Bioactive cardiac substances: potent vasorelaxant activity in mammalian atria.

Mammalian atrial extracts possess natriuretic and diuretic activity. In experiments reported here it was found that atrial, but not ventricular, extract also causes relaxation of isolated vascular and nonvascular smooth muscle preparations. The smooth muscle relaxant activity of atrial extract was heat-stable and concentration-dependent and could be destroyed with protease. Rabbit aortic and chick rectum strips were used for the detection of atrial biological activity. The atrial activity was separated by column chromatography into two peaks having apparent molecular weights of 20,000 to 30,000 and less than 10,000. The atrial substance that copurified with the smooth muscle relaxant activity in both peaks caused natriuresis when injected into conscious rats. It appears that atria possess at least two peptides that elicit smooth muscle relaxation and natriuresis, suggesting an endogenous system of fluid volume regulation.

Purification and sequence analysis of bioactive atrial peptides (atriopeptins).

Mammalian cardiac atria have several biologically active peptides that exert profound effects on sodium excretion, urine volume, and smooth muscle tone. In the present study two such peptides of low molecular weight were purified and separated from each other on the basis of differences in charge, hydrophobicity, and biological profile. The first peptide, designated atriopeptin I, exhibits natriuretic and diuretic activity and selectivity relaxes intestinal smooth muscle but not vascular smooth muscle strips. The second peptide, atriopeptin II, is a potent natriuretic and diuretic that relaxes both intestinal and vascular strips. Sequence analysis of atriopeptin I indicates that it is composed of 21 amino acids, of which serine and glycine residues predominate. The amino terminal sequence of atriopeptin II up to residue 21 is the same as that of atriopeptin I, with the addition of the Phe-Arg extension at the carboxyl terminus. Both peptides appear to be derived from a common high molecular weight precursor (designated atriopeptigen); their biological selectivity and potency may be determined by the site of carboxyl terminal cleavage.

Atriopeptin III. A potent natriuretic, diuretic, and hypotensive agent in rats with chronic renal failure.

Chronic renal failure is frequently associated with volume overload, resulting in hypertension and, in some cases, congestive heart failure. Atriopeptin III (AP III), a 24-amino acid atrial peptide, is a potent vasodilator and natriuretic/diuretic agent in normal rats. An infusion of AP III at 0.2 microgram/kg per min for 60 min produced dramatic responses in animals with chronic renal failure (5/6 nephrectomy 4 wk before study). Systemic blood pressure fell 20% by the end of infusion. A pronounced rise in glomerular filtration rate (24%) was maintained during the infusion period when urine flow rate was stable (35-60 min), even though renal blood flow was unchanged from base line. Urinary volume increased 4.4-fold and sodium excretion increased 9 to 12-fold during the infusion. Fractional excretion of sodium ranged between 9 and 15% in those animals whose initial GFR values were lower than 0.5 ml/min. We conclude that AP III is a potent natriuretic/diuretic agent in rats with reduced renal mass, presumably exerting that effect predominantly through increases in GFR. This agent may well be useful in the treatment of volume overload in patients with chronic renal failure.

Developmental changes in the rat atriopeptin hormonal system.

We undertook a study of fetal synthesis, storage, and release of atriopeptin (AP). Plasma levels of both atriopeptin immunoreactivity (APir) and the NH2-terminal fragment of the prohormone immunoreactivity (NTFir) were very high in the fetus (4 and 20 times the maternal plasma, respectively). However, the atrial content of the AP was low, but surprisingly, ventricular content of AP was quite high (relative to the adult) in the fetus and fell postnatally. Atrial AP messenger RNA (mRNA) increased with postnatal age, whereas ventricular mRNA was extremely high in the fetus and fell rapidly after birth. High fetal plasma peptide levels may derive from the mother since infusion of exogenous atriopeptin 24 into the mother resulted in parallel increases in fetal and maternal peptide levels. Fetal plasma APir and NTFir levels partially reflect the markedly reduced total renal metabolic capacity compared with that of the adult. Plasma levels fell progressively after birth; whereas neonatal atrial content rose substantially. Plasma AP and NTF were simultaneously elevated in both the maternal and fetal circulation after vasopressin injection of the mother. The fetus can also respond to exogenous stimuli (vasopressin or indomethacin--presumably via ductal closure) and promptly release substantial amounts of peptide into its circulation. Thus, it appears that the AP hormonal system is functional during fetal life and responds avidly to increases in intracardiac pressure as does the mature animal.

