Short-term daytime restricted feeding in rats with high salt impairs diurnal variation of Na+ excretion.

Night shift work increases risk of cardiovascular disease associated with an irregular eating schedule. Elevating this risk is the high level of salt intake observed in the typical Western diet. Renal Na+ excretion has a distinct diurnal pattern, independent of time of intake, yet the interactions between the time of intake and the amount of salt ingested are not clear. The hypothesis of the present study was that limiting food intake to the typically inactive period in addition to high-salt (HS) feeding will disrupt the diurnal rhythm of renal Na+ excretion. Male Sprague-Dawley rats were placed on either normal-salt (NS; 0.49% NaCl) or HS (4% NaCl) diets. Rats were housed in metabolic cages and allowed food ad libitum and then subjected to inactive period time-restricted feeding (iTRF) for 5 days. As expected, rats fed NS and allowed food ad libitum had a diurnal pattern of Na+ excretion. The diurnal pattern of Na+ excretion was not significantly different after 5 days of iTRF compared with ad libitum rats. In response to HS, the diurnal pattern of Na+ excretion was similar to NS-fed rats. However, this pattern was attenuated after 5 days of HS iTRF. The diurnal excretion pattern of urinary aldosterone was abolished in both NS iTRF and HS iTRF rats. These data support the hypothesis that HS intake combined with iTRF impairs circadian mechanisms associated with renal Na+ excretion.NEW & NOTEWORTHY Timing of food intake normally has little effect on the diurnal pattern of Na+ and water excretion. However, rats on a high-salt diet were unable to maintain this pattern, yet K+ excretion was more readily adjusted to match timing of intake. These data support the hypothesis that Na+ and water homeostasis are impacted by timing of high-salt diets.

Loss of circadian gene Bmal1 in the collecting duct lowers blood pressure in male, but not female, mice.

Kidney function follows a 24-h rhythm subject to regulation by circadian genes including the transcription factor Bmal1. A high-salt diet induces a phase shift in Bmal1 expression in the renal inner medulla that is dependent on endothelin type B (ETB) receptors. Furthermore, ETB receptor-mediated natriuresis is sex dependent. Therefore, experiments tested the hypothesis that collecting duct Bmal1 regulates blood pressure in a sex-dependent manner. We generated a mouse model that lacks Bmal1 expression in the collecting duct, where ETB receptor abundance is highest. Male, but not female, collecting duct Bmal1 knockout (CDBmal1KO) mice had significantly lower 24-h mean arterial pressure (MAP) than flox controls (105 ± 2 vs. 112 ± 3 mmHg for male mice and 106 ± 1 vs. 108 ± 1 mmHg for female mice, by telemetry). After 6 days on a high-salt (4% NaCl) diet, MAP remained significantly lower in male CDBmal1KO mice than in male flox control mice (107 ± 2 vs. 113 ± 1 mmHg), with no significant differences between genotypes in female mice (108 ± 2 vs. 109 ± 1 mmHg). ETB receptor blockade for another 6 days increased MAP similarly in both male and female CDBmal1KO and flox control mice. However, MAP remained lower in male CDBmal1KO mice than in male flox control mice (124 ± 2 vs. 130 ± 2 mmHg). No significant differences were observed between female CDBmal1KO and flox mice during ETB blockade (130 ± 2 vs. 127 ± 2 mmHg). There were no significant genotype differences in amplitude or phase of MAP in either sex. These data suggest that collecting duct Bmal1 has no role in circadian MAP but plays an important role in overall blood pressure in male, but not female, mice.

Circadian Regulation of Blood Pressure: of Mice and Men.

PURPOSE OF REVIEW: Blood pressure (BP) exhibits strong diurnal variations that have been shown to be important for normal physiology and health. In this review, we highlight recent advances in both basic and clinic research on how the circadian clock affects these BP rhythms. RECENT FINDINGS: Tissue-specific and inducible knockout rodent models have provided novel ways to dissect how circadian clocks regulate BP rhythms and demonstrated that loss of these rhythms is associated with the development of disease. The use of circadian-specific research protocols has translated findings from rodent models to humans, providing insight into circadian control of BP, as well as how sleep, activity, and other factors influence diurnal BP rhythms. Circadian mechanisms play an important role in the regulation of diurnal BP rhythms. Future research needs to extend these findings to clinical populations and determine the extent to which circadian factors may play a role in the development of novel treatment approaches to the management of hypertension.

Renal vascular and glomerular pathologies associated with spontaneous hypertension in the nonhuman primate Chlorocebus aethiops sabaeus.

