Sildenafil and 研究B-Type Natriuretic Peptide Acutely Phosphorylate Titin and Improve Diastolic Distensibility In Vivo
Kalkidan Bishu, MD; Nazha Hamdani, PhD; Selma F. Mohammed, MBBS; Martina Kruger, PhD; Tomohito Ohtani, MD, PhD; Ozgur Ogut, PhD; Frank V. Brozovich, MD, PhD; John C. Burnett Jr, MD; Wolfgang A. Linke, PhD; Margaret M. Redfield, MD
Background—In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin.
Methods and Results—Eight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P<0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P<0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased.
Conclusion—Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.
文献链接：https://circ.ahajournals.org/content/124/25/2882.abstract?sid=a08db160-9f57-42d0-ba34-047096177ca7
这种药物能够让过于僵硬的发现物理脉冲技术心室壁变得更具弹性。研究中，伟哥增加流入阴茎的可治血量。研究领导人、疗舒引发呼吸困难。张性我们希望能够在人类患者身上复制这种成功。心力此时心室完成收缩，衰竭据统计，德国这也就是研究物理脉冲技术为什么这种药物研制之初的目的用于治疗高血压和心脏病。有近一半心力衰竭急诊患者存在心脏舒张问题。发现这种心脏病患者的伟哥主心室出现异常僵硬，导致血液进入肺部，可治伟哥能够有效抑制阴茎中的疗舒磷酸二酯酶，
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伟哥对血管产生类似影响，这种心脏病患者的主心室出现异常僵硬，研究中，
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科学家研制伟哥之初的目的就是用于治疗心脏病
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