Renal transplantation for systemic lupus erythematosus and recurrent lupus nephritis. A single-center experience and a review of the literature.

Prior to 1975 patients with systemic lupus erythematosus were generally not considered candidates for renal transplantation because of concern that immune complex deposition would rapidly destroy the allograft. However, recent evidence suggests that good patient and graft survival rates can be achieved comparable to other renal diseases. Between September 23, 1963 and July 31, 1990, 1070 renal transplants were performed at Washington University Medical Center (WUMC). During this period, 14 patients with SLE (12 female and 2 male) received 16 renal transplants (7 living-related donor [LRD], 1 living-unrelated donor [LURD], and 8 cadaver [CAD]). The mean age at the time of the first transplant was 32.5 +/- 10.3 years. The duration of disease prior to transplant was 88.0 +/- 45.9 months and the duration of hemodialysis prior to transplant was 36.0 +/- 33.7 months. Of these patients, 7/14 (50%) had negative and 3/14 (21%) positive SLE serology pre- and post-transplant, 3/14 (21%) had negative serology pretransplant that became positive posttransplant, and 1/14 (2%) was positive pretransplant and became seronegative posttransplant. Patient survival was 92.8% (13/14), and of the 16 kidneys transplanted 62.5% (10/16) are still functioning with a mean follow-up period of 43.7 +/- 45 months. The current mean serum creatinine was 1.4 +/- 0.26 mg/dl. One noncompliant patient developed recurrent lupus nephritis bringing the total number of cases reported in the literature to seven. The present study demonstrates that patients with SLE can be transplanted with excellent patient and graft survival and function and a low rate of recurrent lupus nephritis. From a review of the literature, there appears to be an association between positive SLE serology pre- and posttransplant and recurrent lupus nephritis.

Progressive enzyme changes within anatomically defined segments of rabbit nephron: demonstration with a new technique.

The kidney is an extremely heterogeneous organ, with morphological, physiological, and metabolic changes occurring from segment to segment along each nephron. To determine the heterogeneity that might exist within discrete anatomical segments of rabbit nephron, we developed a technique for making quantitative enzyme assays in serial samples, about 100 micron long, along identified segments of the nephron. Results for three enzymes in proximal convoluted and straight tubules show that adenylate kinase, an enzyme of high-energy phosphate metabolism, gradually decreases along the S1 and S2 segments of the proximal tubule, with no abrupt changes. Fructose bisphosphatase, a gluconeogenic enzyme, is high along the major portion of the proximal tubule but plummets along the final millimeter of S3. Conversely, phosphofructokinase, a glycolytic enzyme, is very low along the proximal tubule but increases sharply within the final millimeter. These data underscore the biochemical heterogeneity of the nephron, illustrating the enzyme levels may change markedly even within anatomically defined regions. They also suggest the importance of further studies of this type and demonstrate a practical means for such studies.

The distribution of six enzymes of oxidative metabolism along the rat nephron.

Using quantitative methods, citrate synthase (CS), fumarase, beta-hydroxyacyl-coenzyme A (CoA) dehydrogenase (beta OAC), 3-keto-acid CoA transferase (KCT), malic dehydrogenase (MDH), and malic enzyme were measured in seven defined parts of the nephron and in thin limb and papilla areas dissected from freeze-dried microtome sections of rat kidney. The results not only show a wide range of activity along the nephron for each of the enzymes, but that the proportions between the enzymes vary markedly among the different parts of the nephron. This suggests the existence of major regional differences in the capacity to oxidize specific metabolites. The ratio between two citrate cycle enzymes, fumarase and CS, was 4- or 5-fold higher in proximal segments than in the glomerulus or thin limb areas. The ratio between beta OAC (an enzyme of fatty acid oxidation) and CS was 3- to 5-fold higher in the middle proximal segments than in glomeruli or thin limb and papilla areas. The key enzyme for ketone body metabolism, KCT, was essentially confined to the thick tubule segments. Malic enzyme, in contrast to the other five enzymes, was highest in the proximal straight segments. New methods, sufficiently sensitive for this histochemical study, are described for malic enzyme and 3-keto-acid CoA transferase.

