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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