The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.

The effects of static and dynamic passive stretch and shortening on electrical activity and active force were analyzed in the isolated rat portal vein. Static stretch by 40% of muscle length evoked moderate excitatory effects with enhanced mechanical activity and an average increase in spike discharge of 12% above the control value of 55 ± 2.6 spikes/min. The dynamic responses studied at various rates of length change (dL/dt) over the range between -12 and +12 mm/min, i.e., -3 and +3% muscle length/sec, were much more pronounced. Active force and spike activity showed graded increases with increasing rates of stretch. The electrical activity reached a value of 180 spikes/ min (r= 325% of control) at 5 mm/min; this frequency was then maintained for stretch rates up to 12 mm/min. Mechanical activity during stretch was further reinforced by the shift along the length-tension diagram. Passive shortening at rates from -1 to -12 mm/min caused graded decreases in mechanical and electrical activity below the control levels, complete inhibition being observed at the latter dL/dt. Blockade of a and /3 receptors indicated that the responses were myogenic in nature. The findings seem to provide direct support for the myogenic hypothesis of vascular tone and responses to stretch of the vascular wall, but they indicate that emphasis should be placed on the dynamic characteristics of the stimulus rather than its static nature. This emphasis constitutes a new concept in the myogenic control of the peripheral circulation.

The aims of this study were to elucidate the distribution of angiotensin receptors (AT(1) and AT(2)) in the duodenal wall and to investigate whether AT(2) receptors are involved in the regulation of duodenal mucosal alkaline secretion, which is of importance for the mucosal defense against gastric acid. Immunohistochemistry was used to locate AT(1) and AT(2) receptors in chloralose-anesthetized rats. Duodenal mucosal alkaline output was measured by use of in situ pH-stat titration. Immunohistochemistry demonstrated a distinct staining for both AT(1) and AT(2) receptors in the lamina propria of the villi and also for AT(1) receptors in the muscularis interna. When angiotensin II was infused in the presence of the AT(1) receptor antagonist losartan, mucosal alkaline secretion increased by ~50%. This response was inhibited by the AT(2) receptor antagonist PD-123319. The AT(2) receptor agonist CGP-42112A increased mucosal alkaline secretion by ~50%. This increase was absent in the presence of PD-123319 but not in the presence of losartan or the local anesthetic lidocaine. We conclude that angiotensin II stimulates duodenal mucosal alkaline secretion by activation of AT(2) receptors located in the duodenal mucosa/submucosa.

EGIL HAGGENDAL and BORJE JOHANSSON. Effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow autoregulation in dogs. Acta physiol. scand. 1965. 66. Suppl. 258. 27-53. -Pressure-flow relationships of the cerebral circulation under influence of variations in arterial carbon dioxide tension and oxygen saturation were studied in pentobarbital anaesthetized dogs. Cerebral blood flow was measured by recording of the yemission of radioactive krypton ( K P ) , which was injected into the vertebral

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Responses to isotonic quick release of AC-stimulated smooth muscle strips from rabbit urinary bladder were analysed. Releases were performed at the peak of contraction and at a preset tension level in the contraction and relaxation phase. In other expts. responses at 37 degrees C and 27 degrees C were compared. The length response always consisted of 3 parts: (1) elastic recoil, (2) rapid length change (isotonic transient), (3) steady length change. Qualitatively, phases (1)-(3) could be distinguished also in responses to isotonic quick stretch. The immediate elastic recoils, phase (1), were described by exponential stress-strain relations. Stiffness was found to be somewhat lower during relaxation than during contraction. No effect of temperature on the elastic recoil was seen. The initial velocity in phase (2) was 2-3 times greater than the velocity 100 ms after release. By means of computer analysis of the length records during phases (2) and (3) two decaying exponential processes with widely different time constants could be separated. The time constant of the faster process was of the order of 15-30 ms at 37 degrees C. It decreased with increasing force steps and with increasing temperature. The amount of shortening associated with this process was correlated with the size of the force step, reaching a maximum of about 1.2% of the muscle length. The shortening velocities in phase (3), measured 100 ms after release, were described by Hill's equation. Vmax in the rising part and at the peak of contraction were 0.7 and 0.6 L/s respectively at 37 degrees C. Lower values were found during relaxation and at 27 degrees C. We suggest that part of the elastic recoil in phase (1) occurs in structures associated with the individual cross-bridges, that phase (2) is dominated by a change in the distribution of conformations of bridges in the attached position and that the shortening rate in phase (3) is determined by the entire cycle of events during turnover of bridges after the muscle has adapted to the new load. Observations on the force response to length steps and on shifts from isometric to afterloaded isotonic contraction and vice versa are consistent with this interpretation.

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Abstract. It has been realized that resilience as a concept involves several contradictory definitions, both for instance resilience as agile adjustment and as robust resistance to situations. Our analysis of resilience concepts and models suggest that beyond simplistic definitions, it is possible to draw up a systemic resilience model (SyRes) that maintains these opposing characteristics without contradiction. We outline six functions in a systemic model, drawing primarily on resilience engineering, and disaster response: anticipation, monitoring, response, recovery, learning, and self-monitoring. The model consists of four areas: Event-based constraints, Functional Dependencies, Adaptive Capacity and Strategy. The paper describes dependencies between constraints, functions and strategies. We argue that models such as SyRes should be useful both for envisioning new resilience methods and metrics, as well as for engineering and evaluating resilient systems.