Effects of the aldosterone receptor antagonist potassium canrenoate on renal blood flow and urinary output during prolonged increased intraabdominal pressure (IAP) in pigs.

BACKGROUND: Increased intraabdominal pressure can be found after major abdominal trauma and necrotizing pancreatitis and is used during laparoscopic surgery. The purpose of this study was to investigate the effect of the aldosterone receptor antagonist (potassium canrenoate) on renal hemodynamics and urinary output in pigs during increased intraabdominal pressure (IAP). METHODS: The IAP was kept at 30 mmHg for 3 h by instillation of Ringer's solution into the peritoneal cavity. Eight animals were treated with potassium canrenoate and eight animals served as controls. Renal blood flow, hormones in femoral artery blood, and the urinary output were measured. RESULTS: The administration of potassium canrenoate was followed by increased aldosterone concentrations in arterial blood, increased blood concentration of potassium, and increased concentration of sodium in the urine, indicating satisfactory inhibition of aldosterone. Potassium canrenoate did not cause changes in cardiac output and arterial pressure. It did not affect the renal vascular resistance that increased at an IAP of 30 mmHg, or the renal blood flow that remained constant during the experiments. The group treated with potassium canrenoate had higher mean urinary output than the controls, but the difference was not significant. CONCLUSION: Increased IAP in pigs is associated with markedly reduced urinary output and increased serum concentrations of aldosterone. Although the urinary output did not increase significantly, the increased sodium concentration in the urine of canrenoate-treated animals suggests that the high blood level of aldosterone contributes to the oliguria under increased IAP.

Role of angiotensin II under prolonged increased intraabdominal pressure (IAP) in pigs.

BACKGROUND: The aim of the study was to investigate the effect of the angiotensin II receptor antagonist losartan on renal hemodynamics and diuresis in pigs with increased intraabdominal pressure (IAP). METHODS: The IAP was maintained at 30 mmHg for 3 h by intraperitoneal instillation of Ringer's solution. Ten animals were treated with losartan; another 10 animals served as controls. Renal blood flow, hormones in renal vein blood, and diuresis were measured. RESULTS: In control animals, the renal vascular resistance increased renal blood flow remained constant, the blood concentration of aldosterone increased and the diuresis decreased during increased IAP. Losartan prevented the increase in vascular resistance and improved renal blood flow under increased IAP. It also prevented the rise in aldosterone concentration and increased the urine output to baseline level. CONCLUSION: Our results suggest that the renal vasoconstriction associated with increased IAP is due to increased production of angiotensin II. The oliguria associated with increased IAP is probably due, at least partly, to increased reabsorbtion of sodium and water in the renal tubuli caused by increased tissue concentration of aldosterone.

[Hereditary thyroxin-binding globulin deficiency--changed thyroid function tests]. / Hereditaer tyroksinbindande globulinmangel--endringar i thyreoideafunksjonsprøver.

BACKGROUND: Variation in concentrations of carrier proteins of hormones may influence the effect of the hormones and may cause confusion in the interpretation of laboratory results. MATERIAL AND METHOD: A Caucasian family with a hereditary thyroxin-binding globulin (TBG) deficiency was investigated. 22 persons in two generations had blood tests for TBG, thyrotropin (TSH), three-iodothyronin (T3), thyroglobulin (TG), thyroxin and for free thyroxin (FT4) by two different commercial tests, Delfia and IMx Abbott (IMx). Relevant health information was collected of all persons. RESULTS: Six males had very low T4 values, non-detectable TBG, increased FT4 values on the Delfia test and within normal range on the IMx test. Six females had lower borderline T4 and TBG. All persons were clinical euthyroid. INTERPRETATION: The condition is considered to represent X-chromosome linked inheritance with hemizygote affected males and heterozygote female carriers with intermediate values for T4 and TBG. Commercial test kits for FT4 may present considerably different results in conditions with TBG deficiency. When a high level of measured FT4 combined with normal TSH is found; TBG deficiency should be considered.

Long-term central hemodynamic effects at rest and during exercise of losartan in essential hypertension.

