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5. B-type natriuretic peptide 8-32, which is produced from mature BNP 1-32 by the metalloprotease meprin A, has reduced bioactivity

Author

Boerrigter, Guido, Costello-Boerrigter, Lisa C., Harty, Gail J., Huntley, Brenda K., Cataliotti, Alessandro, Lapp, Harald, and Burnett, John C., Jr.

Subjects
Cardiovascular diseases -- Care and treatment, Cardiovascular diseases -- Research, Enzyme inhibitors -- Health aspects, Enzyme inhibitors -- Research, Natriuretic peptides -- Physiological aspects, Natriuretic peptides -- Research, Proteases -- Physiological aspects, Proteases -- Research, Biological sciences
Abstract

32-amino acid B-type natriuretic peptide (BNP 1-32) plays an important role in cardiovascular homeostasis. Recently, it was reported that BNP 1-32 is cleaved by the metalloprotease meprin A to BNP 8-32, the bioactivity of which is undefined. We hypothesized that BNP 8-32 has reduced vasodilating and natriuretic bioactivity compared with BNP 1-32 in vivo. Human BNP 8-32 and BNP 1-32 were compared in a crossover study in eight anesthetized normal canines. After a pre-infusion clearance, BNP 1-32 was infused at 30 ng x [kg.sup.-1] x [min.sup.-1] for 45 min followed by a 60-min washout and a second preinfusion clearance. Then, equimolar BNP 8-32 was infused. In half of the studies, the peptide sequence was reversed. Changes with peptides from the respective preinfusion clearance to infusion clearance were compared with paired tests. Mean arterial pressure was reduced by both BNP 8-32 and BNP 1-32 (-8 [+ or -] 3 vs. -6 [+ or -] 2 mmHg, P = 0.48). Changes in right atrial pressure, pulmonary capillary wedge pressure, heart rate, cardiac output, and glomerular filtration rate were similar. However, urinary sodium excretion increased less with BNP 8-32 than with BNP 1-32 (+171 [+ or -] 24 vs. +433 [+ or -] 43 [micro]Eq/min; P = 0.008), as did urinary potassium excretion, urine flow, and renal blood flow. While BNP 8-32 has similar vasodilating actions as BNP 1-32, its diuretic and natriuretic actions are reduced, suggesting a role for meprin A in the regulation of BNP 1-32 bioactivity in the kidney. Meprin A inhibition may be a potential strategy to increase the bioactivity of endogenous and exogenous BNP 1-32 in cardiovascular diseases. hormone; peptidase; cardiorenal regulation; natriuretic peptides

Published
2009

6. Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation

Author

Boerrigter, Guido, Costello-Boerrigter, Lisa C., Harty, Gail J., Lapp, Harald, and Burnett, John C., Jr.

Subjects
Natriuretic peptides -- Health aspects, Natriuretic peptides -- Research, Sodium channels -- Analysis, Blood vessels -- Dilatation, Blood vessels -- Analysis, Biological sciences
Abstract

Brain natriuretic peptide (BNP 1-32) plays an important physiologic role in cardiorenal homeostasis. Recently, it has been reported that BNP 1-32 is rapidly cleaved by the ubiquitous enzyme dipeptidyl peptidase IV to BNP 3-32, which lacks the two N[H.sub.2]-terminal amino acids of BNP 1-32. The bioactivity of BNP 3-32 in cardiorenal regulation is unknown. We hypothesized that BNP 3-32 has reduced vasodilating and natriuretic bioactivity compared with BNP 1-32 in vivo. Synthetic human BNP 3-32 and BNP 1-32 were administered to eight anesthetized normal canines. After baseline measurements, BNP 1-32 at 30 ng * [kg-.sup.-1] * [min.sup.-1] was administered, followed by a washout, a postinfusion clearance, and a clearance with an equimolar dose of BNP 3-32. In four studies, the sequence of BNP 1-32 and BNP 3-32 infusion was reversed. Peptides were compared by analyzing the changes from the respective preinfusion clearance to the respective infusion clearance. * P < 0.05 between peptides. BNP 3-32, unlike BNP 1-32, did not decrease mean arterial pressure (0 [+ or -] 1 vs. -7 [+ or -] 2 * mmHg, respectively) and did not increase renal blood flow (+12 [+ or ] 10 vs. +52 [+ or -] 10 * ml/min). Effects on heart rate and cardiac output were similar. Urinary sodium excretion increased 128 [+ or -] 18 [micro]eq/min with BNP 3-32 and 338 [+ or -] 40 * [micro]eq/min with BNP 1-32. Urine flow increased 1.1 [+ or -] 0.2 ml/min with BNP 3-32 and 2.8 [+ or -] 0.4 * ml/min with BNP 1-32. Plasma BNP immunoreactivity was lower with BNP 3-32, suggesting accelerated degradation. In this study, BNP 3-32 showed reduced natriuresis and diuresis and a lack of vasodilating actions compared with BNP 1-32. hormone; enzymatic degradation product; cardiorenal regulation; BNP 3-32

