney Injury↗
Prostacyclin biosynthesis by human arterial tissue in vitro: dependence on oxygen tension.
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6-Ketoprostaglandin F1 alpha↗
[Hemodynamic studies on the action kinetics of phenoxybenzamine in healthy persons and hypertensive patients].
The hemodynamic profile of the pre- and postsynaptic alpha-receptor blocker phenoxybenzamine (POB) was investigated by a non-invasive technique in healthy subjects and in patients with essential hypertension. At a dose of 0.03 mg POB/kg body weight no hemodynamic changes were detected. POB at a dose of 0.07 mg/kg resulted in an initial transient rise in systemic vascular resistance and mean arterial pressure and a fall in heart rate without changes in stroke volume or cardiac index. 6 h after administration of 0.13 mg POB/kg a transient fall in peripheral vascular resistance and mean arterial pressure with an increase in heart rate and cardiac index was observed. A rise of orthostatic index, however, occurred within 1 h after administration of POB and reached its maximum after 4 h. 8 h after POB no hemodynamic changes were detectable. In patients with essential hypertension a similar fall in systemic vascular resistance and mean arterial pressure was observed after 0.13 mg POB/kg body weight. No change in heart rate occurred and the hemodynamic effects were significant already 3 h after administration of POB and persisted up to 8 h after POB administration. In contrast to healthy subjects, patients with essential hypertension showed no significant changes in the orthostatic index after POB. These hemodynamic findings point to a previously unexpected rapidly reversible functional alpha-receptor blockade by POB.
Adult↗
Converting enzyme inhibitor ramipril stimulates prostacyclin synthesis by isolated rat aorta: evidence for a kinin-dependent mechanism.
The present study was performed to investigate the effect of the angiotensin I-converting enzyme inhibitor ramipril on vascular synthesis of prostacyclin (PGI2). Administration of ramipril (Hoe 498) to rats significantly stimulated prostacyclin (PGI2) synthesis, quantified by radioimmunoassay of its stable hydrolysis product 6-keto-PGF1 alpha, by portions of the animals' isolated aorta. This effect was maximal at a dose range of 10(-7) mol/kg ramipril. The addition of the active ramipril metabolite ramipril diacid directly into the incubation buffer at final concentrations of 10(-9), 10(-6), and 10(-4) M resulted in a dose-dependent stimulation of 6-keto-PGF1 alpha released by isolated aortic tissue. Pretreatment of rats with aprotinin (40,000 U s.c. 60 min before the incubations) attenuated the ramipril-induced effect on aortic 6-keto-PGF1 alpha synthesis. Our results show that the angiotensin I-converting enzyme inhibitor ramipril stimulates PGI2 synthesis in vascular tissue and that this effect may be secondary to changes in the activity of the kinin system.
6-Ketoprostaglandin F1 alpha↗
Effects of standard diuretics and RPH 2823 on transepithelial Na+ transport in isolated frog skin.
Short-circuit current (SCC) techniques were used to monitor the effects of various diuretic agents on Na+ transport in isolated frog skin, a model for the late distal tubule and the collecting duct of the mammalian kidney. Acetazolamide, hydrochlorothiazide, torasemide, and ethacrynic acid did not affect sodium transport (as indicated by the SCC) or transepithelial electrical resistance when added either to the apical (outer) or to the inner (basolateral, corial) bathing solution of the tissue. However, Na+ transport was sensitive to amiloride, the triamterene derivate dimethylamino-hydroxypropoxytriamterene (RPH 2823), and to furosemide. Whereas apical amiloride, and RPH 2823 induced a dose-dependent decrease in SCC and increase in transepithelial electrical resistance, apical furosemide resulted in a dose-dependent increase in SCC and a decrease in electrical resistance. None of the three diuretic agents caused a significant change in SCC when applied to the inner bathing Ringer's solution. The small furosemide-induced decrease in resistance compared with the huge increase in SCC suggests that furosemide affects Cl- permeability as well as Na+ permeability. Evidence for this notion was achieved by the following findings: The decrease in resistance after furosemide was more pronounced in tissues bathed in Cl(-)-free solutions compared with Cl(-)-containing solutions. n contrast, SCC stimulation by apical furosemide is Cl(-)-ion independent, but strongly Na+-ion dependent. SCC stimulation by furosemide is amiloride-sensitive. With respect to the onset, locus, and reversibility of action, it seems reasonable to assume that amiloride, RPH 2823, and furosemide all influence transepithelial Na+ transport by interacting with the Na+ channel or a regulator site of it within the apical membrane. The stoichiometry of the amiloride (RPH 2823)-receptor site interaction revealed Hill-coefficient(s) of less than 1, indicating a negative cooperativity among the receptor sites. The interaction between Na+ ions and amiloride or RPH 2823 displayed mixed competitive-noncompetitive inhibition. Taken together, these results support the hypothesis that amiloride and Na+ as well as RPH 2823 and Na+ may act at different loci on the apical entry mechanism in Rana esculenta skin.