BACKGROUND: Losartan reduces blood pressure in patients with essential hypertension, but the long-term central hemodynamic effects at rest and during exercise are not known. METHODS AND RESULTS: After 8 months of losartan treatment (50 to 100 mg daily, mean 82 mg), intra-arterial pressure was reduced from 165/102 mm Hg to 145/91 mm Hg at rest and from 193/104 mm Hg to 179/96 mm Hg during 100 W exercise in 28 patients with essential hypertension. Cardiac index and heart rate remained unchanged, but total peripheral resistance index was reduced 12% to 15%. Stroke index was unchanged at rest but increased 7% to 9% during exercise. Twenty-four-hour ambulatory blood pressure was reduced 10% to 13%. Left ventricular mass was reduced 27% in patients with left ventricular hypertrophy (n = 18). CONCLUSION: Losartan lowers blood pressure by reducing total peripheral resistance at rest and during exercise but cardiac pump function is unchanged or slightly improved. In patients with left ventricular hypertrophy, losartan induces a sizeable reduction in left ventricular mass.

Correlation between fetal sex and human chorionic gonadotropin in peripheral maternal blood and amniotic fluid in second and third trimester normal pregnancies.

BACKGROUND: To study the correlation between fetal sex and human chorionic gonadotropin (hCG) in maternal blood and amniotic fluid. METHOD AND MATERIAL: One hundred and thirty uncomplicated pregnancies, 82 of whom were at sixteen and 48 at thirty-five weeks of gestation. RESULTS: The hCG levels were significantly higher in maternal serum than in amniotic fluid. At 16 weeks there were no sex-related differences in the hCG levels, either in maternal blood or in amniotic fluid. At 35 weeks the hCG levels in maternal blood were significantly higher in pregnancies with female fetuses than in those carrying male fetuses (p<0.004), while in amniotic fluid the hCG levels tended to be slightly higher in the female group than in the male. In pregnancies with female fetuses the hCG levels in maternal blood were significantly higher at 35 than at 16 weeks (p<0.02), while in pregnancies with male fetuses the levels were highest at 16 weeks. For both sexes the hCG levels in amniotic fluid were significantly higher at 16 than at 35 weeks of pregnancy (p<0.001). Whereas a significant correlation between hCG levels in maternal blood and amniotic fluid was seen at 16 weeks of gestation for both sexes (p<0.01 and R value 0.45 for males and 0.41 for females), no correlation was observed at 35 weeks. CONCLUSION: This study shows a significant correlation between hCG and fetal sex at third trimester of gestation only, possibly caused by a gender factor and a shift in synthesis and/or in metabolism of hCG from the second to the third trimester.

Factors influencing reduction in blood pressure and left ventricular mass in hypertensive type-1 diabetic patients using captopril or doxazosin for 6 months.

The effect of doxazosin versus captopril on blood pressure, albuminuria, and left ventricular mass was studied in 33 hypertensive type-1 diabetic patients randomized to 6 months treatment with captopril (17 patients, mean daily dose 100 mg) or doxazosin (16 patients, mean daily dose 9 mg). Casual and 24-h ambulatory blood pressure (24hBP) were reduced from 163/95 to 144/83 mm Hg and 152/86 to 145/81 mm Hg, respectively, in the captopril group, and from 160/93 to 145/86 mm Hg and 156/86 to 147/79 mm Hg in the doxazosin group (all P < .05). The achieved 24hBP on treatment was positively associated with pretreatment levels of glycosylated hemoglobin (HbA1c) and plasma atrial natriuretic peptide (r = 0.53 and 0.59, respectively, both P < .01). Albuminuria did not change significantly in either group. Left ventricular hypertrophy was present in 13 patients (7 in the captopril and 6 in the doxazosin group). Left ventricular mass was reduced by an average of 27% and 23%, respectively, in these patients (both P < .01), but did not change significantly in patients without left ventricular hypertrophy. The reduction in left ventricular mass was positively associated with the presence of baseline left ventricular hypertrophy and inversely with dietary sodium intake and achieved casual blood pressure on treatment (R2 = 0.59, P < .001). We conclude that doxazosin and captopril used for 6 months are equally effective in reducing blood pressure and left ventricular hypertrophy in hypertensive type-1 diabetic patients; the antihypertensive effect is closely related to glycemic control; and dietary sodium intake and achieved casual blood pressure after treatment are independent determinants of the reduction in left ventricular mass seen in these patients.

Pituitary dwarfism in the R271W Pit-1 gene mutation.

