Disease relevance of Fasudil

• CONCLUSIONS: Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm [1].
• Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion [2].
• OBJECTIVES: 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 [1].
• Fasudil hydrochloride (AT877, hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, identical to HA1077) inhibits cerebral vasospasm after subarachnoid hemorrhage in experimental animals and humans [3].
• On a clinical level, we developed the Rho-kinase inhibitor HA-1077 as an anti-spastic that effectively suppresses the spasm of cerebral arteries after subarachnoid hemorrhage [4].

Psychiatry related information on Fasudil

• Evaluation of fasudil hydrochloride treatment for wandering symptoms in cerebrovascular dementia with 31P-magnetic resonance spectroscopy and Xe-computed tomography [5].
• To test whether chronic treatment of an oral Rho kinase inhibitor (fasudil, 5-Isoquinolinesulfonyl homopiperazine) could prevent the development of both vasculogenic erectile dysfunction and pelvic atherosclerosis in a rat model [6].

High impact information on Fasudil

• Both types of MLC phosphorylation were markedly inhibited by fasudil [7].
• Two weeks after the operation, intracoronary serotonin repeatedly induced coronary hyperconstrictions at the IL-1beta-treated site both in vivo and in vitro, which were markedly inhibited by fasudil, an inhibitor of protein kinases, including protein kinase C and MLC kinase [7].
• Two kinds of selective Rho-kinase inhibitors, HA1077 and Y-27632, reduced both GTPgammaS-RhoA-dependent MBS phosphorylation and inactivation of the phosphatase activity [8].
• HA1077 and Y-27632 inhibited MBS phosphorylation in platelets stimulated with these agonists [8].
• In addition, HA1077 and Y-27632 inhibited 20-kD MLC phosphorylation at Ser19 and ATP secretion of platelets stimulated with STA2, thrombin (0.05 U/mL), and simultaneous addition of serotonin and epinephrine, whereas these compounds did not affect MLC phosphorylation or ATP secretion when platelets were stimulated with more than 0.1 U/mL thrombin [8].

Chemical compound and disease context of Fasudil

• 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) [1].
• Chronic fasudil treatment significantly improved renal function (serum creatinine, -26%; blood urea nitrogen, -41%; creatinine clearance, +42%), proteinuria (-24%) and histological findings (glomerular injury score, -49%; afferent arteriolar injury score, -17%) without changing blood pressure compared with untreated DS [9].
• Four groups of perfused rat hearts were subjected to 36 min of zero-flow ischemia and 44 min of reperfusion with continuous measurements of mechanical function and (31)P NMR high-energy phosphate data: 1) untreated, 2) pinacidil (10 microM) to activate K(ATP) channels, 3) fasudil (15 microM) to inhibit ROCK, and 4) both fasudil and pinacidil [10].
• Treatment with fasudil dose-dependently attenuated angiotensin II-induced cardiac hypertrophy, prevented perivascular fibrosis, blunted the increase in ANP and collagen type III expression, and improved cardiac function, without changing blood pressure [11].
• In rabbit mesenteric artery permeabilized with Staphylococcus aureus alpha-toxin, 100 microM HA1077 and 100 microM H-7 inhibited the contraction induced by 0.3 microM Ca2+ [12].

Biological context of Fasudil

• Finally, fasudil, a Rho kinase inhibitor already in clinical use, inhibited both Smad4 translocation and CTGF gene expression [13].
• ROK inhibition with Y-27632 or HA-1077, but not protein kinase C inhibition with Ro 31-8220, blunted ET B-induced vasoconstriction [14].
• Here, using Rho-kinase inhibitors, Y-27632 and HA1077, we found that Rho-kinase is responsible for the phosphorylation of myosin regulatory light chain at Ser19 in the cleavage furrow during cytokinesis [15].
• RESULTS: In SHR-subtotal nephrectomy treated with fasudil, systolic blood pressure was not significantly different from that in SHR-subtotal nephrectomy without fasudil (208 +/- 8 mm Hg vs. 217 +/- 14 mm Hg) [16].
• Liver enzymes and hepatocellular apoptosis were markedly reduced, and sinusoidal perfusion was improved significantly in endotoxemic mice pretreated with fasudil [17].

