A Randomized, Double-blind, Multicenter, Phase Ⅲ Study to Evaluate the Efficacy and Safety of HCP1302 in Both Erectile Dysfunction and Hypertension Patients Being Treated With HGP0904

Trial to Evaluate the Efficacy and Safety of HCP1302

开始日期2014-09-01

申办/合作机构

Hanmi Pharmaceutical Co., Ltd.

100 项与 VDCCs x PDE5A 相关的临床结果

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100 项与 VDCCs x PDE5A 相关的转化医学

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0 项与 VDCCs x PDE5A 相关的专利（医药）

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项与 VDCCs x PDE5A 相关的文献（医药）

2024-06-01·Physiological Reports

Sildenafil amplifies calcium influx and insulin secretion in pancreatic β cells

Article

作者: Seino, Yusuke ; Morikawa, Risa ; Suzuki, Atsushi ; Shimomura, Kenju ; Murao, Naoya ; Yamada, Yuichiro ; Maejima, Yuko

AbstractSildenafil, a phosphodiesterase‐5 (PDE5) inhibitor, has been shown to improve insulin sensitivity in animal models and prediabetic patients. However, its other metabolic effects remain poorly investigated. This study examines the impact of sildenafil on insulin secretion in MIN6‐K8 mouse clonal β cells. Sildenafil amplified insulin secretion by enhancing Ca2+ influx. These effects required other depolarizing stimuli in MIN6‐K8 cells but not in KATP channel‐deficient β cells, which were already depolarized, indicating that sildenafil‐amplified insulin secretion is depolarization‐dependent and KATP channel‐independent. Interestingly, sildenafil‐amplified insulin secretion was inhibited by pharmacological inhibition of R‐type channels, but not of other types of voltage‐dependent Ca2+ channels (VDCCs). Furthermore, sildenafil‐amplified insulin secretion was barely affected when its effect on cyclic GMP was inhibited by PDE5 knockdown. Thus, sildenafil stimulates insulin secretion and Ca2+ influx through R‐type VDCCs independently of the PDE5/cGMP pathway, a mechanism that differs from the known pharmacology of sildenafil and conventional insulin secretory pathways. Our results reposition sildenafil as an insulinotropic agent that can be used as a potential antidiabetic medicine and a tool to elucidate the novel mechanism of insulin secretion.

2005-04-01·Molecular Interventions

Mechanism of Tissue-Selective Drug Action in the Cardiovascular System

Review

作者: Barrett, Terrance D ; Triggle, David J ; Walker, Michael J A ; Maurice, Donald H

Analysis of the human genome project tells us that there may be as few as 3000 genes that are likely to be good drug targets. Although the number of targets is still very large, these data have been interpreted by some to mean that the pharmaceutical industry may someday run out of novel drug targets. Despite the doom and gloom of such analysis, there is considerable reason for optimism. Drugs may exhibit selectivity of action beyond that predicted by target expression alone. Drugs that act at a single molecular target may have very different pharmacology and, as a result, different therapeutic uses. Three well-characterized model systems are highlighted to illustrate this point. The first model system is exemplified by nifedipine and verapamil, both of which act on L-type calcium channels. Both drugs are used to treat hypertension, but only verapamil can be used to produce atrioventricular block in patients with atrial fibrillation. The second model system describes the therapeutic exploitation of unusual conditions that occur in the ischemic myocardium to produce drugs that are more effective for suppressing ischemia-induced arrhythmias. The third model system discusses the mechanisms through which phosphodiesterase-5 (PDE5) inhibitors act selectively to facilitate penile erection while having little effect in the non-penile vasculature that also expresses PDE5.

1997-12-01·The Canadian journal of cardiology

Nitric oxide regulation of atrioventricular node excitability.

Review

作者: Kobzik, L ; Zhao, Y Y ; Smith, T W ; Opel, D J ; Liu, W D ; Han, X ; Kelly, R A

The role of nitric oxide in the autonomical regulation of atrioventricular (AV) spontaneous action potentials and L-type calcium current (ICa-L) in isolated single AV nodal cells from rabbit heart was examined by using the whole cell patch clamp technique, immunohistochemical staining and single cell reverse transcription polymerase chain reaction analysis. The nitric oxide donor 3-morpholino-sydnonimine (SIN-1) (0.1 mmol/L) suppressed the beta-agonist isoproterenol- (1 mumol/L) stimulated increase in ICa-L and decreased the frequency and amplitude of spontaneous action potentials. In cells in which ICa-L had been previously attenuated by the muscarinic agonist carbamylcholine (CCh, 1 mumol/L), SIN-1 had no additive effect. Intracellular dialysis with the nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA, 0.5 mmol/L) blocked CCh- but not SIN-1-induced ICa-L attenuation. However, intracellular dialysis with methylene blue (20 mumol/L), which inhibits nitric oxide-mediated activation of guanylyl cyclase and cGMP production blocked the effects of both CCh and SIN-1 on ICa-L. In these cells, neither L-NMMA nor methylene blue affected the CCh-activated potassium current (IK(ACh)). Internal dialysis with cGMP (10 mumol/L) significantly inhibited isoproterenol-stimulated ICa-L without affecting IK(ACh). In AV nodal cells internally perfused with either a nonhydrolyzable cAMP analogue, 8-Br-cAMP (0.5 mmol/L), or a high concentration of cAMP (0.5 mmol/L), CCh did not inhibit ICa-L but still activated IK(ACh). CCh-induced ICa-L attenuation could be abolished or quickly reversed by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (20 mumol/L) but not by milrinone (5 mumol/L), which only inhibits the cGMP-inhibited phosphodiesterase isozyme (PDE3). Immunohistochemical staining identified the presence of the endothelial constitutive nitric oxide synthase (NOS3) in both single AV node cells in vitro and in cryostat sections of AV node tissue in situ. These results demonstrate that endogenous nitric oxide is involved in the muscarinic cholinergic attenuation of ICa-L in AV nodal cells; the mechanism likely involves the cGMP-stimulated phosphodiesterase.