UNLABELLED: The Pit-1 gene encodes the POU-domain transcription factor Pit-1 which is important for the differentiation of the anterior pituitary and regulation of the PRL, GH and TSH genes. As a member of the POU domain transcription factors, Pit-1 contains a DNA-binding region, consisting of a POU-specific domain and a POU homeodomain. Mutation of the Pit-1 gene causes hypoplasia of the pituitary gland and deficiencies of GH, PRL and TSH. In a DNA sample from a 3-month-old girl with severe growth deficiency from birth, single stranded conformational polymorphism analysis of the Pit-1 gene identified a gel shift in exon 6. DNA-sequencing disclosed a single base mutation in codon 271 (CGG to TGG) that changes arginine to tryptophan (R271W) in the POU homeodomain. The patient presented distinct facial features with prominent forehead, marked mid-facial hypoplasia with depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils. MRI examination showed a hypoplastic pituitary gland. Low serum GH did not respond to insulin-arginine provocation or GHRH tests. PRL levels below the detection limit did not increase in response to a TRH test. T4 and free T4 was below detection limit (< 20 nmol/l and < 4 pmol/l). TSH was 2.0 mU/l and showed a blunt response to 6.0 mU/l following TRH test. TBG was normal. In spite of inappropriately low TSH and very low T4, T3 was in the low normal range (1.4-1.6 nmol/l) and she was clinically euthyroid. The thyroid function tests are consistent with increased monodeiodination activity and increased conversion of T4 to T3, possibly related to the Pit-1 gene mutation. GH and T4 treatment resulted in catch-up growth continued during 5 years of therapy. CONCLUSION: Reports of nine other cases of R271W mutations of different populations as well as the present Norwegian patient suggest codon 271 of exon 6 to be a "hot spot" for Pit-1 mutations. To enable rapid and simple detection of this type of de novo mutation we have designed a specific amplification-created-restriction-site assay to check for the R271W mutation in patients suspected to have this rare form of genetic defect in growth hormone production.

Factors influencing LVM in hypertensive type-1 diabetic patients.

Diabetes mellitus is associated with a high prevalence of hypertension and left ventricular hypertrophy (LVH), and a causative relationship with abnormal sodium metabolism in diabetic patients has been suggested. Factors influencing left ventricular mass (LVM) were assessed in 30 hypertensive type-1 diabetic patients, mean age 46 +/- 9 (range 24-67) years, with a mean duration of diabetes and hypertension of 19 +/- 10 and 6 +/- 5 years, respectively. In the total study population, casual blood pressure was 163/94 +/- 24/10 mmHg and 24 h blood pressure was 155/87 +/- 17/8 mmHg. Twenty-four-hour urine samples were obtained to measure daily albumin excretion (0.77 +/- 1.06 g) and dietary sodium intake was assessed as 24 h sodium excretion (173 +/- 77 mmol). Creatinine clearance averaged 1.41 +/- 0.53 ml/s. LVM determined by echocardiography was 221 +/- 74 g (range 104-408 g) and 33% of the patients had LVH. Multiple regression analysis identified dietary sodium intake and plasma atrial natriuretic peptide as independent predictors of LVM (R2 = 0.52, p < 0.001). No significant association was found between LVM and blood pressure or albuminuria. The results propose dietary sodium intake as an important factor in the development of LVH in hypertensive type-1 diabetic patients.

Salt sensitivity in hypertensive type-1 diabetes mellitus.

UNLABELLED: As sodium retention has been proposed as a causal factor in the development of hypertension in diabetic patients, a high incidence of salt sensitivity has been suggested. To evaluate the influence of dietary sodium intake on blood pressure, casual and 24-h blood pressure was measured in 30 hypertensive type-1 diabetic patients aged 24-67 (mean 46) years while they were on habitual diet, after 6 days of low-sodium diet (50 mmol/day), and after 6 days of high-sodium diet (250 mmol/day). Nine patients (30%) who increased their 24-h mean blood pressure by more than 10% when going from low- to high-sodium intake were classified as salt sensitive; the others as salt resistant. The salt sensitive group had a significantly lower urinary excretion of dopamine at baseline, and a higher diuresis and a more pronounced decrease in 24-h blood pressure during salt depletion (all p < 0.01). Low-sodium diet reduced casual and 24-h blood pressure by 4% in the total study population compared with 9% in the salt sensitive group (p < 0.01). There was no difference in glomerular filtration rate, filtration fraction, proteinuria or urinary sodium excretion between the groups. CONCLUSIONS: Sodium restriction more effectively reduces blood pressure in the salt sensitive minority of hypertensive type-1 diabetic patients irrespective of renal function. The incidence of salt sensitivity is not increased in hypertensive type-1 diabetic patients compared with essential hypertensive patients.

