Changes and Distributions of Peptides Derived From Proadrenomedullin in Left-to-Right Shunt Pulmonary Hypertension of Rats

Abstract

ulmonary hypertension (PHT) is a common and serious complication of left-to-right shunt congenital heart disease (CHD), and the risk and mortality of cardiac surgery in CHD patients complicated with serious PHT are significantly increased. However, the pathogenesis of PHT remains unclear so far.Adrenomedullin (ADM), a potent vasodilation peptide, was originally isolated from human pheochromocytoma and is thought to have an autocrine or paracrine action, playing an important role in the regulation of vascular tone. Later, it was found that its precursor preproadrenomedullin (preproADM) consists of 185 amino acids in length and is cleaved into 4 active peptides by endogenous protease: ADM, adrenotensin (ADT), proadrenomedullin N-terminal 20 peptide (PAMP) and proADM45-92. 1,2 The relationship between the 4 peptides and PHT is being investigated and in the present study, we investigated the changes and distribution of the peptides derived from proADM in a rat model of PHT. Methods Animal Model PreparationMale Wistar rats (n=21, body weight 140-160 g) were randomly divided into a Control group (n=12) and Experiment group (n=9). The study met the National Research Council's Guide for the care and use of laboratory animals.In the Experiment group, a left common carotid artery to external jugular vein shunt operation was performed to establish a left-to-right shunt model. 3 Animals were anesthetized with 0.25% pentobarbital sodium (40 mg/kg ip) and heparin (0.5 mg/kg) was used to prevent solidification. The left common carotid artery and left external jugular vein were connected by a sterilized cuff. Postoperatively, there was obvious pulsation and bulging of the proximal cardiac part of the external jugular vein and the oxygen saturation had increased from 81±4.7% to 91±5.6%, indicating smooth Circ J 2008; 72: 476 -481 (Received May 22, 2007; revised manuscript received November 5, 2007; accepted November 13, 2007 Background Pulmonary hypertension (PHT) is a common complication of congenital heart disease and the pulmonary vascular structural remodeling because of the high pulmonary blood flow is considered to be the key pathologic process. In the present study the change and distribution of peptides derived from proadrenomedullin in a rat model of PHT caused by a left-to-right shunt were measured to elucidate the mechanism. Methods and Results Twelve weeks after a cervical shunt was established by a cuff technique in an experimental group of rats, the systolic pulmonary artery pressure (sPAP) was measured by catheterization. Morphologic assessment included the measurement of the weight ratio of the right ventricle (RV) to the left ventricle plus septum (LV+SP) and the mean percentage of media wall thickness (MT%) in moderate-sized pulmonary arteries. The distribution of adrenomedullin (ADM), adrenotensin (ADT) and proadrenomedullin N-terminal 20 peptide (PAMP) were measured by immunohistochemical staining. The mRNA expressions of ADM, ADT, PAMP and proADM45-92 were investigated by reverse transcription polymerase ch...

Expression of peptide fragments from proADM and involvement of mitogen‐activated protein kinase signaling pathways in pulmonary remodeling induced by high pulmonary blood flow

“…This is consistent with the results of our previous research that the left‐to‐right shunt rats displayed more brown granules of ADM and PAMP in the pulmonary arterial wall (Cuifen et al. ).…”

Adrenomedullin and adrenotensin regulate collagen synthesis and proliferation in pulmonary arterial smooth muscle cells

“…Among them, ADM and adrenotensin (ADT) are distributed throughout the vascular smooth muscle cell layer, whereas proADM N-terminal 20 peptide (PAMP) is found within the tunica adventitia. ADM stimulates blood vessel dilation and inhibits smooth muscle cell proliferation and migration (6,7). ADM activates the potassium channel in smooth muscle cells to enable cellular hyperpolarization (8).…”

Effect of adrenotensin on cell proliferation is mediated by angiotensin II in cultured rat mesangial cells

“…Gumusel et al reported that ADM induces endothelium-dependent vasoconstriction and elevation of blood pressure [5,6] . In a rat model of pulmonary hypertension, Cuifen et al reported that ADM and ADT have opposite effects on vasoactivity and showed reciprocal inhibition in their release [7] . In Qi's study, ADT induced an increase in the concentration of medium ir-ADM [8] .…”