高血圧自然発症ラットにおける酵素処理ローヤルゼリーの血圧降下作用機序

Gastrointestinal enzyme production of bioactive peptides from royal jelly protein and their antihypertensive ability in SHR

Effect of electro-acupuncture on gene expression in heart of rats with stress-induced pre-hypertension based on gene chip technology

A possible role of prostaglandin E2 (PGE2) in the regulation of blood pressure in spontaneously hypertensive rats (SHR) was investigated. The inhibition of PG synthesis by chronic indomethacin treatment accelerated the elevation of blood pressure with the tendency to decrease renal PGE2. We, therefore, confirmed that PGE2 in SHR may play a role in the antihypertensive mechanism. In this connection, the participation of renal PGE2 in the retardation of the development of hypertension in male SHR induced by orchiectomy was examined. Urinary PGE2 which reflects the renal PGE2 level tended to keep a higher level in the castrated group. Urinary electrolytes excretion also inclined to augment in the castrated group throughout the experiment. These results indicate that renal PGE2 may participate in the gonads-mediated blood pressure regulation system, although the mechanism of the retardation of spontaneous hypertension induced by orchiectomy remains obscure.

the renin-angiotensin system (RAS) plays a key role in the control of cardiovascular function. Normal activity of the RAS has been physiologically implicated in maintaining homeostasis of arterial pressure and hydroelectrolyte balance as well as in modulating cell growth and differentiation. In

The acute antihypertensive effects and possible underlying mechanisms of 3 beta-adrenergic-blocking drugs with alpha-blocking activity, i.e. labetalol, drugs with alpha-blocking activity, i.e. labetalol, nipradilol and arotinolol, were studied in conscious spontaneously hypertensive rats (SHR) and compared with the effects of prazosin, propranolol and hydralazine. Prazosin produced a dose-dependent antihypertensive effect which paralleled inhibition of the pressor response to phenylephrine. Labetalol (30 mg/kg), nipradilol (30 and 100 mg/kg) and arotinolol (30 and 100 mg/kg) also produced a fall in blood pressure. However, inhibition of the pressor response to phenylephrine was not seen in association with the antihypertensive effect after the lower dose of nipradilol and arotinolol. Propranolol (100 mg/kg) did not lower blood pressure. These results suggest that a mechanism(s) other than an alpha-adrenergic-blocking effect plays a role in the acute antihypertensive effects produced by the lower dose of nipradilol and arotinolol.

To investigate whether the antihypertensive mechanism of electroacupuncture (EA) is associated with attenuating phenotype transformation of vascular smooth muscle cells (VSMCs) via phosphoinositide3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways. Eight Wistar-ktoyo (WKY) rats were set as normal blood pressure group (normal group). A total of 32 spontaneous hypertensive rats (SHRs) were randomly divided into 4 groups using random number tables: a model group, an EA group, an EA+PI3K antagonist group (EA+P group), and an EA+p38 MAPK agonist+extracellular signal-regulated kinase (ERK) agonist group (EA+M group) (n=8/group). SHRs in EA group, EA+P group and EA+M group received EA treatment 5 sessions per week for continuous 4 weeks, while rats in the normal and model groups were bundled in same condition. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) of each rat was measured at 0 week and the 4th week. After 4-week intervention, thoracic aorta was collected for hematoxylin-eosin (HE) staining, immunohistochemistry [the contractile markers α-smooth muscle actin (α-SMA) and calponin and the synthetic marker osteopontin (OPN)] and Western blot [α-SMA, calponin, OPN, PI3K, phosphorylated-Akt (p-Akt), Akt, p-p42/44 ERK, total p42/44 ERK, p-p38 MAPK and total p38 MAPK]. EA significantly reduced SBP, DBP and MAP (P<0.01). HE staining showed that the wall thickness of thoracic aorta in EA group was significantly decreased (P<0.01). From results of immunohistochemistry and Western blot, EA increased the expression of α-SMA and calponin, and decreased the expression of OPN (P<0.01). In addition, the expression of PI3K and p-Akt increased (P<0.01), while the expression of p-p42/44 ERK and p-p38 MAPK decreased in EA group (P<0.01). However, these effects were reversed by PI3K antagonist, p38 MAPK agonist and ERK agonist. EA was an effective treatment for BP management. The antihypertensive effect of EA may be related with inhibition of phenotypic transformation of VSMCs, in which the activation of PI3K/Akt and the repression of MAPK pathway were involved.