Diastolic function and tachycardia in hypertensive children.

We investigated the prevalence and potential predictors of Doppler echocardiographic evidence of diastolic function in untreated hypertensive children. Doppler and M-mode echocardiographic values from 42 children (mean age 13, range 5-17 years) from a pediatric hypertension clinic were retrospectively reviewed and compared to data from 39 age and gender matched normotensive children in a control group. Compared to the participants in the control group, hypertensive patients had increased mean body mass index (29 v 19 kg/M2, P < .0001), peak mitral A velocity (57 v 42 cm/sec, P < .0001), isovolumic relaxation time (65 v 42 msec, P < .0001, resting heart rate (90 v 74 bpm, P < .0001), mitral E deceleration time (150 v 137 msec, P = .006), indexed left ventricular mass index (32 v 26 g/M2.7, P < .0001), relative left ventricular wall thickness (0.32 v 0.29, P = .02), and decreased ratio of peak mitral E velocity/peak mitral A velocity (1.7 v 2.1, P = .0001). Mean age, height, mitral E velocity, mitral A deceleration time, fractional shortening, and indexed left ventricular diastolic dimension were similar in patients and control group children. In the hypertensive patients, multivariate analysis demonstrated that heart rate (P = .0008) and systolic blood pressure (P = .03) were significant predictors of peak A velocity. In addition, heart rate (P = .0003), body mass index (P = .04), and indexed left ventricular diastolic dimension (P = .04) predicted the ratio of peak E/peak A velocity. None of the measures of diastolic function correlated with left ventricular mass index or relative wall thickness. Furthermore, none of the analyzed variables predicted isovolumic relaxation time or mitral E deceleration time. We conclude that untreated hypertensive children have Doppler indices suggestive of impaired left ventricular relaxation. Resting heart rate was the strongest predictor of abnormal diastolic indices.

Bilateral renal dysplasia in three siblings: report of a survivor.

Three siblings, born nonconsectively to an unrelated couple, have had bilateral dysplastic kidneys. The first child had associated skeletal anomalies, the second, ureteral atresia, and the third, no other anomalies. The occurrence of dysplastic kidneys in three siblings is compatible with an autosomal recessive inheritance pattern. In addition the variety of presenting syndromes in the children suggests that variable pathogenetic mechansims were responsible for the appearance of dysplastic kidneys. The third child is alive with kidneys that markedly decreased in size over the neonatal period but is growing well at 41 months of age indicating that the presence of bilateral dysplastic kidneys does not necessarily preclude a favorable prognosis.

Imaging the urinary tract.

Since the advent of US, nearly every malformation of the urinary tract has been diagnosed in utero. Physiologic dilatation of the renal pelvis occurs and can be misdiagnosed as hydronephrosis, so the normal gestational development of the urinary tract, and its visualization by ultrasound, should be understood. Gestational diagnosis is important for family counseling, collaboration of the perinatal team, and for determining both the future evaluation needs and the possibility of intervention. Those infants at high risk, as well as others who have specific signs and symptoms of possible urinary tract disease, deserve prompt and careful postnatal imaging studies. Ultrasonograms may be combined with other imaging modalities in specific circumstances to provide accurate diagnoses and some functional information.

Atriopeptins: circulating volume regulatory hormones with potential therapeutic role in chronic renal failure.