Unchanged central hemodynamics after six months of moderate sodium restriction with or without potassium supplement in essential hypertension.

Sodium (Na) restriction and potassium (K) supplementation has been recommended as treatment of essential hypertension but the mechanism by which these may reduce blood pressure (BP) is unknown. We examined if moderately reduced Na intake, combined with a low-Na/high-K salt alternative (Pansalt: NaCl 57%, KCl 28%, MgSO4 12%) as substitute for standard table salt, induced clinically significant BP reduction in hypertensive patients and, if this therapy reduced total peripheral resistance. After a 2-month control period 40 patients aged 21-67 years with mean casual BP 156/103 mmHg were given a salt restricted diet (120 mmol Na/24 h) for 6 months. In addition, they were randomised in a double-blind manner to receive either Pansalt (P-group) or standard NaCl (S-group) as table salt in small amounts. Cardiac output was measured by dye dilution. Daily Na excretion was similarly reduced (20%) in both groups while K excretion was slightly increased in the P-group and reduced in the S-group (difference p < 0.05). No large changes occurred in 24-h ambulatory BP (by Accutracker II) or intraarterial pressure (through a brachial artery catheter) at rest or during exercise while casual BP was reduced (p < 0.05) 13/8 mmHg in the P-group and 8/5 mmHg in the S-group. While cardiac output was slightly reduced at rest and during 50W exercise in the P-group, no significant changes were seen in total peripheral resistance in either group. Thus, moderate reduction in Na intake, with or without addition of K, is not sufficient to induce significant long-term intraarterial or 24-h ambulatory BP changes in essential hypertension. Without BP changes invasively determined central hemodynamics remains remarkably stable over a 6-month period.

Salt sensitive essential hypertension evaluated by 24 hour ambulatory blood pressure.

Thirty men with essential hypertension were examined at three different levels of sodium intake, containing 135, 44 and 290 mmol sodium per day, respectively. Ten patients who increased their 24 hour mean ambulatory blood pressure 10% or more when going from low to high sodium intake were defined as salt sensitive, the others as salt resistant. The casual and 24 hour ambulatory blood pressure measurements defined partly different patients as salt sensitive. In multiple regression analysis, salt sensitivity was associated with an increase in diuresis during low sodium intake, demonstrating a dissociation between water and sodium excretion during salt depletion in the salt sensitive group. The change 24 hour ambulatory blood pressure during salt repletion was positively correlated to the increase in the atrial natriuretic peptide (p < 0.01), and inversely correlated to the plasma concentration of atrial natriuretic peptide after salt depletion (p < 0.01). No difference in plasma norepinephrine, renin, aldosterone, plasma volume, blood volume or 24 hour sodium excretion was found between salt sensitive and salt resistant subjects. We conclude that salt sensitivity is difficult to describe as an entity, but seems to be associated with lower levels of atrial natriuretic peptide and a different response to salt depletion.

The Bergen Blood Pressure Study: inappropriately low levels of circulating atrial natriuretic peptide in offspring of hypertensive families.

Plasma atrial natriuretic peptide (ANP), plasma and 24-h urine catecholamines, plasma renin activity (PRA), and serum aldosterone were studied in offspring of hypertensive and normotensive families [n = 82; age 37 +/- 7 years (mean +/- SD)]. Despite higher age, higher blood pressure, and higher urine excretion of catecholamines--all of which are factors associated with increased ANP levels--the mean basal plasma ANP concentration tended to be lower in offspring of hypertensive than normotensive families. The same pattern was found in all age-tertiles, and the between-group difference was statistically significant in subjects aged 34-39 years (p < 0.01). Also, the family history of hypertension was associated with low ANP levels after covariate adjustment (p < 0.05). The 24-h urine excretion of epinephrine and norepinephrine tended to be higher in offspring of hypertensive than normotensive families while the morning venous plasma levels were similar. The ratio between venous plasma ANP and norepinephrine was lower in offspring of hypertensive than normotensive families (p < 0.05). PRA, serum aldosterone level, and 24-h urine excretion of dopamine did not differ significantly between groups. Inappropriately low basal plasma ANP concentrations and low plasma ANP/norepinephrine ratios may be related to the development of essential hypertension in offspring of hypertensive families.