Antihypertensive effects of isoquercitrin and extracts from Tropaeolum majus L.: Evidence for the inhibition of angiotensin converting enzyme

Autoimmune therapeutic chloroquine lowers blood pressure and improves endothelial function in spontaneously hypertensive rats

The effect of gonadectomy on the antihypertensive action of pindolol in male spontaneously hypertensive rats (SHR) was investigated. And we also examined the relationship between the antihypertensive effect of this drug and the renal prostaglandin E2 (PGE2) level. In gonadectomized SHR, the reduction of blood pressure was not observed by the oral administration of pindolol, although the drug exhibited a marked antihypertensive activity in sham operated SHR. Urinary PGE2 in sham operated SHR was increased following the administration of pindolol, but not in gonadectomized SHR. Similar results were obtained in the experiments using Wistar rats. The PG synthesis inhibition induced by indomethacin suppressed the antihypertensive action of pindolol. Results in the present study suggest that renal PGs, particularly PGE2, are involved in the antihypertensive mechanism of pindolol, and that male gonad takes part in the regulation of the stimulation of the renal PGE2 producing system induced by pindolol.

Hypertension is one of the most serious chronic diseases. This study will focus on the systemic antihypertensive mechanisms of 5,7-dihydroxyflavone from in silico simulations to in vivo validations. In-silico studies were applied by network pharmacology, molecular docking, and molecular dynamic simulation. Based on the information of network pharmacology, 5,7-dihydroxyflavone could act on several different blood pressure regulating pathways, molecular docking results confirmed it might direct binding on the active pocket of eNOS, and the average molecular distance between 5,7-dihydroxyflavone -eNOS is less than 0.4 Å by molecular dynamic simulation. The in vivo studies were carried by SHRs oral administrated with 10 mg/kg 5,7-dihydroxyflavone that could alleviate hypertensive symptoms within 30 min, but if SHRs pretreated with L-NAME (10 mg/kg, an eNOS inhibitor) can erase the anti-hypertensive effects of 5,7-dihydroxyflavone, but no affected by aminoguanidine pretreatment (100 mg/kg, the selective antagonist of iNOS). Furthermore, oral administration of 5,7-dihydroxyflavone does not affect the heart rate and pulse pressure difference in SHR rats. In conclusion, the effects of 5,7-dihydroxyflavone on blood pressure regulation may act on eNOS as an agonist to achieve its acute antihypertensive effects. These acute antihypertensive effects suggest that 5,7-dihydroxyflavone has the potential to be a candidate medication for urgently lowering blood pressure requirements without posing hypertensive risks.

The combination of Eucommia ulmoides and Tribulus terrestris (ET) has been widely utilized in clinical practice for thousands of years, but the mechanism underlying its efficacy has not been elucidated to date. This study attempted to investigate the role played by the intestinal microbiota and fecal metabolism in the response of elderly spontaneous hypertensive rats (SHRs) to ET administration as a treatment for hypertension. Fourteen male spontaneously hypertensive rats (SHRs, 18 months old) were randomly divided into an ET group and an SHR group, and 7 Wistar-Kyoto (WKY) rats of the same age were employed as the control group. The ET group was intragastrically administered 1.0 g/kg/d ET for 42 days, and SHRs and WKY rats were administered an equal amount of normal saline intragastrically. The intestinal microbiota and fecal metabolism were analyzed by 16S rRNA sequencing and the GC-MS (gas chromatography-mass spectrometry)/MS assay. ET treatment decreased blood pressure steadily, improved the colonic tissue morphology, and changed the structure and composition of the imbalanced microbiota in SHRs. Specifically, ET treatment increased the abundance of Eubacterium, which might be one of the target microbes for ET, and had a negative correlation with the levels of α-tocopherol, chenodeoxycholic acid, and deoxycholic acid according to the Spearman correlation analysis. The change in the intestinal microbiota affected the fecal metabolic pattern of SHRs. Eight potential biomarkers were determined to be primarily enriched in ABC transporters, phenylalanine metabolism, central carbon metabolism in cancer, purine metabolism, and protein digestion and absorption. The correlation analysis demonstrated that the abundance of Eubacterium and the decreased levels of α-tocopherol, chenodeoxycholic acid, and deoxycholic acid in the ET group were highly correlated. Our results suggest that ET has a good antihypertensive effect, which may be driven by the intestinal microbiota and their beneficial metabolites. The results of this study may help to elucidate the antihypertensive mechanism of ET.

