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Background and Objective: The first circadian study of the 361st Medical Laboratory, USAR, was conducted in May 1969 during the Annual Military Training at Brook Army Hospital, Fort Sam Houston, Texas. The study was approved by the Surgeon General, 5th US Army, and was designed to establish a circadian database for 63 medically relevant variables of 13 young members of the Unit. The subsequent studies, all in the month of May, in 1979, 1988, 1993,1998, and 2003, followed the same protocol and were conducted at Edward Hines Jr., Veterans Administration Hospital, after approval by Human Studies Subcommittees. Since a reduction in Creatinine Clearance (CrCl) to the level of 60 ml/min/1.73m2 signals the onset of kidney malfunction and since a concurrent increase in blood pressure (BP) >140/90 mm Hg, contributes greatly to an unfavorable cardiovascular prognosis, it seemed prudent to examine possible changes in these and in other relevant variables in a group of young Army men, which may have developed over a 34 year period of time., Material and Methods: Thirteen US Army male volunteers (23-27y of age) served as subjects in the 1969 study. A majority of these men, two additional Army men and two non-military subjects, participated in subsequent studies: 1979 (7,2,1), 1988 (8,2,1), 1993 (5,4,1), 1998 (7,2,2), 2003 (7,2,1). In each study, subjects were admitted to a hospital ward, were given medical examination including a 12-lead electrocardiogram and followed the same Protocol. Lights "OUT" at 22:30h and "ON" at 06:30h. The meals, hospital 2400-calorie diets, were served at 17:30, 07:30 and at 13:30h. Vital signs were measured immediately after each 3h urine collections, around the clock, and bloods were collected every 3h. Blood, plasma, serum, saliva and urines were analyzed for numerous analytes including creatinine, using automated laboratory systems. Kidney functions were assessed using the measured and estimated glomerular filtration rates., Results: Over the 34y study span, 16 men provided sixty-one 24h profiles for CrCl-related variables (urine volume, creatinine, and serum creatinine) and fifty-eight profiles for BP. Using all normalized data, a significant circadian rhythm was found for each of these variables. Significant circadian variations in SBP, DBP, serum and urine creatinine, and urine volume, were evident with peak levels, on average, occurring in the evening hours., Conclusions: In healthy subjects, age was associated with an increase in SBP and urine volume and with a decrease in urine creatinine. In diabetic subjects, aging was associated with increases in both blood pressure and Creatinine Clearance. It is interesting to note that for the 3 subjects who at a later date developed diabetes, the CrCl levels were higher than the 5 age-matched controls during each study year, over the entire 34y observation span, including the period prior to diagnosis. Clin Ter 2008; 159(6):409-417.

Objective: To evaluate associations between intraocular pressure (IOP) and blood pressure (BP), heart rate (HR), serum nitric oxide (NO), diurnal variations, diabetes and aging in data collected during 24h studies of men conducted over 34y., Materials and Methods: As part of the Medical Chronobiology Aging Project, male Army veterans, ages 22 to 81y, without a history of eye disease, were studied around-the-clock in May 1969 (n = 13), 1979 (n = 11), 1988 (n = 11), 1993 (n = 11), 1998 (n =12) and 2003 (n = 10). Measurements of IOP (R & L eyes, supine position), BP and HR (sitting position), and collection of blood were obtained every 3h (8 readings/24h) from 19:00h to 16:00h the next day. Individual time series were analyzed for circadian characteristics by the least-squares fit of a 24& 12h cosine. After normalizing all data to percent of mean to reduce inter-subject variability in levels, grouped data were analyzed for time-effect by ANOVA and for circadian rhythm by multiple component (24h&12h) cosine fitting. Individual 24h averages were analyzed by simple and multiple regression for relationships between IOP and systemic variables, diabetic status and age., Results: Over the 34y study span, 22 men provided sixty-three 24h profiles for IOP & HR, 61 for BP, and 21 for NO. Using all normalized data, a significant circadian rhythm was found for each variable at p <0.001. Circadian peaks (orthophases) are located in the late morning for IOP-R (10:20h) and IOP-L (10:52h), and in the evening for HR (18:52h), NO (20:00h), SBP (20:40h) and DBP (21:44h). An out-of-phase relationship of about 10h is noted on a group basis between IOP vs BP, HR and NO. The locations of individual circadian peaks for IOP-R were found around the clock, but with a significant predominance between 10:00 and 16:00h (day type), and 04:00-10:00h (morning type). In contrast, BP, HR and NO showed a significant clustering of evening type or night type peaks. The overall mean IOP for the right eye was slightly, but not significantly, higher than the left eye (17.60+/-0.21 vs 17.34+/-0.18 mmHg; p = 0.385), with a strong positive correlation between both eyes (R = 0.952, p <0.0001). IOP showed a significant positive correlation with SBP (R = 0.49, p <0.001), diabetic status (R = 0.47, p <0.001), age (R = 0.32, p = 0.011), and HR (R = 0.28, p = 0.031). A multiple regression using SBP, DBP, HR, age and diabetic status (5 men became diabetic over the 34y study span) as independent variables resulted in SBP being the strongest predictor of IOP (p = 0.0001), followed by DBP (p = 0.0103). After adjustment for BP, independent effects of age (p = 0.187), HR (p = 0.789) and diabetic status (p = 0.153) were eliminated from the prediction equation., Conclusions: The results of these studies reveal significant circadian variations in IOP, BP, HR and NO, with peak levels, on average, near noon for IOP and in the evening for BP, HR and NO. An increase in SBP was associated with an increase in IOP. While SBP and DBP are significant predictors of IOP levels, single measurements during regular clinic hours may not reveal the full functional relationship between the variables measured in our studies. Therefore, circadian information on total 24h patterns may contribute to the reliability of diagnosis and guide proper individualized timing of optimal patient management (e.g., for glaucoma, hypertension, diabetes, among other conditions).