The Bergen blood pressure study: sodium intake and ambulatory blood pressure in offspring of hypertensive and normotensive families.

Sodium intake, estimated by the 24-h urine sodium excretion, was assessed in 39 offspring of hypertensive families and 37 offspring of normotensive families. The family history of hypertension or normotension was defined according to parental BP data from two surveys conducted 27 years apart. Urine-sodium excretion was similar in offspring of hypertensive and normotensive families, averaging 136 and 137 mmol/24 h, respectively. Monitored by non-invasive methodology in the urine sampling period, the average 24-h ambulatory blood pressure (BP) was approximately 10/10 mmHg higher in offspring of hypertensive than normotensive families. The clinically and statistically significant differences in BP between groups could not be explained by differences in sodium intake. After adjustment for confounding variables, the BP was not associated with the sodium excretion in the material as a whole or in either offspring group.

Alpha-adrenergic vasoconstriction in normal and hypoperfused myocardium during sympathetic nerve stimulation.

Coronary vasoconstriction mediated by postjunctional alpha 1- and alpha 2-adrenergic receptors was studied in normally perfused (control group) and left coronary hypoperfused (stenosis group) hearts of vagotomized, beta-blocked (propranolol) cats. Cardiac sympathetic nerve stimulation was combined with alpha 1- and subsequent alpha 2-adrenergic antagonism (doxazosin and SK&F 104078). Coronary perfusion pressure and heart rate were kept constant within groups; regional myocardial blood flow and cardiac output were obtained by means of microspheres with concomitant measurement of left ventricular myocardial oxygen consumption (MVO2). alpha 1-Adrenergic antagonism alone did not significantly alter blood flow in any wall layer in either group. Subsequent alpha 2-adrenergic antagonism increased epicardial as well as composite transmural flow in the stenosis group (P < 0.025). The inverse correlation between coronary resistance and MVO2 vanished in the stenosis group following alpha 1- and alpha 2-adrenergic antagonism. Maximal first derivative of the left ventricular pressure-time relation (dP/dt) and cardiac output were reduced simultaneously (P < 0.001). Hence, the significance of alpha 1- and alpha 2-adrenergic stimulation of inotropy and cardiac performance are augmented by myocardial hypoperfusion. Furthermore, alpha 2-adrenergic receptors are responsible for epicardial vasoconstriction in hypoperfused myocardium.

Blood flow regulation during acute regional ischemia in feline hearts: importance of postjunctional alpha 1- and alpha 2-adrenoceptors.

Influence of postjunctional alpha 1- and subsequent alpha 2-adrenergic antagonism on myocardial blood flow was measured in a group of anesthetized cats with acute occlusion of the left anterior descending coronary artery (LAD) and a control group (n = 10 for both). The relatively selective postjunctional alpha 1-(doxazosin) and alpha 2-adrenergic (SK&F 104078) antagonists were applied after beta-adrenergic blockade (propranolol). Regional myocardial blood flow was obtained with radiolabeled microspheres. Major hemodynamic determinants for perfusion were kept constant both within and between groups by right atrial pacing and aortic obstruction. Mean coronary resistance in nonischemic myocardium was permanently lower in the occlusion group as compared with controls (p less than 0.01). Subsequent alpha 2-adrenergic antagonism reduced mean coronary resistance in controls only (p less than 0.05). Cardiac output (CO) and dP/dt was reduced in LAD-occluded hearts after alpha 2-adrenergic blockade (p less than 0.01, p less than 0.05). The study demonstrates the significance of postjunctional alpha 2-adrenergic-mediated vasoconstriction in well-perfused myocardium of control hearts, whereas such vasoconstriction was deteriorated in LAD-occluded hearts. A role for myocardial alpha 2-adrenoceptors for maintenance of global cardiac function in acute regional ischemia was also indicated.

