These observations are relevant in vivo as C42S PKG Iα knockin mice, which express an engineered form of the kinase that cannot be activated by oxidants, were resistant to the compound we have identified. Improved indices of RV systolic function, 4. B, Continuous recordings from another cell-attached patch before (control) and 10 minutes after application of 10 μmol/L forskolin. This site uses cookies. Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. This work was supported by the American Heart Association (10SDG2630161 to Dr Blanton) and by the National Institutes of Health (1R03AG042367 to Dr Blanton). Resistant hypertension: diagnosis, evaluation, and treatment. The study demonstrated no difference in mortality in the nesiritide group although it was not adequately powered to detect mortality differences. The specific role for PDE5 inhibition in HFPEF remains unclear, in light of the recent RELAX data. Synthetic BNP (nesiritide) represents the most extensively studied NP to date in ADHF. In addition, secondary end points, such as mortality, quality of life, and 6-minute walk test, did not differ between treatment groups. Protein kinase G (PKG) activity modulates several targets involved in muscular contraction. Restoration of NOS3 coupling inhibited LVH and LV dysfunction after TAC. Previous studies have demonstrated that PKA inhibits BKCa channel activity in neuroendocrine cells45 or in uterine smooth muscle cells.47 Furthermore, PKA-mediated relaxation of mesenteric arteries does not involve potassium channel activity.48 In contrast, there is evidence that PKA may stimulate BKCa channel opening in other types of VSM. In summary, findings from on-cell and cell-free patch-clamp experiments provide direct evidence that cAMP-dependent vasodilators open BKCa channels in coronary myocytes by cross-activation of PKG (but not via PKA). The human recombinant atrial NP compound carperitide reduces PCWP in patients with ADHF when administered as a bolus dose.84 Carperitide remains in clinical use in Japan for treatment of ADHF.85 In addition, more recent studies investigated the effect of carperitide on LV remodeling after acute anterior MI. The apparent regression of LV remodeling and hypertrophy in the absence of reduced afterload in this study strongly suggested a direct effect of sildenafil on myocardial function and remodeling. In vascular smooth muscle cells, only type I PKG is present as two isoforms, Iα and Iβ. However, multiple ensuing studies revealed the CM-specific role of pGC-A in attenuating the cardiac response to LV pressure overload. However, if a drug induces oxidation of C42, this will attenuate the adduction of dBBr with the kinase and so reduce the fluorescence compared with vehicle-treated control (Figure 1A). Findings from both on-cell and cell-free patches demonstrated that cAMP, cAMP-dependent vasodilators, and cGMP opened this potassium channel. Vighi E, Trifunović D, Veiga-Crespo P, Rentsch A, Hoffmann D, Sahaboglu A, Strasser T, Kulkarni M, Bertolotti E, van den Heuvel A, Peters T, Reijerkerk A, Euler T, Ueffing M, Schwede F, Genieser HG, Gaillard P, Marigo V, Ekström P, Paquet-Durand F. Proc Natl Acad Sci U S A. Multiple lines of evidence reveal that NOS3 and pGC inhibit pathological cardiac remodeling in vivo. Proof of Principle for a Novel Class of Antihypertensives That Target the Oxidative Activation of PKG Iα (Protein Kinase G Iα), http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.117.09670/-/DC1, Disruption of Pressure-Induced Ca2+ Spark Vasoregulation of Resistance Arteries, Rather Than Endothelial Dysfunction, Underlies Obesity-Related Hypertension, Nitric Oxide-cGMP Signaling in Hypertension, Blood Pressure–Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of cGMP-Dependent Protein Kinase, Response by Prysyazhna et al to Letter Regarding Article, “Blood Pressure–Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of cGMP-Dependent Protein Kinase”, Development of PKG Iα (Protein Kinase G Iα)–Dimerizing Antihypertensive Drugs, Arteriosclerosis, Thrombosis, Vascular Biology (Basic), Vascular Health and Biology/Thrombosis (Clinical), Hypertension is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. Although the majority of these trials suggest that PDE5 inhibition affects SBP minimally, all of these studies excluded patients taking oral nitrates. More recently, subcutaneous nesiritide has been developed in an attempt to replace intermittent infusion with more chronic delivery of systemic NP therapy. Initial clinical investigations studied the vasodilating properties of these compounds in ADHF. EDHF predominates over NO-cGMP– or prostacyclin-dependent mechanisms of vasodilation in resistance blood vessel control of blood pressure,6–8 operating in various vascular beds in many species, including humans.9–11. A similar model, in which PDE5 expression was genetically enhanced in the CM but could be reversed by doxycycline, demonstrated increased TAC-induced cardiac remodeling in PDE5 transgenic mice, and further that inhibition of PDE5 expression with doxycycline produced a recovery of LV function and remodeling.28 Importantly, this study also demonstrated marked reduction of myocardial PKGI activity in hearts of PDE5 transgenic mice, providing strong correlative evidence for a role of PKGI in this process. Myocytes were isolated by a modification of a procedure described previously.17 For cell-attached patches, several drops of cell suspension were placed in a recording chamber containing (in mmol/L) KCl 140, MgCl2 10, CaCl2 0.1, HEPES 10, and glucose 30 (pH 7.4; 22°C to 25°C). A, Recordings from the same inside-out patch before and 30 minutes after application of the purified catalytic subunit of PKA (PKAcs; 400 U/mL). Figure 7. Recently developed sGC activators can stimulate GC activity even of the oxidized enzyme. NO activates sGC which increases cGMP synthesis, leading to PKGI activation. Hemodynamic effects of orally administered isosorbide dinitrate in patients with congestive heart failure. 2010; 160:821–832. Potentiation by NO of antihypertrophic ACE inhibitor effect. cGMP directly activates a number of molecules, including PDEs and ion channels. PKG appears to be the primary receptor protein for cGMP in VSM, and the present study has demonstrated that cAMP-stimulating agents increased PKG activity in coronary arteries. Pressure overload-induced LV hypertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. For example, the catalytic subunit of PKA opens single BKCa channels in patches from rat tail artery myocytes.49 In artificial lipid bilayers, BKCa channels derived from coronary arteries were stimulated by PKA,50 and studies on inside-out patches from short-term cultured aortic myocytes demonstrated increased BKCa channel NPo after PKA.51 In the present study we used only freshly dissociated myocytes and did not observe PKA stimulation of BKCa channel activity, nor did we observe an effect of selective PKA inhibitors on intact cells. Therefore, the lower nanomolar concentrations used in the present study are well within the selectivity range of these inhibitors. Although NOS3 presumably inhibits LVH and remodeling through NO-dependent cGMP synthesis and resultant PKGI activation, none of the above-mentioned studies tested whether cGMP, or PKGI, mediates the NOS3 effect in vivo. Smooth muscle restricted expression of PKGIβ on whole-body PKGI deletion background. These studies have been reviewed extensively.1 Whole-body PKGI knockout (KO) leads to abnormal vascular relaxation.5 And, selective mutation of the PKGIα LZ interaction domain in mice also produces hypertension and vascular dysfunction.6 To date, multiple PKGIα and PKGIβ LZ-dependent substrates have been identified in VSMC,1 further supporting a critical role of the specific PKGIα and PKGIβ LZ domains in regulating cardiovascular function. Results from enzyme immunoassay demonstrated ∼5 times more cAMP than cGMP in coronary artery smooth muscle under nonstimulated conditions, and these results are consistent with those of Francis et al,2 demonstrating that basal levels of cAMP were 5 times higher than those of cGMP in these same arteries.
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