Rose M. Overton

Adrenomedullin, endothelin, neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure indicators

OBJECTIVES The present investigation was designed to determine the best endogenous plasma marker of early congestive heart failure (CHF). METHODS Forty volunteers with mild CHF (New York Heart Association Class I, n = 12), moderate (Class II, n = 8), or severe (Class III and Class IV, each = n of 5) and 10 age-matched healthy individuals had the simultaneous evaluation of their respective plasma samples by the following radioimmunoassays: atrial natriuretic peptide, ANP; three N-terminal ANP prohormone assays, i.e., proANPs 1-30, 31-67, and 79-98 with the numbers referring to their amino acid (a.a.) sequences in their 126 a.a. prohormone; brain (BNP) and C-natriuretic peptides; N-terminal BNP prohormone; adrenomedullin; neuropeptide Y and endothelin. RESULTS ProANPs 31-67, 1-30 and 79-98 had 100% (P = 0.01), 83% (P = 0.09) and 50% (P = 0.74) sensitivity in differentiating Class I CHF subjects from healthy subjects. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y, and endothelin assays could not differentiate mild CHF subjects from healthy individuals. Logistic regression analysis revealed that only proANP 31-67 significantly (P = 0.0001) discriminated between early CHF (5226 +/- 377 pg/ml) and healthy individuals (1595 +/- 157 pg/ml). The positive and negative predicative values of proANP 31-67 were excellent (100% for each). The peptides measured in these assays were found to be independent markers of CHF with respect to left ventricular ejection fraction. CONCLUSIONS ProANPs 31-67 is the most sensitive marker in discriminating NYHA Class I CHF subjects from healthy individuals. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y and endothelin radioimmunoassays cannot discern mild CHF. These peptides are independent of left ventricular ejection fraction.

Comparison of vessel dilator and long-acting natriuretic peptide in the treatment of congestive heart failure

BACKGROUND Long-acting natriuretic peptide (LANP; proANF 1-30) and vessel dilator (proANF 31-67) enhance sodium and water excretion in healthy human beings. The current investigation was designed to compare the beneficial effects of LANP and vessel dilator in persons with congestive heart failure (CHF). METHODS AND RESULTS LANP and vessel dilator (100 ng/kg body weight/min, respectively) were given intravenously for 60 minutes to subjects with New York Heart Association class III CHF (n = 17) while their urine volume and sodium and potassium excretion were monitored. Vessel dilator increased urine flow more than 5-fold, which was still increased (P <.001) 3 hours after stopping its infusion. Vessel dilator enhanced sodium excretion 3-fold in subjects with CHF (P <.01), which was still significantly (P <.01) elevated 3 hours after infusion. The effects of LANP were diminished, with urine flow only increasing 2-fold (P <.05). The fractional excretion of sodium increased maximally 6-fold secondary to vessel dilator and 3-fold with LANP. The CHF control patients had no changes in the above parameters. Part of the diminished response to LANP was found to be caused by its rapid decrease in the circulation of individuals with CHF. CONCLUSIONS These results indicate that vessel dilator has significant beneficial diuretic and natriuretic properties, which are not diminished, whereas the effects of LANP are diminished in human beings with CHF compared with healthy individuals.

Elevated atrial natriuretic peptides and early renal failure in type 2 diabetic Goto-Kakizaki rats.

The present investigation was designed to determine if atrial natriuretic peptides (ANPs) are increased in a spontaneous model of non-obese type 2 diabetes, the Goto-Kakizaki (GK) rat. Four peptide hormones originating from the ANP prohormone were increased twofold (P < .05) to sixfold (P < .01) in the circulation of GK rats compared with nondiabetic Wistar rats from which the GK colony was originally derived. Thus, ANP, long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide were (mean +/- SE) 497 +/- 78, 1,285 +/- 105, 457 +/- 45, and 385 +/- 87 pg/mL in GK rats, versus 78 +/- 23, 542 +/- 77, 137 +/- 26, and 134 +/- 33 pg/mL, respectively, in Wistar rats. In evaluating the cause of the increased ANPs, the blood volume of GK rats (16.2 +/- 0.4 mL) was significantly (P < .01) increased compared with Wistar rats (9.5 +/- 0.3 mL). The ventricles of GK rats were not dilated when examined by transthoracic echocardiography, but the venous system was markedly distended. GK rats had a 48% to 79% decrease in renal function (ie, increased serum creatinine and blood urea nitrogen [BUN]) compared with Wistar rats. These results indicate that circulating ANPs are increased in the GK spontaneously diabetic rat secondary to (1) increased blood volume, which leads to increased synthesis and release of ANPs, and (2) renal failure, which results in a delayed metabolic processing of these peptides. The early combined increases of the four atrial peptides collectively may contribute to the hyperfiltration that occurs in early diabetes mellitus.

Atrial natriuretic peptide increases Urodilatin in the circulation

Background: Urodilatin is a 32-amino-acid (AA) peptide formed in the kidney. Methods: High-performance gel permeation chromatography and high-pressure liquid chromatography evaluation of plasma followed by sensitive urodilatin and atrial natriuretic peptide (ANP) assays revealed that urodilatin does circulate distinctly from ANP. Results: Urodilatin circulates at very low levels (i.e 9–12 pg/ml). Infusion of ANP increased the circulating concentration of urodilatin 135-fold (p < 0.001), suggesting that some of the effects of ANP may be mediated by urodilatin while long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide did not affect urodilatin in healthy humans (n = 30). Only ANP decreased the renal clearance of urodilatin (60–75%, p < 0.01). Urodilatin was metabolized into peptides smaller than 5 AAs as well as excreted intact into urine. Conclusion: Urodilatin circulates and is increased by ANP in humans.

