Atrial natriuretic peptide accounts for increased cGMP in hypoxia-induced hypertensive rat lungs

Abstract

Perfusate levels of nitric oxide (NO)-containing compounds and guanosine 3',5'-cyclic monophosphate (cGMP) are increased in hypoxia-induced hypertensive rat lungs. To test if increased cGMP was due to NO stimulation of soluble guanylate cyclase (sGC), we examined effects of inhibition of NO synthase with N omega-nitro-L-arginine (L-NNA) on perfusate accumulation of cGMP in physiological salt solution (PSS)-perfused hypertensive lungs isolated from rats exposed for 3-4 wk to hypobaric hypoxia. Because 200 microM L-NNA did not reduce cGMP, we next examined inhibitors of other pathways of stimulation of either sGC or particulate GC (pGC). Neither 5 microM Zn-protophorphyrin, an inhibitor of CO production by heme oxygenase, nor 10 mM aminotriazole, an inhibitor of H2O2 metabolism by catalase, reduced perfusate cGMP. However, an antiserum to atrial natriuretic peptide (ANP; 100 microliters antiserum/30 ml PSS), to inhibit ANP activation of pGC, completely prevented accumulation of the nucleotide. ANP antiserum was also more effective than L-NNA in reducing lung tissue cGMP. In contrast, L-NNA but not ANP antiserum increased resting vascular tone. These results suggested that whereas ANP determined perfusate and tissue levels of cGMP, NO regulated vascular tone. To test if perfusate cGMP reflected ANP stimulation of pGC in endothelial rather than smooth muscle cells, we examined effects of 10 microM Zaprinast, an inhibitor of cGMP hydrolysis in smooth muscle but not endothelial cells, and found no increase of cGMP in hypertensive lungs. ANP levels were not elevated in hypertensive lungs, and it is unclear by what mechanism the ANP-stimulated activity of pGC is increased in hypertensive pulmonary vascular endothelial cells.

Beneficial Effects of Phosphodiesterase 5 Inhibition in Pulmonary Hypertension Are Influenced by Natriuretic Peptide Activity

“…10 -13 Previous studies suggest that ANP is the primary source of cyclic GMP in hypoxia-adapted rats. 9 Consistent with this, NPR-A Ϫ/Ϫ mice showed a small, nonsignificant rise in lung cyclic GMP levels during exposure to hypoxia (compared with NPR-A ϩ/ϩ mice). A significant rise in lung cyclic GMP levels was recorded in sildenafil-treated hypoxic NPR-A Ϫ/Ϫ mice, which may be expected to contribute to the fall in RVSP in these animals.…”

“…4 -8 The major factors stimulating cyclic GMP synthesis in pulmonary vascular tissue are nitric oxide (NO) and the natriuretic peptides (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and c-type natriuretic peptide [CNP]). 9 Natriuretic peptide levels are elevated in all forms of pulmonary hypertension and may influence the response to PDE5 inhibitors in this condition. The cardiovascular response to the natriuretic peptides is transduced by NPR-A, a guanylyl cyclase-linked receptor.…”

Phosphodiesterase Type 5 as a Target for the Treatment of Hypoxia-Induced Pulmonary Hypertension

“…Nitric oxide and the natriuretic peptides are thought to drive cGMP synthesis in the lung, and arguably, the increase in natriuretic peptide levels in hypoxia-induced pulmonary hypertension is largely responsible for the increase in lung cGMP levels measured in this setting. 18 An increase in PDE5 activity with hypoxia would limit this rise and facilitate an increase in pulmonary vascular resistance.…”

A Comprehensive Review: The Evolution of Animal Models in Pulmonary Hypertension Research; Are We there Yet?

“…Adapted from Santibañez et al 186 pressure of 380 mmHg, which is equivalent to half that at sea level). [66][67][68][69][70] A number of experimental treatments have been shown to attenuate PH in this model, including digoxin, A-17 (an inhibitor of microRNA-17), hypercapnia at a CO 2 saturation of 6.5% combined with CHP (10% FiO 2 ), bosentan, dichloroacetate, and targeted gene delivery of BMPR-2. 43,55,67,[70][71][72] The CHP model has greatly contributed to our current understanding of the molecular processes involved in the vascular remodeling induced by chronic pulmonary disease and oxygen deprivation.…”