cardiovascular-agents and fasudil

Pathological stress from cardiovascular disease stimulates hypertrophy of heart cells, which increases the risk of cardiac morbidity and mortality. Recent evidence has indicated that inhibiting such hypertrophy could be beneficial, encouraging drug discovery and development efforts for agents that could achieve this goal. Most existing therapies that have antihypertrophic effects target outside-in signalling in cardiac cells, but their effectiveness seems limited, and so attention has recently turned to the potential of targeting intracellular signalling pathways. Here, we focus on new developments with small-molecule inhibitors of cardiac hypertrophy, summarizing both agents that have been in or are poised for clinical testing, and pathways that offer further promising potential therapeutic targets.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amides; Animals; Cardiomegaly; Cardiovascular Agents; Humans; Models, Biological; Molecular Structure; Pyridines; Receptors, Cell Surface; Signal Transduction

We sought to determine whether a potent Rho-kinase inhibitor fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm.. Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction.. We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or fasudil (4.5 mg intracoronarily, n = 13).. Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125).. Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Acetylcholine; Aged; Cardiovascular Agents; Coronary Circulation; Coronary Vasospasm; Enzyme Inhibitors; Female; Heart Function Tests; Humans; Infusions, Intra-Arterial; Intracellular Signaling Peptides and Proteins; Microvascular Angina; Middle Aged; Myocardial Ischemia; Protein Serine-Threonine Kinases; rho-Associated Kinases; Treatment Outcome; Vasodilator Agents

Rho kinases have been shown to be involved in the pathogenesis of atherosclerosis. This study examined the effects of fasudil, a specific Rho kinase inhibitor, on plaque development and progression in atherosclerotic mice. Sixty apolipoprotein E-knockout (apoE-KO) mice were fed a high-fat diet. Mice started to receive fasudil at the same time as fat feeding (early treatment), or after 12 weeks of fat feeding (delayed treatment). In each administrative schedule, mice were divided into three groups: low dose fasudil group (30 mg/kg/day), high dose fasudil group (100mg/kg/day) and control group (tap water) (n=10, respectively). Plaque size was determined by using ultrasound biomicroscopy (UBM) and histological examinations. Brachiocephalic artery UBM analysis showed that in early treatment, both doses of fasudil significantly reduced lesion size compared with the controls (P<0.05). In delayed-fasudil treatment, plaque area was reduced by 54% (P<0.05) after 12 weeks of treatment at a high dose of fasudil (100mg/kg/day). The UBM findings were confirmed by histological studies at the corresponding arterial sites. The beneficial effect was also observed in the left common carotid arteries that delayed-fasudil treatment reduced the plaque size in a dose-dependent manner. The arterial intima-medial thickness (IMT) and maximal flow velocity of both arteries were lower in fasudil-treated group (100mg/kg/day) in comparison with the control mice. Furthermore, fasudil treatment (100mg/kg/day) reduced the macrophage accumulation in atherosclerotic lesions. However, fasudil had no effects on blood pressure and plasma lipid concentrations in both studies. In conclusion, our studies showed that blocking Rho kinase reduced both the early development and later progression of atherosclerotic plaques in apoE-KO mice by using a novel micro-ultrasound approach.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Apolipoproteins E; Atherosclerosis; Blood Pressure; Brachiocephalic Trunk; Cardiovascular Agents; Carotid Artery Diseases; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Immunohistochemistry; Lipids; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Acoustic; Protein Kinase Inhibitors; rho-Associated Kinases; Time Factors

In addition to high pulmonary vascular resistance (PVR) and low pulmonary blood flow, the fetal pulmonary circulation is characterized by mechanisms that oppose vasodilation. Past work suggests that high myogenic tone contributes to high PVR and may contribute to autoregulation of blood flow in the fetal lung. Rho-kinase (ROCK) can mediate the myogenic response in the adult systemic circulation, but whether high ROCK activity contributes to the myogenic response and modulates time-dependent vasodilation in the developing lung circulation are unknown. We studied the effects of fasudil, a ROCK inhibitor, on the hemodynamic response during acute compression of the ductus arteriosus (DA) in chronically prepared, late-gestation fetal sheep. Acute DA compression simultaneously induces two opposing responses: 1) blood flow-induced vasodilation through increased shear stress that is mediated by NO release and 2) stretch-induced vasoconstriction (i.e., the myogenic response). The myogenic response was assessed during acute DA compression after treatment with N(omega)-nitro-L-arginine, an inhibitor of nitric oxide synthase, to block flow-induced vasodilation and unmask the myogenic response. Intrapulmonary fasudil infusion (100 microg over 10 min) did not enhance flow-induced vasodilation during brief DA compression but reduced the myogenic response by 90% (P<0.05). During prolonged DA compression, fasudil prevented the time-dependent decline in left pulmonary artery blood flow at 2 h (183+/-29 vs. 110+/-11 ml/min with and without fasudil, respectively; P<0.001). We conclude that high ROCK activity opposes pulmonary vasodilation in utero and that the myogenic response maintains high PVR in the normal fetal lung through ROCK activation.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Blood Pressure; Cardiovascular Agents; Constriction; Ductus Arteriosus; Female; Gestational Age; Pregnancy; Protein Kinase Inhibitors; Pulmonary Artery; Pulmonary Circulation; Regional Blood Flow; rho-Associated Kinases; Sheep; Time Factors; Vascular Resistance; Vasoconstriction; Vasodilation