Processing of Long-Acting Natriuretic Peptide and Vessel Dilator in Human Plasma and Serum

High performance-gel permeation chromatography (HP-GPC) evaluation of human plasma and serum incubated at 37 degrees C up to 24 h after the addition of long-acting natriuretic peptide (LANP) revealed a 25% decrease in LANPs peak at 2 h followed by an increase in plasma without EDTA at 8 h (p < 0.001). Vessel dilators HP-GPC peak did not decrease until after 8 h of incubation. These findings help explain the prolonged half-lives and 6-24 higher plasma concentrations of vessel dilator and LANP compared to atrial natriuretic factor and kaliuretic peptide, which are completely degraded in plasma within 2 h.

Evidence for an Atrial Natriuretic Peptide–-Like Gene in Plants

The presence of a gene found in the animal kingdom expressing a peptide hormonal system in plants has never been demonstrated. However, there is at least one potential hormonal system in plants (i.e., the atrial natriuretic peptide–-like hormonal system) based upon high-performance gel permeation chromatography and radioimmunoassay evidence. In plants, atrial natriuretic–like peptides enhance the flow of water up stems to leaves and flowers. The present investigation was designed to determine within plants the presence of the atrial natriuretic peptide (ANP) gene as defined by Southern blot hydridization, indicating the presence of the ANP gene sequence, and by Northern blots assessing the ability of this gene to express ANP prohormone mRNA. Southern blots of English ivy (Hedra helix) genomic DNA revealed that the ANP gene sequence was present in its roots, stems, and leaves. Northern blot analysis of total plant RNA isolated from leaves, roots, and stems of Hedra helix revealed a single 0.85-kilobase prohormone ANP transcript in stems similar to that detected in rat heart. Semiquantitative analysis suggested that ANP gene expression was less in English ivy compared with that of rat heart atria but similar to the amount found in extra atrial rat tissues when corrected for total RNA when quantitated by 2D scanning. The demonstration of the ANP gene sequences and expression of the ANP-like gene in plants suggests that plants and animals may have evolved much more similarly than previously thought.

Atrial natriuretic peptides increase calcitonin gene-related peptide within human circulation

Long-acting natriuretic peptide (LANP), vessel dilator, and atrial natriuretic factor (ANF) (each infused at 100 ng/kg body weight [BW].min for 60 minutes) increased the circulating concentration of calcitonin gene-related peptide (CGRP) threefold to fourfold in 30 healthy humans. Within 30 minutes of stopping ANF infusion, the CGRP circulating concentration had returned to preinfusion levels, whereas its increase secondary to the other atrial peptides was still significant 2 to 3 hours after cessation of their infusions. There was a 50% decreased excretion (P < .001) of CGRP into the urine secondary to LANP and vessel dilator, which correlated with the increase of CGRP in the circulation. The ANF-induced 50% decreased CGRP excretion occurred after the circulating concentration of CGRP had returned to preinfusion levels. Kaliuretic peptide did not affect CGRP circulating concentration or excretion into urine. These data suggest that LANP and vessel dilator inhibit the metabolic breakdown of CGRP as part of their mechanism of increasing CGRP in plasma, whereas the ANF effect of increasing CGRP in plasma appears to be secondary to stimulating the release of CGRP.

Processing of kaliuretic peptide in human plasma and serum

High performance-gel permeation chromotography (HP-GPC) evaluation of human plasma and serum incubated at 37 degrees C for 0, 0.5, 1, 1.5, 2, 4, 8, and 24 h after the addition of the human synthetic form of kaliuretic peptide revealed only a peak where the pure synthetic form of kaliuretic peptide elutes and that this peak decreased by 60% or greater in plasma-EDTA, plasma-heparin, and serum within 30 min. The metabolic processing of kaliuretic peptide in plasma-EDTA, plasma-heparin, and serum, respectively, was complete in 2 h with only 4%, 1%, and 2% of kaliuretic peptides originally added concentration being still present.

Prospective evaluation of the Batista procedure with circulating atrial natriuretic peptides

A proposed treatment of end-stage heart disease is partial left ventricular resection (i.e., Batista procedure). To determine if congestive heart failure objectively improves after this procedure, we prospectively evaluated partial left ventriculectomy with objective plasma markers of the severity of congestive heart failure (i.e., three N-terminal atrial natriuretic peptide prohormone radioimmunoassays and atrial natriuretic peptide radioimmunoassay) prior to and during the 12 months after partial left ventriculectomy. The four measured atrial natriuretic peptides improved in 30% of the subjects at 1 month post-surgery. Eighty percent of the subjects, however, had higher circulating atrial natriuretic peptides (P<0.01) at 3, 6, and 12 months than prior to surgery indicating that their congestive heart failure was objectively worse than prior to surgery. Likewise, at 3, 6, and 12 months post-surgery the ejection fractions were not significantly better than prior to surgery. By 6 months the subjects with the highest circulating atrial natriuretic peptides had died (60% of subjects). In conclusion, congestive heart failure improves within 1 month in some patients but then deteriorates at 3, 6, and 12 months after the Batista procedure. There was no survival benefit with 60% of the patients expiring within 6 months after the Batista procedure.

Corrigendum to: “Adrenomedullin, endothelin, neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure indicators” [Cardiovascular Research 36 (1997) 246–255]

Fig. 1 of the article by Daggubati et al. in Cardiovascular Research 1997;36:246-255 was inadvertently the plotted values for high performance gel permeation chromatography (HP-GPC) of healthy individuals rather than the plotted values of patients with congestive heart failure as shown overleaf. Fig. 1 High-performance gel permeation chromatography evidence that (A) atrial natriuretic peptide prohormone (proANP) 1–30, (B) atrial natriuretic peptide prohormone (proANP) 31–67, (C) atrial natriuretic peptide (ANP), and (D) …