Abnormal blood pressure (BP) elevation in early morning is known to cause cardiovascular events. Previous studies have suggested that one of the reasons in abnormal dairy BP variability is sympathoexcitation. We have demonstrated that brain angiotensin II type 1 receptor (AT1R) causes sympathoexcitation. The aim of the present study was to investigate whether central AT1R blockade attenuates the excess BP elevation in rest-to-active phase in hypertensive rats or not. Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with intracerebroventricular infusion (ICV) of AT1R receptor blocker (ARB), oral administration of hydralazine (HYD), or ICV of vehicle (VEH). Telemetric averaged mean BP (MBP) was measured at early morning (EM), after morning (AM), and night (NT). At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD. At NT, MBP was also significantly lower in ARB than in HYD. These results in MBP were compatible to those in sympathoexcitation and suggest that central AT1R blockade attenuates excess BP elevation in early active phase and continuous BP elevation during rest phase independent of depressor response in hypertensive rats.
Hypertension is established as a major risk factor for cardiovascular disease, and antihypertensive treatments are necessary to prevent the cardiovascular events [
Sympathetic nerve activity is mediated by brain, especially by rostral ventrolateral medulla (RVLM) known as vasomotor center [
The study protocol was reviewed and approved by the Committee on the Ethics of Animal Experiments at the Kyushu University Graduate School of Medical Sciences and conducted according to the Guidelines for Animal Experiments of Kyushu University. Experiments were performed on male stroke-prone spontaneously hypertensive rats (SHRSP) as a hypertensive model with sympathoexcitation (14 to 18 weeks old, SLC Japan, Hamamatsu, Japan). SHRSP were divided into 3 groups, treated with intracerebroventricular infusion (ICV) of AT1R receptor blocker (ARB,
In ARB, losartan (1 mg
Mean blood pressure (MBP) and heart rate (HR) were measured using the UA-10 radiotelemetry system (Data Sciences International, Saint Paul, MN, USA) as described previously [
We assessed sympathoexcitation by spectral analysis using an adaptive autoregressive model to provide power spectra for systolic blood pressure (SBP). The low-frequency power of SBP (integrating the spectra between 0.04 and 0.15 Hz) was computed by MATLAB (MathWorks, USA), and sympathoexcitation is presented as the normalized unit of the low-frequency component of SBP (LFnuSBP), as previously done in our and other studies [
We assessed baroreflex sensitivity by spontaneous sequence method, as done in our and other previous experiments [
All values are expressed as the mean ± SEM. An unpaired
At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD (Figure
Telemetric averaged mean blood pressure in stroke-prone spontaneously hypertensive rats treated with intracerebroventricular infusion of losartan (ARB,
Throughout a day, HR was significantly lower in ARB than in HYD and VEH (Figure
Telemetric averaged heart rate in stroke-prone spontaneously hypertensive rats treated with intracerebroventricular infusion of losartan (ARB,
LFnuSBP was shown in Figure
Normalized unit of the low-frequency component of systolic blood pressure as parameters
Throughout EM, AM, and NT, baroreflex sensitivity was significantly higher in ARB than in HYD and VEH (Figure
Baroreflex sensitivity calculated by spontaneous sequence method in stroke-prone spontaneously hypertensive rats treated with intracerebroventricular infusion of losartan (ARB,
Our obtained new findings were as follows. (1) At EM and NT, MBP was decreased in ARB to a greater extent than in HYD. (2) At AM, MBP was the same in ARB and HYD. (3) Throughout EM, AM, and NT, LFnuSBP was significantly lower in ARB than in VEH and HYD, and (4) baroreflex sensitivity was improved in ARB, but not in HYD. These results suggest that central AT1R blockade would attenuate the excess blood pressure elevation in early active phase and continuous blood pressure elevation during rest phase independent of depressor response in hypertension and that these benefits of central AT1R blockade on dairy blood pressure variability might be due to sympathoinhibition with baroreflex improvement.
The most impressive results were that central AT1R blockade attenuates the excess blood pressure elevation in early active phase. Dairy blood pressure variability and/or morning surge is associated with abnormal regulation of sympathetic nerve activity [
In the aspects of mechanisms, we also consider that central infusion of losartan could improve baroreflex sensitivity, resulting in the improvement of blood pressure variability. Previously we demonstrated that central infusion of AT1R blocker improved the impaired baroreflex sensitivity with sympathoinhibition and antioxidant effect in the brain of hypertensive rats [
Although we showed that central application (intracerebroventricular infusion) of AT1R blocker is beneficial to abnormal blood pressure elevation, as previously shown in our and other works [
Our results proposed a novel clinical aspect. We had better focus on the central AT1R as the suitable target of the treatment with AT1R blockers. Recently, we have suggested that the beneficial effects on central AT1R were different among oral-administered AT1R blockers [
Central AT1R blockade potentially attenuated excess blood pressure elevation in early active phase and continuous blood pressure elevation during rest phase via sympathoinhibition with improvement of baroreflex, independent of depressor response in hypertensive rats.
There is no conflict of interests.
This study was supported by a Grant-in-Aid for Scientific Research (C) (no. 22790709 to Dr. Kishi) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and, in part, Takeda Medical Research Foundation and Kimura Memorial Foundation Research Grant to Dr. Kishi. Department of Advanced Cardiovascular Regulations and Therapeutics, Kyushu University Graduate School of Medical Sciences (Yoshitaka Hirooka), is supported by Actelion Pharmaceuticals. Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences (Takuya Kishi), is supported by Otsuka Pharmaceutical and Nippon Boehringer Ingelheim.