Michael T. McCormick

Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, and/or kaliuresis in humans.

BackgroundThree peptides consisting of amino acids 1-30, 31-67, and 79-98 of the 126–amino acid atrial natriuretic factor prohormone (proANF), which have blood pressure-lowering, diuretic, natriuretic, and/or kaliuretic properties in animals, were investigated to determine if they have similar properties in humans. Methods and ResultsThirty-six healthy, normotensive human volunteers (18 men and 18 women, ages 20 to 58 years) were divided into six similar groups based on age, sex, weight, blood pressure, and heart rate. After a 60-minute baseline period, 100 ng of proANFs 1-30, 31-67, 79-98, or ANF/kg body wt per minute was given intravenously for 60 minutes followed by a 3-hour postinfusion data collection period. Each of the atrial natriuretic peptides decreased systolic and diastolic blood pressures (P<.05), with proANF 31-67 causing the largest decrease. Urine flow increased 4- to 12-fold and was still significantly increased (P<.01) for 2 to 3 hours after stopping the respective infusions of proANFs 1-30, 31-67, and 79-98. Atrial natriuretic factor (ANF) increased urine flow 4- to 11-fold but by 2 hours after infusion was significantly increased in only 1 of 6 subjects. Sodium excretion increased 3-to 8-fold, 3- to 6-fold, 0- to 2-fold (NS), and 3- to 11-fold, respectively, with proANFs 1-30, 31-67, 79-98, and ANF. Natriuretic effects of proANFs 1-30 and 31-67 were significantly prolonged (P<.001) compared with ANF. ProANFs 1-30, 31-67, 79-98, and ANF increased potassium excretion 2- to 3-fold, 0-fold, 3- to 4-fold, and 2-fold, respectively. High-performance gel permeation chromatography followed by the respective radioimmunoassays revealed that proANFs 1-30, 31-67, 79-98, and 68-98, as well as ANF circulate as distinct peptides. ConclusionsProANFs 1-30, 31-67, and 79-98, as well as ANF have significant blood pressure-lowering and diuretic properties. ProANFs 1-30 and 31-67 also have natriuretic properties in humans that are significantly (P<.001) prolonged compared with ANF. ProANF 79-98, although not possessing any natriuretic property, is the strongest stimulator of potassium excretion of the four atrial natriuretic peptides.

Vessel Dilator Enhances Sodium and Water Excretion and Has Beneficial Hemodynamic Effects in Persons With Congestive Heart Failure

BACKGROUND Vessel dilator, a 37-amino acid peptide hormone synthesized in the heart, enhances urine flow 4- to 12-fold and sodium excretion 3- to 6-fold in healthy humans. The present investigation was designed to determine whether vessel dilator might have similar beneficial effects in persons with congestive heart failure (CHF). METHODS AND RESULTS Vessel dilator (100 ng/kg body weight per minute) given intravenously for 60 minutes to NYHA class III CHF subjects increased urine flow 2- to 13-fold, which was still increased (P<0.001) 3 hours after its infusion was stopped. Vessel dilator enhanced sodium excretion 3- to 4-fold in CHF subjects (P<0.01), which was still significantly (P<0.01) elevated 3 hours after infusion. Vessel dilator decreased systemic vascular resistance 24%, pulmonary vascular resistance 25%, pulmonary capillary wedge pressure 33%, and central venous pressure 27% while increasing cardiac output 34%, cardiac index 35%, and stroke volume index 24% without significantly affecting heart rate or pulmonary artery pressure in the CHF subjects. The control CHF patients did not have any changes in the above parameters. CONCLUSIONS These results indicate that vessel dilator has significant beneficial diuretic, natriuretic, and hemodynamic properties in humans with congestive heart failure.

Atrial natriuretic peptide increases adrenomedullin in the circulation of healthy humans

Adrenomedullin (ADM) is a new 52 amino acid peptide originally isolated from extracts of human pheochromocytoma. ADMs biologic properties are nearly identical to those of atrial natriuretic peptides. Thus, the 4 peptide hormones originating from amino acids 1-30 [long acting natriuretic peptide], 31-67 [vessel dilator], 79-98 [kaliuretic peptide] and 99-126 [atrial natriuretic factor; ANF] of the 126 amino acid ANF prohormone as well as ADM have blood pressure lowering and diuretic properties. The present investigation was designed to determine if one or more of these 4 atrial natriuretic peptides increase adrenomedullin within the circulation of healthy humans. Infusion of 100 ng/kg body weight/minute for 60 minutes of the respective atrial peptides resulted in a 4-fold (P < 0.001) increase in the circulating concentration of adrenomedullin secondary to the ANF infusion but no increase in adrenomedullin with the long acting natriuretic peptide, vessel dilator, or kaliuretic peptide infusions. The four-fold increase of adrenomedullin in the circulation persisted throughout the infusion of ANF, but returned to pre-infusion levels within 30 minutes of stopping the ANF infusion. Infusion of 10 pg/kg body weight/minute for 60 minutes of ANF resulted in a 2 1/2-fold increase (P < 0.05) in the circulating concentration of adrenomedullin. There was a significant (P < 0.01) diuresis and blood pressure lowering effect with each of the atrial natriuretic peptides in the present investigation. This investigation suggests that 1) atrial natriuretic factor increases the release of adrenomedullin and 2) that the diuretic and blood pressure lowering effects previously attributed to atrial natriuretic factor may be partially due to adrenomedullin since both increased during the ANF infusion and both have similar biologic effects. As opposed to atrial natriuretic factor, adrenomedullin was not increased by long acting natriuretic peptide, vessel dilator, or kaliuretic peptide suggesting that their biologic effects do not involve adrenomedullin.

