Graduation Year

2008

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Physiology and Biophysics

Major Professor

John R. Dietz, Ph.D.

Co-Major Professor

William R. Gower. Jr., Ph.D.

Committee Member

Kendall F. Morris, Ph.D.

Committee Member

Stanley J. Nazian, Ph.D.

Committee Member

Ravi Sankar, Ph.D.

Keywords

BNP, volume regulation, heart failure, interorgan communication, non-muscle myosins

Abstract

Natriuretic peptides are a family of hormones released by several different tissues and exert various physiological functions by coupling with cell surface receptors and increasing intracellular cyclic gyanylyl monophosphate (cGMP). Atrial Natriuretic Peptide (ANP) and B-type Natriuretic Peptide (BNP) are released in response to mechanical stretch of the atrial or ventricular myocardium, respectively and their plasma level is markedly elevated during myocardial infarction and heart failure. Heart failure in turn is associated with symptoms suggestive of perturbed gastrointestinal function such as nausea, indigestion and malabsorption.

Intragastric pressure was monitored using a balloon catheter in anesthetized mice. The pressure before and after treatment with a 10 ng/g intravenous dose of ANP, BNP, CNP or vehicle was compared and analyzed. All the natriuretic peptides significantly decreased intragastric pressure compared to vehicle. These effects were attenuated or absent in natriuretic peptide receptor type-A (NPR-A) knockout mice. Furthermore, the effect of BNP on gastric emptying and intestinal absorption was examined using a meal consisting of fluorescence labeled dextran gavage fed to awake mice. BNP significantly decreased gastric emptying and absorption as compared to vehicle control. Using a cryoinfarction acute myocardial injury model, our investigation showed that mice with acute cryoinfarction had a significantly lower gastric emptying and absorption of a gavage fed meal compared to sham. Circulating BNP levels were significantly higher in the infarcted mice compared to controls. Immunostaining showed amplified distribution of the non-muscle myosin type-II (MCH-II) in BNP treated mice. MCH-II is involved in movement of intestinal villi.

In summary, natriuretic peptides in general and BNP in particular, have gastrointestinal effects including reduced gastric contractility, emptying and absorption. In addition to their effect on smooth muscle relaxation mediated by cGMP, natriuretic peptides appear to have an effect on distribution of MHC-II in cells of the intestinal villi.

We postulate that these effects are aimed at mediating a 'communication' between the cardiovascular and gastrointestinal systems. Further characterization of such a link will not only add a dimension to the understanding of the pathophysiology of heart failure but also enhances the search for further therapeutic targets.

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