The seeds of Swietenia macrophylla King (SM) (Meliaceae) are used as a folk medicine for the treatment of hypertension in Malaysia. However, the antihypertensive and vasorelaxant effects of SM seeds are still not widely studied. Thus, this study was designed to investigate the in vivo antihypertensive effects and in vitro mechanism of vasorelaxation of a 50% ethanolic SM seed extract (SM50) and the fingerprint of SM50 was developed through tri-step Fourier transform infrared (FTIR) spectroscopy. The vasorelaxant activity and the underlying mechanisms of SM50 were evaluated on thoracic aortic rings isolated from Sprague-Dawley rats in the presence of antagonists. The pharmacological effect of SM50 was investigated by oral administration of spontaneously hypertensive rats (SHRs) with three different doses of SM50 (1000, 500, and 250 mg/kg/day) for 4 weeks and their systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were measured weekly using tail-cuff method. The tri-step FTIR macro-fingerprint of SM50 showed that SM50 contains stachyose, flavonoids, limonoids, and ester, which may contribute to its vasorelaxant effect. The results showed that the vasorelaxant activity of SM50 was mostly attributed to channel-linked receptors pathways through the blockage of voltage-operated calcium channels (VOCC). SM50 also acts as both potassium channels opener and inositol triphosphate receptor (IP3R) inhibitor, followed by β2-adrenergic pathway, and ultimately mediated through the nitric oxide/soluble guanylyl cyclase/cyclic 3',5'-guanosine monophosphate (NO/sGC/cGMP) signaling pathways. The treatment of SM50 also significantly decreased the SBP and DBP in SHRs. In conclusion, the antihypertensive mechanism of SM50 was mediated by VOCC, K+ channels, IP3R, G-protein-coupled β2-adrenergic receptor, and followed by NO/sGC/cGMP signaling mechanism pathways in descending order. The data suggested that SM50 has the potential to be used as a herbal medicament to treat hypertension.

Neo-fermented buckwheat sprouts (neo-FBS) contain angiotensin-converting enzyme (ACE) inhibitors and vasodilators with blood pressure-lowering (BPL) properties in spontaneously hypertensive rats (SHRs). In this study, we investigated antihypertensive mechanisms of six BPL peptides isolated from neo-FBS (FBPs) by a vasorelaxation assay and conventional in vitro, in vivo, and a new ex vivo ACE inhibitory assays. Some FBPs demonstrated moderate endothelium-dependent vasorelaxation in SHR thoracic aorta and all FBPs mildly inhibited ACE in vitro. Orally administered FBPs strongly inhibited ACE in SHR tissues. To investigate detailed ACE-inhibitory mechanism of FBPs in living body tissues, we performed the ex vivo assay by using endothelium-denuded thoracic aorta rings isolated from SHRs, which demonstrated that FBPs at low concentration effectively inhibited ACE in thoracic aorta tissue and suppressed angiotensin II-mediated vasoconstriction directly associated with BPL. These results indicate that the main BPL mechanism of FBP was ACE inhibition in living body tissues, suggesting that high FBP's bioavailability including absorption, tissue affinity, and tissue accumulation was responsible for the superior ACE inhibition in vivo. We propose that our ex vivo assay is an efficient and reliable method for evaluating ACE-inhibitory mechanism responsible for BPL activity in vivo.

Acetylcholine (ACh) acts as a neurotransmitter and neuromodulator. A small dose of eggplant powder rich in ACh (equivalent to 22 g fresh eggplant/d) has been shown to reduce blood pressure (BP) in individuals with higher BP. Here, we investigated the mechanisms underlying the antihypertensive effects of low-dose orally administered ACh in spontaneously hypertensive rats (SHRs). The effects of ACh on BP and sympathetic nervous activity (SNA), including lumbar SNA (LSNA) and renal SNA (RSNA), were evaluated by subjecting conscious SHRs to a telemetry method. Single oral administration of ACh decreased LSNA and lowered BP. Repeated oral administration of ACh for 30 d decreased RSNA and suppressed the elevated BP. Noradrenaline levels in the urine also decreased. However, vagotomy and co-administration of M3 muscarinic ACh receptor antagonist reversed the BP-lowering effect; the dynamics of non-absorbable orally administered ACh was revealed using stable isotope-labeled ACh. In conclusion, ACh acts on the gastrointestinal M3 muscarinic ACh receptor to increase afferent vagal nerve activity, which decreases SNA by autonomic reflex, suppressing noradrenaline release and lowering BP. This study suggests the use of exogenous ACh as an antihypertensive food supplement for controlling the autonomic nervous system, without absorption into the blood.

Ala-His-Leu-Leu (AHLL) was isolated and purified from the loach (Misgurnus anguillicaudatus) hydrolysate in our previous study. The aim of this study was to investigate the antihypertensive effects of angiotensin-I-converting enzyme (ACE) inhibitory peptide AHLL in spontaneously hypertensive rats (SHRs). AHLL showed good antihypertensive effects in SHRs during the long-term oral administration and no allergic reactions or coughing were observed. After 2 months of oral administration of AHLL, the body weight growth was normal. The decrements in systolic blood pressure of the high dose (5 mg/kg bw) and the low dose of AHLL (1 mg/kg bw) treatment groups were 22.1 and 5.0 mmHg at week 8, respectively. Compared to the control group, the concentrations of triglyceride and sodium in serum were reduced significantly in the high-dose group after 2 months. The ACE activity of kidney and lung decreased significantly, which indicated that AHLL exerted an antihypertensive effect on kidney and lung and they were the target sites of AHLL. These results strongly supported the in vivo antihypertensive mechanism of AHLL.