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.

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.

Atrial natriuretic peptides negatively and positively modulate circulating endothelin in humans

The present investigation was designed to examine the effect of four atrial peptide hormones with vasodilatory properties on the circulating immunoreactive (ir) levels of the vasoconstrictive peptide endothelin (ET) in 36 healthy human subjects. Circulating levels of human ET and cyclic guanosine monophosphate ([cGMP], a potential mediator of the effects of atrial peptides), were measured every 30 minutes during 1-hour preinfusion, 1-hour infusion, and 3-hour postinfusion periods. Atrial natriuretic factor ([ANF] amino acid (aa) 99 to 126 of the 126-aa ANF prohormone) and kaliuretic peptide (aa 79 to 98 of this same prohormone) significantly (P<.05) decreased circulating ET concentrations. Kaliuretic peptide effects were early and ANF effects were delayed until kaliuretic peptide effects began to wane. Long-acting natriuretic peptide (LANP), consisting of aa 1 to 30 of the ANF prohormone, on the other hand, significantly (P<.05) increased ET circulating concentrations during a 1-hour infusion period. The increase in ET in the circulation secondary to LANP became nonsignificant, although it was still elevated, within 30 minutes of ceasing LANP infusion. Vessel dilator, consisting of aa 31 to 67 of the ANF prohormone, and infusion of vehicle alone did not significantly change circulating levels of ET during the 5 hours of this investigation. ANF infusion increased plasma cGMP sevenfold, but plasma cGMP had decreased to only onefold above normal during the period that ANF had an effect on circulating ET levels. There was not any significant increase or decrease in plasma cGMP concentrations secondary to the other atrial peptide hormones. These data suggest that kaliuretic peptide and ANF negatively modulate circulating ET concentrations, while LANP, which is released simultaneously with ANF in response to physiologic stimuli, positively modulates circulating ET concentrations to help maintain circulating ET within a narrow normal range. The data from the present investigation would further suggest that circulating cGMP levels do not mediate the various atrial peptide effects on circulating ET levels.

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.

Atrial Natriuretic Peptides and Cyclic Guanosine Monophosphate Metabolism

Atrial natriuretic factor (ANF), consisting of amino acids 99–126 of the 126 amino acid ANF prohormone, increases cyclic guanosine monophosphate (GMP) (thought to be the mediator of its physiologic effects) in plasma and urine of human subjects. Long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide, consisting of amino acid 1–30, 31–67, and 79–98, respectively, of this same prohormone have natriuretic, diuretic, kaliuretic, and blood pressure lowering properties in humans. These three new peptide hormones increase cyclic GMP in vitro but were never investigated to determine whether they also cause extrusion of cyclic GMP from cells, resulting in an increase of cyclic GMP in plasma and/or urine. Infusion of each of these peptide hormones at their 100 ng/kg body weight/min concentrations for 60 minutes into healthy humans resulted in a sevenfold increase in cyclic GMP in plasma and urine secondary to ANF, but no significant increase secondary to the other atrial peptide hormones. Based on the current data, ANF has a unique effect on the metabolism of cyclic GMP, causing it to be extruded from the cell, whereas the other three atrial peptides represent the more classical metabolism of cyclic GMP via cyclic GMP phophodiesterases.

Using a data warehouse to monitor clinical outcomes associated with simvastatin tablet splitting

A data warehouse was used to monitor therapeutic outcomes for a simvastatin tablet-splitting initiative. The data included prescription and laboratory information for all patients taking simvastatin between October 1, 1998 and February 28, 2003. Among 44,038 patients receiving simvastatin, the low-density lipoprotein (LDL) levels of 194,213 patients were reported. The tablet-splitting initiative was started in April 1999 and 5,683 patients were converted from whole to half tablets. The average LDL for these patients decreased by 15 mg/dL. A subset of patients (464 or 8.1%) had an increase in LDL greater than 10% and were above levels established in therapeutic guidelines. Based on the findings, concern about tablet splitting is most warranted during the initial period, when patients are switched from whole to split tablets. The economic benefit was more than

Incremental improvements in physician-computer interaction in response to clinical needs and user feedback

300,000 per year at our facility. Simvastatin tablet splitting appears to be an effective cost savings measure with little associated risk.