Markus P. Gnädinger

Blood levels and renal effects of atrial natriuretic peptide in normal man.

Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.

Effect of various therapeutic approaches on plasma potassium and major regulating factors in terminal renal failure

PURPOSE The development of life-threatening hyperkalemia poses a risk for patients with chronic preterminal renal failure. Various therapeutic options have been suggested for hyperkalemic emergencies in these patients; to date, however, no study has evaluated the relative efficacies of these measures in the presence of renal failure. Our goal was to examine the acute effects of a variety of therapeutic approaches, as well as those of hemodialysis, on plasma potassium levels in a hemodialysis population. PATIENTS AND METHODS Ten patients with terminal renal failure undergoing maintenance hemodialysis were enrolled in the study. Blood gas parameters and plasma sodium, potassium, glucose, osmolality, renin, aldosterone, epinephrine, norepinephrine, dopamine, and insulin were measured before, during, and after 60-minute infusions of bicarbonate, epinephrine, and insulin in glucose, and before, during, and after performance of regular hemodialysis for one hour. RESULTS Hypertonic as well as isotonic intravenous bicarbonate (2 to 4 mmol/minute) induced a marked rise in plasma bicarbonate and pH, but failed to lower the plasma potassium level (5.66 versus 5.83 mmol/liter before and after). Epinephrine, 0.05 microgram/kg/minute administered intravenously, decreased plasma potassium only slightly from 5.57 to 5.25 mmol/liter, and five patients showed no decline. On the other hand, insulin in glucose, 5 mU/kg/minute intravenously, effectively lowered plasma potassium levels from 5.62 to 4.70 mmol/liter, and hemodialysis induced the most rapid decline from 5.63 to 4.29 mmol/liter. Plasma aldosterone was elevated before treatment; it correlated with plasma potassium and dropped during intravenous bicarbonate administration or hemodialysis. Pretreatment plasma renin activity, insulin, epinephrine, norepinephrine, and dopamine levels were generally normal. CONCLUSION We conclude that in patients with terminal renal failure undergoing maintenance hemodialysis, intravenous bicarbonate is ineffective in lowering plasma potassium rapidly, and epinephrine is effective in only half the patients, whereas insulin in glucose is a fast and reliable form of therapy for hyperkalemic emergencies. Plasma aldosterone levels are appropriate in relationship to plasma potassium levels, and levels of other potassium-influencing hormones are generally normal.

Increase in circulating insulin induced by atrial natriuretic peptide in normal humans.

To search for possible metabolic interactions of α-human-atrial natriuretic peptide (αhANP), we evaluated in 20 normal subjects blood levels of αhANP, glucose, insulin, cortisol, electrolytes, catecholamines, free fatty acids, carnitine and amino acids, blood pressure (BP), and heart rate before, during, and after a 45-min infusion of synthetic αhANP. Group A [n = 10] was studied on liberal and Group B on three consecutive sodium (Na) intakes of 17, 140, and 310 mM/day. Plasma αhANP was slightly but not significantly higher following 5 days on “normal” or high than on low Na+ intakes. ahANP infused at 0.1 μg/kg/min produced on all Na+ intakes comparable percentage increases in plasma insulin (+ 34 to 63%, p < 0.001), norepinephrine (+ 76 to 155%, p < 0.001) and heart rate (p < 0.001), and a similar fall in diastolic BP (p < 0.001). Plasma glucose tended to be decreased slightly and cortisol was reduced; epinephrine, dopamine, and potassium levels were not significantly modified. As evaluated in group A, serum free fatty acids were increased (p < 0.01), plasma free carnitine levels were reduced (p < 0.001), and amino acids were not consistently altered. These findings indicate that in normal humans ahANP may, on various sodium intakes, modulate insulin secretion and/or metabolism and elicit a possibly baroreflex-mediated sympathetic activation and lipolysis.

