The onset and duration of sleep are thought to be primarily under the control of a homeostatic mechanism affected by previous periods of wake and sleep and a circadian timing mechanism that partitions wake and sleep into different portions of the day and night. The mouse Clock mutation induces pronounced changes in overall circadian organization. We sought to determine whether this genetic disruption of circadian timing would affect sleep homeostasis. The Clock mutation affected a number of sleep parameters during entrainment to a 12 hr light/dark (LD 12:12) cycle, when animals were free-running in constant darkness (DD), and during recovery from 6 hr of sleep deprivation in LD 12:12. In particular, in LD 12:12, heterozygous and homozygous Clock mutants slept, respectively, ϳ1 and ϳ2 hr less than wild-type mice, and they had 25 and 51% smaller increases in rapid eye movement (REM) sleep during 24 hr recovery, respectively, than wild-type mice. The effects of the mutation on sleep are not readily attributable to differential entrainment to LD 12:12 because the baseline sleep differences between genotypes were also present when animals were free-running in DD. These results indicate that genetic alterations of the circadian clock system and/or its regulatory genes are likely to have widespread effects on a variety of sleep and wake parameters, including the homeostatic regulation of sleep.

Abstract-The influence of chronic administration of the converting enzyme inhibitor captopril on blood pressure and sodium balance was evaluated in conscious Swiss Webster mice. Arterial pressure was measured with chronic indwelling catheters, and sodium balance was determined by infusing sodium intravenously in isotonic saline and collecting urine 24 h/d. Experiments to validate sodium balance measurements in mice demonstrated recovery of 100Ϯ3% of sodium intake under steady-state conditions (nϭ20 mice on 70 individual days, sodium intake range 160 to 1000 mol/d). It was further demonstrated that mean arterial pressure, heart rate, and body weight were unaltered from 115Ϯ7 mm Hg, 646Ϯ12 bpm, and 34Ϯ0.6 g, respectively, as sodium intake was increased stepwise from 150 to 900 mol NaCl per day. An additional validation group (nϭ7) demonstrated that daily and cumulative sodium balance can be accurately determined during and after the intravenous administration of an agent known to alter renal sodium handling (furosemide 50 mg ⅐ kg). Experiments were then performed to examine the influence of intravenous captopril infusion (40 mg ⅐ kg, nϭ7) in mice in which the daily sodium intake was fixed at Ϸ200 mol/d. This dose of captopril was determined to significantly decrease the pressor response to a 10-ng bolus of angiotensin I (Ang I) from 24Ϯ5 in the control state to 6Ϯ2 mm Hg (nϭ5). After 5 days of infusion of the converting enzyme inhibitor, mean arterial pressure significantly fell from 114Ϯ3 to 58Ϯ2 mm Hg, body weight significantly decreased from 36Ϯ1 to 33Ϯ1 g, and cumulative sodium balance significantly decreased to Ϫ270Ϯ55 mol. These parameters returned toward control during 5 postcontrol days. Results of this study demonstrate that accurate sodium balance measurements can be obtained from individual conscious mice over a 5-fold range of sodium intake. The experiments also indicate that converting enzyme inhibition has a potent influence to lower blood pressure in normal mice; the hypotensive response appears to be due in part to increased urinary sodium excretion. (Hypertension. 1998;32:923-928.) Key Words: renin-angiotensin system Ⅲ captopril Ⅲ blood pressure Ⅲ sodium T echniques in molecular biology have allowed the development of a number of interesting transgenic and knockout models in which important cardiovascular/renal control systems have been genetically altered.1 One cardiovascular regulatory system that has been the subject of intense investigation using transgenic technology in the mouse has been the renin-angiotensin system (RAS). Manipulation of the genes encoding renin, 2,3 angiotensinogen, 2-4 angiotensinconverting enzyme (ACE), 5-7 and the AT 1 8,9 and AT 2 receptors 10,11 has produced profound effects on cardiovascular homeostasis. One of the most potent effects observed with manipulation of the RAS has been the hypotensive effect of deletion of the ACE gene. Arterial blood pressure, measured by both tail-cuff plethysmography 5,7 and direct arterial cannulation, 6 has been reported to decrease ...