Published
2007

8. CRRL269

Author

Chen, Yang, primary, Harty, Gail J., additional, Zheng, Ye, additional, Iyer, Seethalakshmi R., additional, Sugihara, Shinobu, additional, Sangaralingham, S. Jeson, additional, Ichiki, Tomoko, additional, Grande, Joseph P., additional, Lee, Hon-Chi, additional, Wang, Xiaoli, additional, and Burnett, John C., additional

Published
2019
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10. CRRL269: a novel designer and renal-enhancing pGC-A peptide activator

Author

Chen, Yang, primary, Harty, Gail J., additional, Huntley, Brenda K., additional, Iyer, Seethalakshmi R., additional, Heublein, Denise M., additional, Harders, Gerald E., additional, Meems, Laura, additional, Pan, Shuchong, additional, Sangaralingham, S. Jeson, additional, Ichiki, Tomoko, additional, and Burnett, John C., additional

Published
2018
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11. MANP: Structural Insights of a Novel GC-A Receptor and cGMP Activator with Cardiorenal Enhancing and Aldosterone Suppressing Actions in Vivo

Author

Sugihara, Shinobu, primary, Ichiki, Tomoko, additional, Chen, Yang, additional, Harty, Gail J., additional, Heublein, Denise M., additional, Iyer, Seethalakshimi R., additional, Huntley, Brenda K., additional, Sangaralingham, S. Jeson M., additional, McCormick, Daniel J., additional, Buglioni, Alessia, additional, and Burnett, John C., additional

Published
2017
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15. CRRL269: a novel designer and renal-enhancing pGC-A peptide activator.

Author

Yang Chen, Harty, Gail J., Huntley, Brenda K., Iyer, Seethalakshmi R., Heublein, Denise M., Harders, Gerald E., Meems, Laura, Shuchong Pan, Sangaralingham, S. Jeson, Ichiki, Tomoko, and Burnett, Jr., John C.

Abstract

The natriuretic peptides (NPs) B-type NP (BNP) and urodilatin (URO) exert renal protective properties via the particulate guanylyl cyclase A receptor (pGC-A). As a potential renal-enhancing strategy, we engineered a novel designer peptide that we call CRRL269. CRRL269 was investigated in human cell lines and in normal canines to define potential cardiorenal enhancing actions. The mechanism of its cardiorenal selective properties was also investigated. In vitro NP receptor activity was quantified with guanosine 3′,5′-cyclic monophosphate generation. In vivo effects were determined in normal canine acute infusion studies. We observed that CRRL269 demonstrated enhanced pGC-A activity in renal compared with nonrenal cell lines. CRRL269 exerted enhanced resistance to neprilysin compared with URO. Importantly, CRRL269 exhibited significant and greater increases in urinary sodium excretion and diuresis, with less blood pressure reduction, than BNP or URO in normal canines. CRRL269 retained potent renin-angiotensin-aldosterone system (RAAS) suppressing properties shared by URO and BNP. Also, CRRL269 exerted less arterial relaxation and higher cAMP cardiomyocytes generation than BNP. CRRL269 possessed superior renal and pGC-A activating properties compared with BNP or URO in vitro. CRRL269 exerted enhanced renal actions while suppressing RAAS in vivo and with less hypotension compared with URO or BNP. Together, our study suggests that CRRL269 is a promising innovative renal-enhancing drug, with favorable protective actions targeting cardiorenal disease states through the pGC-A receptor. [ABSTRACT FROM AUTHOR]

Published
2018
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28. Progressive Bi-Ventricular Dysfunction in a Large Animal Model of Heart Failure With Rapid Ventricular Pacing: Echocardiographic Parameters and Invasive Characterization

Author

Mangiafico, Sarah, primary, Bellavia, Diego, additional, Costello-Boerrigter, Lisa C., additional, Boerrigter, Guido, additional, Harty, Gail, additional, Oehler, Elise, additional, Cataliotti, Alessandro, additional, Tamburino, Corrado, additional, and Burnett, John C., additional

Published
2012
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41. Abstract 584: Simultaneous Antagonism of the V2 Receptor with Tolvaptan and Activation of the Natriuretic Peptide A-Receptor with B-Type Natriuretic Peptide: A Novel Strategy to Physiologically Enhance Water and Sodium Excretion Without Adversely Affecting Renal Function in a Canine Model of Congestive Heart Failure

Author

Costello-Boerrigter, Lisa C, primary, Boerrigter, Guido, additional, Harty, Gail J, additional, and Burnett, John C, additional

Published
2006
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42. Oral Human Brain Natriuretic Peptide Activates Cyclic Guanosine 3′,5′-Monophosphate and Decreases Mean Arterial Pressure

Author

Cataliotti, Alessandro, primary, Schirger, John A., additional, Martin, Fernando L., additional, Chen, Horng H., additional, McKie, Paul M., additional, Boerrigter, Guido, additional, Costello-Boerrigter, Lisa C., additional, Harty, Gail, additional, Heublein, Denise M., additional, Sandberg, Sharon M., additional, James, Kenneth D., additional, Miller, Mark A., additional, Malkar, Navdeep B., additional, Polowy, Karen, additional, and Burnett, John C., additional

Published
2005
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