Chan CK, Mak J, Gao Y, Man RY, Vanhoutte PM. Endotheliumderived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries. Am J Physiol Heart Circ Physiol 301: H2313-H2321, 2011. First published October 7, 2011 doi:10.1152/ajpheart.00258.2011.-The present study investigated the mechanism underlying the transient potentiation of vasoconstriction by hypoxia in isolated porcine coronary arteries. Isometric tension was measured in rings with or without endothelium. Hypoxia (PO2 Ͻ30 mmHg) caused a transient further increase in tension (hypoxic augmentation) in contracted (with U46619) preparations. The hypoxic response was endothelium dependent and abolished by inhibitors of nitric oxide synthase [N -nitro-L-arginine methyl ester (L-NAME)] or soluble guanylyl cyclase (ODQ and NS2028). The addition of DETA NONOate (nitric oxide donor) in the presence of L-NAME restored the hypoxic augmentation, suggesting the involvement of the nitric oxide pathway. However, the same was not observed after incubation with 8-bromo-cyclic GMP, atrial natriuretic peptide, or isoproterenol. Assay of the cyclic GMP content showed no change upon exposure to hypoxia in preparations with and without endothelium. Incubation with protein kinase G and protein kinase A inhibitors did not inhibit the hypoxic augmentation. Thus the hypoxic augmentation is dependent on nitric oxide and soluble guanylyl cyclase but independent of cyclic GMP. The hypoxic augmentation persisted in calcium-free buffer and in the presence of nifedipine, ruling out a role for extracellular calcium influx. Hypoxia did not alter the intracellular calcium concentration, as measured by confocal fluorescence microscopy. This observation and the findings that hypoxic augmentation is enhanced by thapsigargin (sarco/endoplasmic reticulum calcium ATPase inhibitor) and inhibited by HA1077 or Y27632 (Rho kinase inhibitors) demonstrate the involvement of calcium sensitization in the phenomenon. soluble guanylyl cyclase; calcium sensitization; nitric oxide ENDOTHELIUM-DEPENDENT AUGMENTATION of contraction by hypoxia has been observed in canine femoral and coronary arteries (10,22,41), in the rat mesenteric artery (57), and in the human coronary artery (56). In the dog, augmented hypoxic coronary vasoconstrictions, which significantly reduce the blood supply to the cardiac muscle, occur in vivo only after previous ischemia-reperfusion injury (41). Considering that the hypoxic augmentation can be repeated consistently even after several episodes of exposure to hypoxia (10), this phenomenon could be important in patients (particularly if they have a previous history of coronary disease) exposed to repeated episodes of reduced oxygen content in the blood, as in the case for example in sleep apnea.The exact mechanism underlying hypoxic endothelium-dependent augmentation of vasoconstriction is not fully understood. Bioassay studies (45) on canine coronary arteries demonstrated that a diffusible substance released by the endothelium contributes to th...

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Rho kinase is involved in the pathogenesis of hypertension, which favors the occurrence of endothelium-dependent contractions. The present study was designed to determine the effects of two Rho kinase inhibitors, HA1077 [1-(5-isoquinolinesulfonyl)-homopiperazine (fasudil)] and Y27632 [(ϩ)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihydrochloride], on endothelium-dependent and -independent contractions. Isometric tension of 1-year-old spontaneously hypertensive rat and Wistar Kyoto aortae were measured. In the presence of N

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Background: The ability of lateral meniscal allograft transplantation (MAT) to improve knee stability and the meniscal load-bearing function in patients after meniscectomy is critical for surgical success. Purpose: To compare the effects of 2 lateral MAT fixation techniques—bone block and suture only—on knee kinematics and forces. Study Design: Controlled laboratory study. Methods: With a robotic testing system, loads were applied during flexion on 10 fresh-frozen cadaveric knees: 134-N anterior tibial load + 200-N axial compression, 5-N·m internal tibial + 5-N·m valgus torques, and 5-N·m external tibial + 5-N·m valgus torques. Kinematic data were recorded for 4 knee states: intact, total lateral meniscectomy, lateral MAT bone block, and lateral MAT suture-only fixation. In situ force in the anterior cruciate ligament and resultant forces in the lateral meniscus and in the meniscal allograft were quantified via the principle of superposition. A repeated measures analysis of variance was used to analyze variations in kinematics and forces at 0°, 30°, 60°, and 90° of knee flexion. Significance was set at P < .05. Results: When anterior loads were applied, a decrease in medial translation of the tibia that was increased after total lateral meniscectomy was observed at 30°, 60°, and 90° of knee flexion for both the lateral MAT bone block (54.2%, 48.0%, and 50.0%) and the MAT suture-only (50.0%, 40.0%, and 34.6%) fixation techniques ( P < .05). Yet, most of the increases in knee kinematics after lateral meniscectomy were not significantly reduced by either lateral MAT technique ( P > .05 for each MAT technique vs the total lateral meniscectomy state). Resultant forces in the meniscal allograft were 50% to 60% of the resultant forces in the intact lateral meniscus in response to all loading conditions at all flexion angles ( P < .05). Overall, no significant differences between lateral MAT techniques were observed regarding kinematics and forces ( P > .05). Conclusion: Lateral MAT partially restored medial translation of the tibia, and the resultant forces in the meniscal allograft were only 50% to 60% of the intact lateral meniscus forces in the cadaver model. In the majority of testing conditions, no significant changes of the in situ force in the anterior cruciate ligament were observed. Surgeons should consider the potential benefits of lateral MAT when deciding the appropriate treatment for symptomatic patients after lateral meniscectomies. Both lateral MAT techniques functioned similarly. Clinical Relevance: The load-bearing function of the meniscal allograft observed in this study may be beneficial in ameliorating the short- and long-term disability associated with lateral meniscal deficiency.