Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow

Abstract

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.

Chronic thromboembolic pulmonary hypertension: animal models

“…ET-1 is a potent vasoconstrictor and mitotic peptide for vascular smooth muscle cells. ET-1 overexpression has been found in other animal models of high pulmonary flow [38][39][40]. ET-1 overproduction is probably a response to stimuli such as shear stress resulting from arterial pressure elevation [47].…”

Progressive dysfunction of nitric oxide synthase in a lamb model of chronically increased pulmonary blood flow: a role for oxidative stress

“…In fact, this early pulmonary vascular dysfunction is often exacerbated in the immediate postoperative period, manifesting as increased vascular reactivity that may produce severe hypoxemia, acidosis, low cardiac output, and death if not treated immediately (7,11,31). A complete understanding of the mechanisms responsible for this pulmonary vascular dysfunction is lacking, but evidence suggests that aberrant nitric oxide (NO)-cGMP signaling and oxidative stress may participate (1,3,6,11,15,33,39,41).Basal NO production by the vascular endothelium is integral to the maintenance of the normal low resistance state of the pulmonary vasculature, and dynamic alterations in NO production modulate vascular relaxation and constriction in response to various stimuli. NO is produced in vascular endothelial cells by nitric oxide synthase (NOS) from the oxidation of the guanidino nitrogen moiety of L-arginine.…”

“…Once formed, NO diffuses into vascular smooth muscle cells where it activates soluble guanylate cyclase (sGC), which produces cGMP from GTP, resulting in smooth muscle relaxation through activation of a cGMP-dependent protein kinase (19,25). Both animal and human studies indicate that abnormally increased pulmonary blood flow results in an early selective impairment of endothelium-dependent pulmonary vascular relaxation, suggestive of decreased NO bioavailability (11,33).Impaired bioavailable NO has been implicated in a number of cardiovascular diseases and has been associated with oxidative stress resulting from the production of reactive oxygen species (ROS) (10, 15). Although multiple pathological mechanisms have been proposed, the reaction of superoxide anion with NO may be particularly important.…”

“…Once formed, NO diffuses into vascular smooth muscle cells where it activates soluble guanylate cyclase (sGC), which produces cGMP from GTP, resulting in smooth muscle relaxation through activation of a cGMP-dependent protein kinase (19,25). Both animal and human studies indicate that abnormally increased pulmonary blood flow results in an early selective impairment of endothelium-dependent pulmonary vascular relaxation, suggestive of decreased NO bioavailability (11,33).…”

Hypoxic Pulmonary Arterial Hypertension in the Chicken Model

“…Impairment of NO production in chronic hypoxia occurs in pulmonary hypertensive animals (Maruyama and Maruyama, 1994;Reddy et al, 1996;Tozzi and Riley, 1990) and humans (Cooper et al, 1996;Dinh-Xuan et al, 1992;Dinh-Xuan et al, 1989). However, the cause of this impairment remains unknown.…”