Pressure dependence of atrial natriuretic peptide during norepinephrine infusion in humans

The relative contribution of increased blood pressure (BP) or norepinephrine (NE), or both, to the stimulatory effect of an NE pressor infusion on circulating immunoreactive atrial natriuretic peptide (ANP) was evaluated in 10 healthy young men. They were studied during an infusion of NE, which was applied initially alone and then in combination with sodium nitroprusside. NE infusion rate was increased in four 30-minute intervals to a final dose of 200 ng/kg body weight per minute, leading to 12-fold higher plasma NE levels than were seen during control conditions. This increased mean BP (from a mean basal value of 94 +/- 3 to 119 +/- 4 [SEM] mm Hg; p less than 0.001) and plasma immunoreactive ANP (from 50 +/- 7 to 112 +/- 17 pg/ml; p less than 0.001), whereas heart rate decreased (p less than 0.001). The NE infusion was continued at the highest dose and an additional infusion of sodium nitroprusside was started to titrate mean BP in 30-minute intervals down to control values; a mean sodium nitroprusside dose of 0.95 micrograms/kg/min restored mean BP to 93 +/- 4 mm Hg (p less than 0.001), decreased plasma immunoreactive ANP to basal values (51 +/- 4 pg/ml; p less than 0.001), increased heart rate (p less than 0.001), and left plasma levels of NE largely unchanged. Plasma protein and hematocrit rose about 5 to 6% (p less than 0.001) during the NE infusion and then decreased about 3 to 4% (p less than 0.001 and p less than 0.01) when sodium nitroprusside was added.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Hypotension and Renal Impairment during Infusion of Atrial Natriuretic Factor in Liver Cirrhosis with Ascites

Plasma immunoreactive atrial natriuretic factor (irANF) levels and the effects of alpha-human ANF (alpha-hANF) infusion were investigated in 7 patients with liver cirrhosis and ascites. Under basal conditions, supine blood pressure (BP) averaged 136/76 +/- 9/4 mm Hg (mean +/- SEM). Plasma irANF concentrations (124 +/- 33 pg/ml) were higher (p less than 0.01) than those in age-matched normal subjects (47 +/- 5 pg/ml). Plasma renin activity (PRA 5.9 +/- 2.2 ng/ml/h), aldosterone (18 +/- 7 ng/dl) and norepinephrine (NE, 66 +/- 5 ng/dl) levels were also elevated compared to the age-related normal range. Alpha-hANF infusion for 60 min at 0.036 micrograms/kg/min decreased the mean BP (-14%; p less than 0.05), increased PRA (+179%; p less than 0.05) and plasma NE (+24%; p less than 0.05). Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), diuresis and natriuresis were not modified. A subsequent 60-min infusion of alpha-hANF at 0.067 micrograms/kg/min produced a marked fall in mean BP (-26%; p less than 0.001), hemoconcentration (hematocrit +6%; p less than 0.001) despite stable body fluid balance and a further increase in PRA (+350%, p less than 0.005). GFR and ERPF were severely reduced (-55 and -56%, respectively; p less than 0.001), while diuresis and natriuresis were not modified. Plasma aldosterone was unaltered during, but rose (+72%; p less than 0.01) after the cessation of alpha-hANF infusion. Variations in natriuresis during alpha-hANF infusion correlated positively with BP (r = 0.47; p less than 0.01), ERPF (r = 0.53; p less than 0.01) or GFR (r = 0.51; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertensive Dysregulation and Its Modification by Calcium Channel Blockade in Nonoliguric Renal Failure

UNLABELLED To investigate the pathogenetic constellation and its modification by calcium channel blockade in hypertension associated with chronic nonoliguric renal failure, blood pressure (BP), various pressor factors or correlates, cardiovascular responsiveness, and plasma atrial natriuretic peptide (ANP) were assessed in 15 hypertensive patients (serum creatinine 160-715 mumol/l) before and after 6 weeks of intervention with the agent nitrendipine. On placebo, these patients had a lower plasma angiotensin II (AngII) clearance and higher values of supine plasma AngII, aldosterone, norepinephrine (NE), and heart rate than healthy humans. Acute responses of BP to AngII and of heart rate to isoproterenol were blunted in the patients (p less than 0.05-0.001). Plasma ANP was elevated, correlated positively with systolic BP, and rose in response to NE pressor infusion (p less than 0.05-0.001). Exchangeable sodium and blood volume did not differ significantly from normal values. Nitrendipine reduced the cardiovascular responses to AngII, NE, and isoproterenol and lowered supine BP from 173/102 +/- 5/2 to 146/81 +/- 3/3 mm Hg and upright BP from 170/105 +/- 5/2 to 145/86 +/- 4/3 mm Hg (p less than 0.05-0.001); except for slightly increased plasma AngII, the levels of other endocrine variables, exchangeable sodium, blood volume, and creatinine clearance were not significantly modified. CONCLUSIONS Hypertension accompanying chronic nonoliguric renal impairment seems to be strongly AngII and probably also NE dependent. Circulating ANP levels are high in this setting. Calcium channel blockade with nitrendipine effectively reduces cardiovascular AngII and NE dependence and BP.