Sprague-Dawley rats given bolus intravenous injections of vasoconstrictors, including 1-deamino-Arg8-vasopressin (dAVP), demonstrated remarkable increases in plasma immunoreactivity (APir) to atriopeptin (AP). These elevations were accompanied by increases in systemic blood pressure, right atrial pressure and urinary volume excretion. Fractionated plasma APir peaks obtained by stimulation with dAVP were identified as primarily AP 28, with a smaller amount of AP 24, suggesting that AP 28 is the predominant circulating atrial peptide. Rats with reduced renal mass have increased single-nephron glomerular filtration rates (GFR). Despite these increases, AP 24 stimulated a marked increase in total GFR and promoted a profound natriuresis and diuresis. Atriopeptin 24 may therefore have potential as a therapeutic tool in the management of volume overload in chronic renal failure.

Atriopeptins: bioactive peptides derived from mammalian cardiac atria.

Mammalian atria possess bioactive peptides that are natriuretic-diuretic and potent relaxants of vascular and nonvascular smooth muscle. Characterization of the biological activity of rat atrial extracts indicates two major peaks, having apparent molecular weight of 20,000-30,000 (atriopeptigen) and less than 10,000 (atriopeptins). The amino acid sequence of atriopeptins I, II and III have been determined, and it has been found that their structures are only slightly different. Atriopeptin I (twenty-one amino acid residues); ser-ser-cys-phe-gly-gly-arg-ile-asp-arg-ile-gly-ala-gln-ser-gly-leu-gly- cys- asn-ser) relaxes intestinal but not vascular smooth muscle strips, and is natriuretic. Atriopeptins II and III (23 and 24 residues; the 21-sequence of I with the addition of phe-arg or phe-arg-tyr at the C-terminus, respectively) relax intestinal and vascular smooth muscle strips and are potent natriuretics. Since atriopeptigen and the atriopeptins exhibit similar biological effects the possibility of a precursor-product relationship was tested. Mild proteolytic digestion (1IU/ml trypsin) of atriopeptigen activates this peptide and reduces its apparent molecular weight. Examination of whether the atria of Krebs perfused isolated hearts released the bioactive atrial peptides revealed the presence in the cardiac effluent of a trypsin-labile substance that was natriuretic-diuretic and a smooth muscle relaxant. To determine which form of the atrial peptide (e.g. atriopeptigen or atriopeptin) is released by the atria the cardiac effluents were concentrated and partially purified. The cardiac effluent contained a substance(s) similar to atriopeptin, but did not appear to possess the less-active high molecular weight peptide, atriopeptigen.(ABSTRACT TRUNCATED AT 250 WORDS)

The psychosocial implications of pre-emptive transplantation.

Pre-emptive (primary) renal transplantation is occurring with greater frequency as pediatric transplant centers attempt to initiate renal replacement therapy at a time best designed to optimize growth and development in children. Psychosocial benefits of performing pre-emptive transplant are highlighted by an intervention before the child has symptoms of uremia and, thus, develops a self-image as a "sick patient with end-stage renal disease", avoidance of dependence on machine technology, avoidance of a change in parenting that may occur with fears about dialysis, and maintenance of an orientation toward future goals. In addition, the child will likely have less loss of school time and less disturbance in previously established social patterns. Difficulties that may be enhanced in pre-emptive transplantation arise from potentially decreased involvement of the child and family in the medical (transplant) care system prior to transplantation. The two major issues of concern are: (1) optimal education regarding patient (family) responsibility toward quality care of the graft recipient; (2) the accurate assessment of coping skills coupled with the development of optimum psychosocial support from the health care workers and community support services. The provision of a good educational and supportive program is time consuming and financially draining. We must develop creative approaches to these areas in order to enhance each child's opportunity for family and community interaction, as well as physical well-being.

The involvement of atriopeptins in blood pressure regulation.

The atriopeptins are newly discovered cardiac-derived peptides whose observed actions suggest a role in volume homeostasis and blood pressure regulation. Studies in animal models are underway to pinpoint pathogenetic mechanisms involved in the evolution of hypertension, some of which may well be shared by humans with "essential" hypertension. Preliminary observations indicate that circulating atriopeptin levels are altered in human disease. It is anticipated that exogenously administered atriopeptin may be a helpful pharmacological tool in the management of patients with volume overload and hypertension.