The influence of supine relaxation on blood pressure, heart rate and atrial natriuretic peptide in normal subjects.

The effect of recumbent rest on plasma atrial natriuretic peptide (ANP) concentration, mean blood pressure (MBP) and heart rate was studied in 26 normal human volunteers. Plasma ANP concentration, MBP and heart rate were determined after 10 min sitting and after 2, 5, 8, 15 and 30 min of recumbency. During the first 5 min of recumbency there were significant decreases in both MBP (p less than 0.001) and heart rate (p less than 0.001) compared with sitting. There was a small but significant fall in plasma ANP concentration (p = 0.02) after 30 min of recumbency compared with sitting. No further reduction in MBP or heart rate occurred after 5 min supine. The level of MBP following 5 min supine correlated significantly (r = 0.44; p = 0.02) with the plasma ANP concentration 25 min later. Blood pressure and heart rate are highly dependent on posture and relaxation, and plasma ANP concentration in lesser degree. It is necessary to wait for stable baseline values to develop before any comparisons between blood pressure and plasma ANP are done. If it is assumed that a causative relation exists between blood pressure and plasma ANP level, it appears there may be a delay of 20-30 min between a change in blood pressure and the physiological response of plasma ANP level. This observation may have implications for the interpretation of the relation between blood pressure and plasma ANP concentration in healthy individuals.

Human chorionic gonadotropin in cord blood and peripheral maternal blood in singleton and twin pregnancies at delivery.

The influence of fetal sex on human chorionic gonadotropin (hCG) in cord and peripheral maternal blood was studied at delivery in 57 twin and 66 singleton uncomplicated pregnancies. In twin pregnancies the hCG levels were about twice as high in female-female and in female-male vis-à-vis male-male combinations in both maternal and cord blood. In singleton pregnancies the hCG levels were significantly higher in maternal and in cord blood in cases of female vis-à-vis male infants. The ratio of maternal hCG/placental weight was also highest in the twin pregnancies when one or both infants were female. This suggests a "female effect", possibly genetically based.

Human chorionic gonadotropin in uterine and peripheral blood tested with an enzyme-linked immunosorbent assay and a radio-immuno assay in cases of spontaneous abortion.

Human chorionic gonadotropin (hCG) was analysed by a hCG-beta-subunit radio-immunoassay (hCG-beta-Ria) and a rapid serum test in uterine and peripheral blood in 29 cases of spontaneous abortion. The levels of hCG were significantly higher in uterine than in peripheral blood. The rapid serum test was correctly positive in all 29 samples of uterine and in 28 of peripheral blood.

Human chorionic gonadotropin in early normal and pathologic pregnancy. Discordant levels in peripheral maternal blood and blood from the uterine and abdominal cavities.

Human chorionic gonadotropin was assayed in 25 cases after first-trimester induced abortion, in 45 cases of spontaneous abortion in the first trimester, and in 27 cases of ectopic pregnancy. Blood was obtained from an antecubital vein and from the uterine cavity. In the cases of ectopic pregnancy blood was also obtained from the abdominal cavity. In the group of induced abortion the human chorionic gonadotropin levels in peripheral maternal blood did not differ significantly from the levels in the uterine cavity. In the groups of spontaneous abortion and ectopic pregnancy the human chorionic gonadotropin levels were significantly higher in blood from the uterine cavity and the abdominal cavity, respectively. In four cases (three with spontaneous abortion and one with an ectopic pregnancy) human chorionic gonadotropin was not detectable in peripheral maternal blood, while it was found in blood from the uterine and abdominal cavities.

Evaluation of new serum and urine tests in cases of suspected pathologic early pregnancy.

Two pregnancy tests, ModEL serum hCG Assay and ModEL Urine hCG Assay, were evaluated using sera and urine from 46 patients suspected of pathologic early pregnancy, of whom 22 patients had spontaneous abortion and 9 an ectopic pregnancy. ModEL Serum hCG Assay had a 100% sensitivity and specificity, thus demonstrating its value in these cases. With a sensitivity of 94% and a specificity of 87%, ModEL Urine hCG Assay gave poorer results. Both tests have a relative high "detection limit" of 25 U/l (serum) and 50 U/l (urine) which may impair their ability to distinguish between presence and absence of pregnancy by very low levels of hCG.