Vessel dilator consisting of amino acids (a.a.) 31-67 and atrial natriuretic factor (ANF) composed of a.a. 99-126 of the 126 a.a. ANF prohormone circulate in humans and have potent vasodilatory properties. To determine whether these atrial natriuretic peptides are directly related to blood pressure in healthy normotensive humans, we recently had the unique opportunity to examine the circadian rhythms of vessel dilator, ANF, and blood pressure in seven individuals in 1988 and again in 1993. The changes in mean arterial pressure and systolic and diastolic blood pressure in these individuals during this 5-year hiatus allows comparison in the same individual, if circulating concentrations of atrial natriuretic peptides directly correlate with naturally occurring changes in blood pressure. In both 1988 and in 1993 vessel dilator and ANF each had significant (p < 0.001) circadian rhythms with their peak concentrations at 4:00 AM being nearly twice their concentrations at 4:00 PM. Mean arterial pressure, systolic blood pressure, and diastolic blood pressure also had significant circadian rhythms with peaks and troughs that were exactly opposite to those of ANF and vessel dilator. A significant inverse correlation between 24-hour averages of mean arterial blood pressure and 24-hour averages of vessel dilator (p = 0.05) and ANF (p = 0.02) was also found. These data suggest that vessel dilator and ANF are important for the maintenance of blood pressure within the normotensive range.

Long-acting natriuretic peptide, vessel dilator, and atrial natriuretic factor consisting of amino acids (a.a.) 1 to 30, 31 to 67, and 99 to 126 of the 126-a.a. atrial natriuretic factor (ANF) prohormone, respectively, circulate in humans and have potent vasodilatory properties. To determine if these atrial natriuretic peptides are directly related to blood pressure in clinically healthy normotensive humans, we obtained 24-h profiles of vessel dilator, long-acting natriuretic peptide, ANF, and blood pressure in 10 men in 1988 and 11 men in 1993 (seven men were studied twice) to compare circulating concentrations of atrial natriuretic peptides with naturally occurring changes in blood pressure. Overall, vessel dilator, long-acting natriuretic peptide, and ANF each had significant (p<0.001) circadian rhythms, with peak concentrations late during sleep (at 04:00 h) being nearly twice their concentrations in the afternoon and evening. This high-amplitude circadian change allowed for the refinement of normal limits for ANF peptides by computing 3-hourly tolerance intervals (chronodesms) against which to compare time-specified single samples for normality. Systolic, diastolic, and mean arterial blood pressure also had significant circadian rhythms (p<0.001) with peaks and troughs that were exactly opposite those of the ANF peptides. In addition to this inverse temporal relationship, there was a significant inverse correlation between absolute values for blood pressure and each ANF peptide (p<0.001), implying a functional relationship. These data suggest that in addition to other well-established neurochemical factors, the ANF peptides (vessel dilator, long-acting natriuretic peptide, and ANF) are important for the maintenance of blood pressure and modulation of its circadian rhythm.