Disease relevance of HYDROXYFASUDIL

• OBJECTIVES: We examined whether hydroxyfasudil, a specific Rho-kinase inhibitor, exerts cardioprotective effect on coronary ischemia/reperfusion (I/R) injury and, if so, whether nitric oxide (NO) is involved [1].
• CONCLUSION:These data indicate that inhibition of rho-kinase with hydroxyfasudil attenuates AVP-induced myocardial ischemia independent of changes in MAP and are consistent with an inhibitory effect on coronary vasoconstriction [2].
• However, neither hypoxia nor hydroxyfasudil had any effects on eNOS gene transcription [3].
• Hydroxyfasudil also significantly reduced myocardial infarct size [4].
• Cardioprotective effect of hydroxyfasudil as a specific Rho-kinase inhibitor, on ischemia-reperfusion injury in canine coronary microvessels in vivo [4].

High impact information on HYDROXYFASUDIL

• RESULTS: Hydroxyfasudil significantly attenuated serotonin (IC)-induced vasoconstriction of SA (-7 +/- 1% vs. 2 +/- 1%, p < 0.01) [1].
• Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo [1].
• Expression of endothelial nitric oxide synthase (eNOS) protein in the ischemic endocardium of left anterior descending coronary artery area (as determined by Western blotting) significantly decreased (79 +/- 4%) compared with the nonischemic endocardium of LCX area (100 +/- 7%), which was improved by hydroxyfasudil (105 +/- 6%, p < 0.01) [1].
• Hydroxyfasudil, an active metabolite of fasudil hydrochloride, relaxes the rabbit basilar artery by disinhibition of myosin light chain phosphatase [5].
• The effects of hydroxyfasudil on tension, intracellular Ca2+ concentration ([Ca2+]i), and phosphorylation of the myosin light chain were examined using the isolated and intact or permeabilized rabbit basilar artery without endothelium in vitro [5].

Chemical compound and disease context of HYDROXYFASUDIL

• Inhibition of rho-kinase by hydroxyfasudil prevents vasopressin-induced myocardial ischemia in Donryu rats by attenuating coronary vasoconstriction [2].
• The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension [6].
• Furthermore, either Rho-kinase inhibition (hydroxyfasudil or Y27632) or actin cytoskeletal deactivation (cytochalasin-D) during sustained ischemia achieved the same infarct limitation as preischemic PKA activation without affecting systemic hemodynamic parameters, the area at risk, or collateral blood flow [7].
• METHODS AND RESULTS: To determine whether hypoxia regulates eNOS expression through Rho-kinase, we exposed human saphenous and pulmonary artery endothelial cells to hypoxia (3% O2) with and without a Rho-kinase inhibitor, hydroxyfasudil (0.1 to 100 micromol/L), for various durations (0 to 48 hours) [3].

Biological context of HYDROXYFASUDIL

• In the permeabilized preparation, hydroxyfasudil inhibited the contraction induced by ET-1, guanosine 5'-O-(3-thiotriphosphate), or the catalytic subunit of rho-associated kinase, but it did not inhibit Ca2+-induced contraction under the condition of inhibited myosin light chain phosphatase [5].
• In the intact rabbit basilar artery, hydroxyfasudil elicited a concentration-dependent relaxation of the artery precontracted with 1 nmol/L endothelin-1 (ET-1) plus 20 mmol/L KCl without any significant decrease in [Ca2+]i as determined by fura-2 microfluorometry (IC50: 5.1 +/- 4.6 micromol/L) [5].
• Effects of hydroxyfasudil administered to the nucleus tractus solitarii on blood pressure and heart rate in spontaneously hypertensive rats [8].
• Coronary I/R significantly impaired coronary vasodilation to acetylcholine, whereas hydroxyfasudil completely preserved the responses, as did preconditioning [4].
• The Rho kinase (ROCK) inhibitor, hydroxyfasudil, prevents the downregulation of endothelial NO synthase (eNOS) under hypoxic conditions [9].

Anatomical context of HYDROXYFASUDIL

• In the current study, the vasorelaxing mechanism of hydroxyfasudil, a hydroxylated metabolite of fasudil hydrochloride, was determined in the rabbit basilar artery [5].
• CONCLUSION: These results indicate that hydroxyfasudil-sensitive Rho-kinase-mediated pathway appears to mediate the enhanced MLC phosphorylations (on Ser19 and Ser19/Thr18 residues) and plays a central role in the pathogenesis of coronary artery spasm [10].
• The migration of monocytes in vitro elicited by N-formyl-methionyl-leucyl-phenylalanine was potently inhibited by fasudil and its active metabolite, hydroxyfasudil [11].
• METHODS: Human vascular endothelial cells were treated with increasing concentrations of hydroxyfasudil (0.1 to 100 micromol/L) and eNOS expression and activity were measured [9].
• In organ chamber experiments, serotonin caused hypercontraction of vascular smooth muscle cells (VSMC) from RLP-treated segment, which was significantly inhibited by hydroxyfasudil (P<0.001, n=6) [12].

Associations of HYDROXYFASUDIL with other chemical compounds

• Stretch induced the membrane accumulation of Rho A and Rho kinase inhibitors (Y-27632 and hydroxyfasudil) and dominant negative Rho A mutant significantly prevented stretch-induced SMC proliferation [13].
• After treatment with verapamil or chelation of external Ca(2+) with EGTA, PGF(2alpha) increased the MLC(20) phosphorylation and tension without an increase in [Ca(2+)](i), all of which were sensitive to fasudil and hydroxyfasudil [14].
• Activation of Akt and eNOS by HF was completely blocked by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002 (10 micromol/L) [15].

Gene context of HYDROXYFASUDIL

• Two weeks after the operation, phorbol ester caused coronary spasm in vivo and coronary hypercontractions in vitro at the IL-1beta-treated segment; both were significantly inhibited by hydroxyfasudil, a specific Rho-kinase inhibitor [16].
• METHODS AND RESULTS: In human endothelial cells, the Rho-kinase inhibitor, hydroxyfasudil (HF) (1 to 100 micromol/L), increased Akt serine-473 phosphorylation within 15 minutes, leading to a 2.2-fold and 4.0-fold increase in Akt kinase activity and nitric oxide (NO) release, respectively [15].
• The effect of hydroxyfasudil, another potent Rho-kinase inhibitor, was also evaluated [17].
• TGF-beta2, but not PDGF-BB, also caused myofibroblast-like transdifferentiation with alphaSMA overexpression, which was downregulated by hydroxyfasudil in part (P <0.01) [17].
• Hydroxyfasudil, a specific inhibitor of Rho-kinase, increased BMP-2 and osteocalcin expression [18].

Analytical, diagnostic and therapeutic context of HYDROXYFASUDIL

• After oral administration, fasudil is metabolized to a specific Rho kinase inhibitor, hydroxyfasudil [19].
• The microinjection of hydroxyfasudil was performed unilaterally or bilaterally into the NTS of WKY rats and SHR [8].
• Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation [20].

References