Amiloride↗
Studies on the tubular effects of atrial extract and of atriopeptin III in conscious rats.
To investigate a tubular action of atrial natriuretic peptide (ANP), in the present study the effects of rat atrial extract (AE) and of synthetic rat atriopeptin III (AP III) were assessed in conscious rats during hypotonic saline infusion. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were estimated by the clearances (C) of PAH and of endogenous creatinine, respectively. CPO4 was used as a marker of proximal tubular function. Distal delivery (DD) and distal fractional absorption of chloride (DFACl), a measure of solute absorption in the diluting segments, were calculated from CH2O and CCl. AE and AP III increased RPF in all groups of animals. Low doses of AP III (40 ng/100 g B.W.) significantly increased urine flow rate and CCl, whereas GFR, CNa, CPO4, and CK remained unaltered. The marked natriuresis at high doses of ANP was associated with a rise in GFR and in absolute and fractional CPO4 as well as an increase in DD and CK. AE and AP III (1 microgram/100 g B.W.) decreased DFACl from 0.94 +/- 0.03 and 0.87 +/- 0.03 to 0.80 +/- 0.07 (p less than 0.05) and 0.54 +/- 0.07 (p less than 0.01), respectively. Some of the effects on tubular reabsorptive capacity probably result from medullary wash-out which thereby contributes to the natriuresis by potentiating the rise in the filtered load of sodium at high ANP levels. In the absence of changes in GFR and CPO4, the tubular action of ANP is more accurately reflected by CCl which may result from decreased absorption in the medullary collecting tubule.
Animals↗
Studies on the role of sodium- and potassium-activated adenosine triphosphatase inhibition in the pathogenesis of human hypertension. Changes in vascular and cardiac function following inhibition of the sodium pump in normotensive subjects and effects of calcium entry blockade.
An endogenous humoral factor which inhibits the sodium- and potassium-activated adenosine triphosphatase (Na-K-ATPase) enzyme in vitro has been incriminated recently of playing a pathogenetic role in experimental and human hypertension. The present study was therefore performed in six healthy volunteers to investigate the hemodynamic consequences of an inhibition of this enzyme by ouabain, a potent and specific inhibitor of Na-K-ATPase. In addition, the role of intracellular calcium as a potential mediator was studied indirectly by the administration of nifedipine, a potent calcium entry blocker with predominant vasodilator properties. Intravenous administration of 8.5 micrograms ouabain/kg body weight inhibited red blood cell (RBC) - Na-K-ATPase by 49% which was accompanied by a significant increase in RBC - ATP and a decrease in intracellular potassium concentrations. This enzyme inhibition resulted in a 24% increase in peripheral vascular resistance. The parallel decrease in cardiac output and heart rate, however, prevented a rise in arterial pressure. This increase in vascular resistance was completely abolished by pretreatment with nifedipine (10 mg orally). In the absence of an effect of nifedipine on Na-K-ATPase, its attenuation of the vasoconstrictor effect of ouabain suggests that the effects of ouabain on the vascular smooth muscle cell are mediated by intracellular calcium. These results demonstrate that inhibition of the Na-K-ATPase enzyme in vivo causes a marked peripheral vasoconstriction. They are also compatible with the concept that an endogenous inhibitor of Na-K-ATPase - in the presence of decreased baroreceptor reflex sensitivity due to blood volume expansion - may play a role in the pathogenesis of human arterial hypertension.
