Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases.

Stock assessment from 1986 through 1990 of 15 populations of burbot Lota lota in small to moderate-size Alaskan lakes is described. Adult (≥450 mm total length) and juvenile (300–449 mm total length) burbot were captured in baited hoop traps set in systematic patterns across lakes when lakes were ice-free. Mark–recapture experiments were used to estimate abundance, and catch per unit effort was used to index abundance, All 15 populations had been exploited in winter recreational fisheries. Catch rates of burbot just after lakes became ice-free in the spring and just before their freezing over in the fall were about twice those during the intervening summer. Movements of marked burbot across depth zones were extensive and random; burbot were not concentrated, but were dispersed across lakes. No relationship between catches of juvenile and adult burbot in the same sets was found. Depth preferences of burbot followed their published thermal preferences except that juveniles were concentrated in deeper waters during the first month after lakes opened. Immediate and delayed mortality from decompression of burbot captured deeper than 15 m was indicated. Changes in abundance could be detected with mean catch per unit effort in all lakes. Mean catch per unit effort was mildly density-dependent; saturation of hoop traps with burbot was postulated as the reason. Suggestions on how to use behavior of burbot in planning stock assessment are given.

The general four-parameter size-age growth model of Schnute incorporates many classical formulations, such as the von Bertalanffy, Gompertz, and Richards, as submodels. The general model has different submodels depending on the values of two model parameters a and b. We develop here the equivalent model representations for mark-recapture data, consisting of size measurements at the times of marking and recapture and the times at large. The general mark-recapture model for these data contains only three distinct parameters, because actual fish age is not included in the data set. Thus, mark-recapture data can be used to determine a general growth model only if one of the parameters, most likely size at the starting age, is specified beforehand. The model is applied to two data sets with both size-age and mark-recapture data: Arctic char in the Wood River system, Alaska and rainbow trout in the Kenai River, Alaska. Different growth formulations are isolated for the two data sets, illustrating the versatility of Schnute's formalism of growth. In only one instance is the ubiquitous von Bertalanffy growth model selected, suggesting that alternative growth models should be considered more frequently. We discuss how growth variations of individuals may be incorporated into the general model.