Anatomical context of Fasudil

• Both LPA-induced CRMP-2 phosphorylation and LPA-induced growth cone collapse were inhibited by Rho-kinase inhibitor HA1077 or Y-32885 [18].
• Furthermore, fasudil, a specific Rho-kinase inhibitor, successfully ameliorated PAN-induced podocyte damage and proteinuria [19].
• In the current study, the vasorelaxing mechanism of hydroxyfasudil, a hydroxylated metabolite of fasudil hydrochloride, was determined in the rabbit basilar artery [3].
• Administration of fasudil reduced LPS-induced leukocyte adhesion in postsinusoidal venules and sequestration in sinusoids [17].
• The Rho kinase (ROK) inhibitor HA1077 that blocked focal adhesion formation by bombesin, had no effect on the focal adhesion assembly induced by calyculin-A [20].

Associations of Fasudil with other chemical compounds

• In 5,5'-dimethyl-BAPTA-treated platelets, Y-27632 and HA 1077 completely abolished both ADP-induced platelet shape change and myosin light chain phosphorylation [21].
• MAP and renal vascular resistance (RVR) responses to Ang II were recorded with and without a Rho kinase inhibitor, fasudil, in anesthetized NZGH [22].
• Furthermore, fasudil (100 microM) significantly attenuated tyrosine phosphorylation and the activity of pp60(src) augmented in situ by pressure [23].
• On the other hand, serine/threonine protein kinase (PK) inhibitors, H-7, fasudil hydrochloride and M3, inhibited the Nef-induced apoptosis, and not the Fas-mediated one, without affecting the cell-binding activity of Nef and Nef-binding capacity of the activated cells [24].
• The Nef-induced apoptosis was efficiently suppressed by serine/threonine protein kinase inhibitors, H7, fasudil hydrochloride and M3, which did not inhibit CD95 (Fas)-mediated apoptosis [25].
• In vitro studies showed that AngII induced the down-regulation of both nephrin and WT-1 expression in podocytes, which was reversed by fasudil in a dose-dependent manner [26].

Gene context of Fasudil

• PKN1 kinase activity is not necessary for this translocation, and in fact the PKN inhibitor HA1077 is also shown to induce PKN1 vesicle accumulation [27].
• Treatment with fasudil suppressed the production and transcription of collagen and TIMP, stimulated the production and transcription of MMP-1, and enhanced collagenase activity [28].
• Moreover, Rho-kinase inhibitors, Y-27632 and fasudil, suppressed the synthesis of PAI-1 in this culture system [29].
• Phosphorylation was inhibited by the calmodulin (CaM) inhibitor W-7, but not by the Rho kinase inhibitor HA-1077, i.e. it is exclusively regulated by Ca2+/CaM-dependent MLC kinase [30].
• Fasudil increased AngII-induced relaxation in SHRSP vessels [31].

Analytical, diagnostic and therapeutic context of Fasudil

• Urinary protein excretion was markedly increased in SHR-subtotal nephrectomy (124 +/- 16 mg/day), but this increase was significantly suppressed by fasudil (79 +/- 12 mg/day) [16].
• Furthermore, Western blot analyses showed that both expression and activity of Rho-kinase were enhanced in SHR-subtotal nephrectomy, compared with those in SHR without nephrectomy, and fasudil suppressed Rho-kinase activity [16].
• Finally, fasudil up-regulated the expression of p27kip1, a cyclin-dependent kinase inhibitor, and increased the p27kip1 immunopositive cells in both glomeruli and tubulointerstitium with the use of immunohistochemistry [16].
• METHODS: In an in vivo rat model of liver transplantation using cold ischemia for 12 hr followed by reperfusion, a specific Rho-kinase inhibitor, fasudil (30 mg/kg), was administered orally 1 hr before the transplantation [32].
• RESULTS: The intimal thickening was significantly suppressed in the fasudil group compared with the control group at 2 and 4 weeks after the operation [33].

References