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Pulmonary Hypertension (PH) is a serious disease characterized by various degrees of pulmonary vasoconstriction and progressive fibro-proliferative remodeling and inflammation of the pulmonary arterioles that lead to increased pulmonary vascular resistance, right ventricular hypertrophy and failure. Pulmonary vascular tone is regulated by a balance between vasoconstrictor and vasodilator mediators, and a shift in this balance to vasoconstriction is an important component of PH pathology, Therefore, the mainstay of current pharmacologic therapies centers on pulmonary vasodilation methodologies that either enhance vasodilator mechanisms such as the NO-cGMP and prostacyclin-cAMP pathways and/or inhibit vasoconstrictor mechanisms such as the endothelin-1, cytosolic Ca2+, and Rho-kinase pathways. However, in addition to the increased vascular tone, many patients have a "fixed" component in their disease that involves altered biology of various cells in the pulmonary vascular wall, excessive pulmonary artery remodeling, and perivascular fibrosis and inflammation. Pulmonary arterial smooth muscle cell (PASMC) phenotypic switch from a contractile to a synthetic and proliferative phenotype is an important factor in pulmonary artery remodeling. While current vasodilator therapies also have some anti-proliferative effects on PASMCs, they are not universally successful in halting PH progression and increasing survival. Mild acidification and other novel approaches that aim to reverse the resident pulmonary vascular pathology and structural remodeling and restore a contractile PASMC phenotype could ameliorate vascular remodeling and enhance the responsiveness of PH to vasodilator therapies.
Pulmonary Hypertension (PH) is a serious disease characterized by various degrees of pulmonary vasoconstriction and progressive fibro-proliferative remodeling and inflammation of the pulmonary arterioles that lead to increased pulmonary vascular resistance, right ventricular hypertrophy and failure. Pulmonary vascular tone is regulated by a balance between vasoconstrictor and vasodilator mediators, and a shift in this balance to vasoconstriction is an important component of PH pathology, Therefore, the mainstay of current pharmacologic therapies centers on pulmonary vasodilation methodologies that either enhance vasodilator mechanisms such as the NO-cGMP and prostacyclin-cAMP pathways and/or inhibit vasoconstrictor mechanisms such as the endothelin-1, cytosolic Ca2+, and Rho-kinase pathways. However, in addition to the increased vascular tone, many patients have a "fixed" component in their disease that involves altered biology of various cells in the pulmonary vascular wall, excessive pulmonary artery remodeling, and perivascular fibrosis and inflammation. Pulmonary arterial smooth muscle cell (PASMC) phenotypic switch from a contractile to a synthetic and proliferative phenotype is an important factor in pulmonary artery remodeling. While current vasodilator therapies also have some anti-proliferative effects on PASMCs, they are not universally successful in halting PH progression and increasing survival. Mild acidification and other novel approaches that aim to reverse the resident pulmonary vascular pathology and structural remodeling and restore a contractile PASMC phenotype could ameliorate vascular remodeling and enhance the responsiveness of PH to vasodilator therapies.
Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of NO/sGC signalling, and we have recently demonstrated that coronary artery spasm (CAS) is engendered by severe impairment of platelet NO/sGC activity resulting in combined platelet and vascular endothelial damage. We therefore sought to determine whether sGC stimulators or activators might normalise NO/sGC homeostasis in platelets. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. Three groups of individuals were compared: normal subjects (n = 9), patients (Group 1) with myocardial ischaemia, heart failure and/or atrial fibrillation (n = 30), and patients (Group 2) in the chronic stage of CAS (n = 16). As expected, responses to SNP were impaired (p = 0.02) in patients versus normal subjects, with Group 2 patients most severely affected (p = 0.005). RIO alone exerted no anti-aggregatory effects but potentiated responses to SNP to a similar extent irrespective of baseline SNP response. CINA exerted only intrinsic anti-aggregatory effects, but the extent of these varied directly (r = 0.54; p = 0.0009) with individual responses to SNP. Thus, both RIO and CINA tend to normalise anti-aggregatory function in patients in whom NO/sGC signalling is impaired. The anti-aggregatory effects of RIO consist entirely of potentiation of NO, which is not selective of platelet NO resistance. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS.
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