8-bromocyclic-gmp and Hypertrophy--Right-Ventricular

To investigate the effects of long-term nitric oxide (NO) inhalation on the recovery process of right ventricular hypertrophy (RVH) and functional alterations in the NO-cyclic guanosine monophosphate (cGMP) relaxation pathway in rat conduit pulmonary arteries (PAs) in established chronic hypoxic pulmonary hypertension.. A total of 35 rats were exposed to chronic hypobaric hypoxia (380 mm Hg, 10% oxygen), and 39 rats were exposed to air for 10 days. Both groups were then exposed to 3 or 10 days of NO 10 ppm, NO 40 ppm, or air (control groups for each NO concentration), resulting in a total of 16 groups. Acetylcholine- and sodium nitroprusside (SNP)-induced relaxation were evaluated in precontracted PA rings. RVH was assessed by heart weight ratio of right ventricle to left ventricle plus septum.. NO inhalation had no effect on either the regression of RVH or the recovery process of impaired relaxation induced by acetylcholine or SNP in a endothelium-intact hypertensive conduit extrapulmonary artery or intrapulmonary artery (IPA). In a normal endothelium-intact conduit IPA, 40 ppm NO inhalation for 10 days partially augmented SNP-induced relaxation, but not that induced by acetylcholine.. Continuous NO inhalation did not affect the regression process of either established RVH or the impaired endogenous NO-cGMP relaxation cascade in a conduit PA in rats during the recovery period after chronic hypoxia.

Topics: Acetylcholine; Administration, Inhalation; Animals; Chronic Disease; Cyclic GMP; Endothelium-Dependent Relaxing Factors; Endothelium, Vascular; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Male; Nitric Oxide; Nitroprusside; Pulmonary Artery; Rats; Rats, Wistar; Vasodilation; Vasodilator Agents

Chronic hypoxia (CH) augments endothelium-derived nitric oxide (NO)-dependent pulmonary vasodilation; however, responses to exogenous NO are reduced following CH in female rats. We hypothesized that CH-induced attenuation of NO-dependent pulmonary vasodilation is mediated by downregulation of vascular smooth muscle (VSM) soluble guanylyl cyclase (sGC) expression and/or activity, increased cGMP degradation by phosphodiesterase type 5 (PDE5), or decreased VSM sensitivity to cGMP. Experiments demonstrated attenuated vasodilatory responsiveness to the NO donors S-nitroso-N-acetylpenicillamine and spermine NONOate and to arterial boluses of dissolved NO solutions in isolated, saline-perfused lungs from CH vs. normoxic female rats. In additional experiments, the sGC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, blocked vasodilation to NO donors in lungs from each group. However, CH was not associated with decreased pulmonary sGC expression or activity as assessed by Western blotting and cGMP radioimmunoassay, respectively. Consistent with our hypothesis, the selective PDE5 inhibitors dipyridamole and T-1032 augmented NO-dependent reactivity in lungs from CH rats, while having little effect in lungs from normoxic rats. However, the attenuated vasodilatory response to NO in CH lungs persisted after PDE5 inhibition. Furthermore, CH similarly inhibited vasodilatory responses to 8-bromoguanosine 3'5'-cyclic monophosphate. We conclude that attenuated NO-dependent pulmonary vasodilation after CH is not likely mediated by decreased sGC expression, but rather by increased cGMP degradation by PDE5 and decreased pulmonary VSM reactivity to cGMP.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blotting, Western; Chronic Disease; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Female; Guanylate Cyclase; Hypertrophy, Right Ventricular; Hypoxia; In Vitro Techniques; Lung; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Nitroarginine; Polycythemia; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Vasodilation