Adenosine Triphosphate↗
Effects of trifluoperazine and verapamil on the hydro-osmotic response to antidiuretic hormone in the urinary bladder of the toad.
To investigate the role of the intracellular calcium-calmodulin complex in the hydro-osmotic response to antidiuretic hormone (ADH), the effects of trifluoperazine (TFP), a well-established inhibitor of calmodulin-mediated functions, and of verapamil (V), a calcium entry blocker, were examined in the urinary bladder of the toad, a model for the late distal tubule and the collecting duct of the mammalian nephron. Preincubation of the hemibladders with TFP at serosal concentrations of 10(-5) and 10(-4) M was without effect on basal water flow but markedly reduced the maximal hydroosmotic response to ADH (50 mU/ml) in a dose-dependent manner as compared to control hemibladders (23.60 +/- 1.23 vs. 42.17 +/- 4.18 mg/min per hemibladder (10(-5) M TFP) and 5.43 +/- 0.59 vs. 52.50 +/- 4.67 mg/min per hemibladder (10(-4) M TFP). This inhibitory effect of TFP on the ADH-stimulated osmotic water flow persisted in the presence of naproxen (10(-5) M), a known inhibitor of prostaglandin synthesis. The hydro-osmotic response to cyclic adenosine 3',5' monophosphate (cAMP, 10(-3) M) was also significantly reduced in TFP-pretreated tissues (11.68 +/- 1.84 vs. 32.83 +/- 3.14 mg/min per hemibladder), suggesting a post-cAMP inhibitory effect of TFP. V (10(-4) M) had no effect on basal water flow but significantly reduced the hydro-osmotic effect of 50 mU/ml ADH (15.17 +/- 1.05 vs. 38.00 +/- 3.39 mg/min per hemibladder). In contrast, cAMP-stimulated osmotic water flow was significantly stimulated in V-treated tissues (48.07 +/- 1.95 vs. 27.13 +/- 1.50 mg/min per hemibladder).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of angiotensin II and captopril on renal tubular function in man.
The effects of nonpressor doses of intravenous angiotensin II and of the converting enzyme inhibitor captopril on renal excretory function were investigated in eight healthy volunteers during sustained water diuresis on a constant intake of 150 mmol sodium per day. The angiotensin II-analogue val5-angiotensin II-asp1-beta-amide was infused i.v. at an average dose of 2.6 ng kg-1 min-1 which was the highest dose without a significant effect on arterial blood pressure. This subpressor dose of angiotensin II significantly decreased urine volume, urinary excretion of sodium, chloride and phosphate and distal delivery [(CH2O + CCl)/GFR X 100] in the absence of changes in GFR or distal fractional chloride absorption [CH2O/(CH2O + CCl)]. In a second series of experiments, an oral dose of 50 mg of the angiotensin I-converting enzyme inhibitor captopril was given to the sodium replete volunteers. In this study, captopril did not affect arterial blood pressure, GFR or any of the determined parameters of renal tubular function. Our results strongly suggest that the nonpressor dose of angiotensin II induced renal retention of sodium chloride via increased absorption in the proximal tubule. Thus, they further support the concept that angiotensin II participates in the regulation of renal sodium chloride excretion by affecting proximal tubular absorptive capacity. However, in the sodium replete stage, angiotensin II is of no major importance in regulating sodium chloride excretion.
Adult↗
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.
Adult↗
Prostacyclin synthesis by isolated rat aorta: role of 8-arginine-vasopressin.
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6-Ketoprostaglandin F1 alpha↗