Hypertension is a complex, multifactorial disease affecting an estimated 78 million adults in the United States. Despite scientific gains, the etiology of human essential hypertension is unknown and current experimental models do not recapitulate all the behavioral and physiological characteristics of the pathology. Researchers should assess the translational capacity of these models and look to other animal models for the discovery of new therapies. Chlorocebus aethiops sabaeus, the African Green Monkey (AGM), is a nonhuman primate that develops spontaneous hypertension and may provide a novel translational model for the study of hypertension and associated diseases. In a randomly selected group of 424 adult AGMs, 37% (157/424) exhibited systolic blood pressures (SBP) >140 mmHg (SBP: 172.0 ± 2.2 mmHg) and were characterized as hypertensive (HT). 44% (187/424) were characterized as normotensive with SBP <120 mmHg (NT, SBP: 99.6 ± 1.0 mmHg) and the remaining 18% (80/424) as borderline hypertensive (BHT, SBP: 130.6 ± 0.6 mmHg). When compared with NT animals, HT AGMs are older (8.7 ± 0.6 vs. 12.4 ± 0.7 yr, P < 0.05) with elevated heart rates (125.7 ± 2.0 vs. 137.7 ± 2.2 beats/min, P < 0.05). BHT animals had average heart rates of 138.2 ± 3.1 beats/min (P < 0.05 compared with NT) and were 11.00 ± 0.9 yr old. NT and HT animals had similar levels of angiotensinogen gene expression, plasma renin activity, and renal cortical renin content (P > 0.05). HT monkeys exhibit renal vascular remodeling (wall-to-lumen ratio NT 0.11 ± 0.01 vs. HT 0.15 ± 0.02, P < 0.05) and altered glomerular morphology (Bowman's capsular space: NT 30.9 ± 1.9% vs. HT 44.4 ± 3.1%, P < 0.05). The hypertensive AGM provides a large animal model that is highly similar to humans and should be studied to identify novel, more effective targets for the treatment of hypertension.

Open problem-based instruction impacts understanding of physiological concepts differently in undergraduate students.

Student populations are diverse such that different types of learners struggle with traditional didactic instruction. Problem-based learning has existed for several decades, but there is still controversy regarding the optimal mode of instruction to ensure success at all levels of students' past achievement. The present study addressed this problem by dividing students into the following three instructional groups for an upper-level course in animal physiology: traditional lecture-style instruction (LI), guided problem-based instruction (GPBI), and open problem-based instruction (OPBI). Student performance was measured by three summative assessments consisting of 50% multiple-choice questions and 50% short-answer questions as well as a final overall course assessment. The present study also examined how students of different academic achievement histories performed under each instructional method. When student achievement levels were not considered, the effects of instructional methods on student outcomes were modest; OPBI students performed moderately better on short-answer exam questions than both LI and GPBI groups. High-achieving students showed no difference in performance for any of the instructional methods on any metric examined. In students with low-achieving academic histories, OPBI students largely outperformed LI students on all metrics (short-answer exam: P < 0.05, d = 1.865; multiple-choice question exam: P < 0.05, d = 1.166; and final score: P < 0.05, d = 1.265). They also outperformed GPBI students on short-answer exam questions (P < 0.05, d = 1.109) but not multiple-choice exam questions (P = 0.071, d = 0.716) or final course outcome (P = 0.328, d = 0.513). These findings strongly suggest that typically low-achieving students perform at a higher level under OPBI as long as the proper support systems (formative assessment and scaffolding) are provided to encourage student success.

Timing of Food Intake Drives the Circadian Rhythm of Blood Pressure.

Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure (BP) and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-h lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 mmHg vs 100 ± 2 mmHg, respectively; P < 0.0001); however, RF for 6 days inverted the diurnal rhythm of MAP (99 ± 3 vs 110 ± 3 mmHg, respectively; P < 0.0001). In contrast to MAP, diurnal rhythms of urine volume and sodium excretion remained intact after RF. Male Bmal1 knockout mice (Bmal1KO) underwent the same feeding protocol. As previously reported, Bmal1KO mice did not exhibit a diurnal MAP rhythm during ad libitum feeding (95 ± 1 mmHg vs 92 ± 3 mmHg, lights-off vs lights-on; P > 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 mmHg vs 95 ± 2 mmHg, lights-off vs lights-on phase; P < 0.01). Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 in ex vivo tissue cultures. The timing of the PER2::LUC rhythm in the renal cortex and suprachiasmatic nucleus was not affected by RF; however, RF induced significant phase shifts in the liver, renal inner medulla, and adrenal gland. In conclusion, the timing of food intake controls BP rhythms in mice independent of Bmal1, urine volume, or sodium excretion.

Diurnal Control of Blood Pressure Is Uncoupled From Sodium Excretion.

The diurnal rhythms of sodium handling and blood pressure are thought to be regulated by clock genes, such as Bmal1. However, little is known about the regulation of these factors by Bmal1, especially in rats. Using a novel whole-body Bmal1 knockout rat model (Bmal1-/-), we hypothesized that time of day regulation of sodium excretion is dependent on Bmal1. Using telemetry to continuously record mean arterial pressure, we observed that male and female Bmal1-/- rats had significantly reduced mean arterial pressure over the course of 24 hours compared with littermate controls. The circadian mean arterial pressure pattern remained intact in both sexes of Bmal1-/- rats, which is in contrast to the Bmal1-/- mouse model. Male Bmal1-/- rats had no significant difference in baseline sodium excretion between 12-hour active and inactive periods, indicating a lack of diurnal control independent of maintained mean arterial pressure rhythms. Female Bmal1-/- rats, however, had significantly greater sodium excretion during the active versus inactive period similar to controls. Thus, we observed a clear dissociation between circadian blood pressure and control of sodium excretion that is sex dependent. These findings are consistent with a more robust ability of females to maintain control of sodium excretion, and furthermore, demonstrate a novel role for Bmal1 in control of diurnal blood pressure independent of sodium excretion.