Valsartan chronotherapy reverts the non-dipper pattern and improves blood pressure control through mediation of circadian rhythms of the renin-angiotensin system in spontaneous hypertension rats

ABSTRACT

Background: Numerous clinical studies have evaluated valsartan and found more efficacious control of blood pressure (BP) variability when administered before sleep. The treatment leads to improved outcomes when compared to administration upon awakening. The mechanism underlying this etiology is not fully understood. The present study investigates the safety and efficacy of asleep administration of valsartan in spontaneously hypertensive rats (SHR) with a non-dipping blood pressure pattern compared to SHRs receiving administration during awake time. Materials and Methods: 84 Male SHRs and 28 male Wistar-Kyoto rats (WKY) were kept under a strict alternating 12-h light/dark cycle. WKYs were utilized as a non-disease control. Meanwhile, SHRs were randomly divided into three groups: untreated, Valsartan asleep administration (VSA) and Valsartan awake administration (VWA) respectively. The VSA group was treated with valsartan (30 mg/kg/d) after the light onset, while the VWA group was treated with valsartan (30 mg/kg/d) after light offset. Both groups were treated for 6 weeks. Tail artery blood pressure was measured every 4 h via a noninvasive tail cuff blood pressure measurement method. HE and Masson staining were used to evaluate any damage within the target organs. ELISA was used to determine the 24-h plasma renin-angiotensin system (RAS) concentration at 4-h intervals. Results: Based on our findings, VSA significantly reduced 24-h and evening mean BP and restored the abnormal circadian rhythm compared to VWA, which attenuated injuries in the majority of target organs except for the kidneys. Furthermore, VSA was found to activate RAS during the light cycle and inhibit it during the dark cycle. Conversely, VWA was found to deactivate RAS throughout the day which may be related to the circadian BP rhythm. Conclusion: VSA may be more efficacious than VWA in controlling BP, circadian BP rhythm and blood RAS rhythm. Recent cardiovascular outcome investigations substantiate that chronotherapy treatment might be a novel therapeutic strategy for hypertension therapy.

Abbreviations: Angiotensin-converting enzyme (ACE); Angiotensin converting enzyme inhibitors (ACEIs); Angiotensin II (ANG II); Analysis of variance (ANOVA); Angiotensin receptor blockers (ARBs); Blood Pressure (BP); Calcium Antagonists Calcium Channel Blockers (CCB); Chronic kidney diseases (CKD); Sodium carboxyl methyl cellulose (CMC-Na); Cardiac mass index (CMI); Cardiovascular diseases (CVD); Diastolic blood pressure (DBP); Enzyme-linked immunosorbent assay (ELISA); Hematoxylin-eosin (H&E); Kidney mass index (KMI); Liver mass index (LMI); Mean arterial blood pressure (MAP); Plasma renin concentration (PRC); Renin-angiotensin system (RAS); Rennin (REN); Systolic blood pressure (SBP); Student-Newman-Keuls q test (SNK-q test); Spontaneous hypertension rats (SHR); Valsartan asleep Administration (VSA); Valsartan awake Administration (VWA); Wistar-Kyoto (WKY); Mesor (M); Amplitude (A); Phase (φ).     

Chronotherapy of hypertension: advantages of 48-h ambulatory blood pressure monitoring assessments in MAPEC and Hygia Chronotherapy Trial

ABSTRACT

The specific purpose of this communication is to summarize the relevant details of the methods utilized to conduct, analyze, and interpret the ambulatory blood pressure (BP) monitoring (ABPM)-obtained patient data in both MAPEC and Hygia Chronotherapy Trial, including details of the sampling requirements in terms of duration and frequency, proper calculation of ABPM-derived mean values, prognostic and therapeutic implications of BP dipping, and limitations of the 24 h BP mean as diagnostic/prognostic parameter still mistakenly recommended by some hypertension guidelines.     

Relationships of Different Blood Pressure Categories to Indices of Inflammation and Platelet Activity in Sustained Hypertensive Patients with Uncontrolled Office Blood Pressure

Failure to decrease blood pressure (BP) normally during nighttime (non-dipping) in hypertension is associated with higher cardiovascular morbidity and mortality. In addition, non-dipping BP is associated with increased platelet activity and inflammatory response; however, there has been no study to evaluate the relationship of non-dipping BP to indices of platelet activity and inflammation in uncontrolled hypertensive patients. In the present study, hypertensive subjects with uncontrolled office BP were firstly divided into three groups: 84 subjects with white coat effect and 365 subjects with true uncontrolled hypertension. Then, true uncontrolled hypertensive patients were divided into two groups: 158 patients with dipping and 207 patients with non-dipping. Mean platelet volume (MPV), uric acid (UA), γ-glutamyltransferase (GGT), C-reactive protein (CRP), and high-sensitivity CRP (hs-CRP) levels were studied. The general characteristics and risk factors for coronary artery disease (CAD) of the study population were similar among the groups. MPV, UA, GGT, CRP, and hs-CRP levels were significantly higher in non-dipper group than both dipper and white coat effect groups, and were significantly higher in dipper group than in white coat effect group (MPV: 9.1?±?1.3, 8.7?±?1.1, and 8.0?±?0.9 fL; UA: 6.9?±?1.2, 5.9?±?1.4, and 4.1?±?0.8?mg/dL; GGT: 38.9?±?11.1, 33.6?±?14.9, and 25.2?±?9.2 U/L; CRP: 7.1?±?2.4, 6.2?±?1.9, and 3.9?±?0.8?mg/dL; hs-CRP: 3.8?±?1.5, 3.3?±?1.2, and 2.0?±?0.6, non-dipper, dipper, and white coat effect groups, respectively, all p values <0.01). All study parameters strongly correlated with each other. In conclusion, in hypertensive patients with uncontrolled office BP, presence of non-dipping BP is associated with increased platelet activity and inflammation, which can be one of the underlying plausible mechanisms of non-dipping BP status.