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Blood Pressure Reducing Effects of Piromelatine and Melatonin in Spontaneously Hypertensive Rats

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Blood Pressure Reducing Effects of Piromelatine and Melatonin in Spontaneously Hypertensive Rats Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2013; 17: 2449-2456 Blood pressure reducing effects of piromelatine and melatonin in spontaneously hypertensive rats L. HUANG 1,2 , C. ZHANG 1, Y. HOU 1, M. LAUDON 4, M. SHE 3, S. YANG 3, L. DING 3, H. WANG 2, Z. WANG 5, P. HE 1, W. YIN 1,3 1Institute of Cardiovascular Research, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang, Hunan, People's Republic of China, China 2Department of Operative Surgery, University of South China, Hengyang, Hunan, People's Republic of China, China 3Department of Biochemistry and Molecular Biology, School of Life Sciences and Technology, University of South China, Hengyang, Hunan, People's Republic of China, China 4Drug discovery, Neurim Pharmaceuticals Ltd, Tel-Aviv, Israel 5Department of Laboratory Animal Science, University of South China, Hengyang, Hunan, People's Republic of China, China Abstract. – BACKGROUND : Recently, wide - Key Words: spread interest has grown regarding melatonin Piromelatine, Melatonin, Hypertension, Sponta - treatment of hypertension including its cardiopro - neously hypertensive rats, Metabolic diseases. tective effects. Studies in rodents indicate that melatonin plays a role in the pathogenesis of hy - pertension in rats with metabolic syndrome. Piromelatine, a melatonin agonist, serotonin Introduction 5-HT-1A and 5-HT-1D agonist and serotonin 5- HT2B antagonist is a multimodal agent with sleep promoting, anti-diabetic, analgesic, anti- The pineal hormone melatonin is secreted with neurodegenerative, anxiolytic and antidepres - a marked circadian rhythm. The endogenous sant potential, currently in development for the rhythm of secretion is generated by the suprachi - treatment of insomnia. asmatic nuclei, entrained to the light/dark cycle AIM: In this report we assessed the effects of and conveys information concerning the daily cy - piromelatine and melatonin treatment on blood cle to body physiology functions such as sleep, pressure in spontaneously hypertensive rats 1 (SHR) and normotensive Wistar-Kyoto (WKY) rats. immune system and glucose regulation . Recent MATERIALS AND METHODS: Five groups of data indicate that impaired melatonin production 12-wk-old rats (10/group) were treated for 5 weeks is involved in several cardiovascular pathologies with a vehicle, piromelatine (5, 15 and 50 mg/kg including hypertension and ischemic heart dis - BW) and melatonin (10 mg/kg BW) and an age- ease 2. In addition, some reported that melatonin matched WKY control group. Systolic blood pres - can reduce increased blood pressure both in hy - sure (tail-cuff method) was measured weekly at 3 9:00 a.m. and at 9:00 p.m. The rats body weight, pertensive humans and animals . The blood pres - plasma glucose, insulin, triglyceride, adiponectin, sure lowering effect of melatonin was demon - total cholesterol, HDL and LDL/VLDL cholesterol strated in healthy women taking contraceptive were also measured . pills, postmenopausal women with hormone re - RESULTS: Our results showed that both pirome - placement therapy, healthy men and hypertension latine and melatonin reduced SHR blood pressure 4 significantly both during the morning and the patients . evening. Piromelatine, but not melatonin, also re - Diminished melatonin production at night is duced SHR body weight gain and both significant - consistently reported in hypertensive patients ly decreased plasma glucose and insulin levels with nondipping blood pressure and in patients and increased adiponectin levels. with coronary heart disease. Pinealectomy, which CONCLUSIONS: Piromelatine, similar to mela - was associated with decreased melatonin produc - tonin, has an antihypertensive effect and also at - tenuates body weight, improves metabolic pro - tion, caused vasoconstriction and temporary hy - files and might be useful in the treatment of hy - pertension in adult rats while continuous light pertension and the metabolic syndrome. (24 hours/day), which prevented the nocturnal Corresponding Author: Weidong Yin, MD; e-mail: [email protected] 2449 L. Huang, C. Zhang, Y. Hou, M. Laudon, M. She, S. Yang, L. Ding, H. Wang, Z. Wang, et al rise of melatonin plasma levels, also resulted in Materials and Methods suppression of circadian heart rate and blood pressure variability 1. Melatonin has been shown Materials to reduce blood pressure, oxidative load and to Piromelatine (C17H16N2O4) and melatonin increase nitric oxide bioavailability in sponta - were provided by Neurim Pharmaceuticals Ltd. neously hypertensive rats (SHR). Blood pressure (Tel-Aviv, Israel), both were dissolved in 1% di - decreased after 6 weeks of melatonin treatment methylsufoxide (DMSO)/water solution. (10 m/kg) of SHR, which was associated with a reduction of interstitial renal tissue inflammation, Animals and Treatment decreased oxidative stress and attenuation of ex - 12-wks-old male spontaneously hypertensive pression of nuclear factor kappa B in the kidney 5. rats (SHR) were randomly divided into 5 groups In the same model of hypertension, melatonin, (n=10 in each group): control SHR group, in addition to lowering mean arterial pressure piromelatine (5 mg/kg/day) treated SHR group, and causing a heart rate reduction, restored plas - piromelatine (15 mg/kg/day) treated SHR group, ma norepinephrine concentration and the propor - piromelatine (50 mg/kg/day) treated SHR group tion of β1/ β2 receptors in the heart, enhanced and melatonin (10 mg/kg/day) treated SHR maximal relaxation of mesenteric arteries and group. In addition age-matched Wistar-Kyoto improved baroreflex responses, which relate to rats (WKY) were divided into 5 groups (n=10 in its antioxidant effects. Acute administration of each group) with the same treatment as the SHR melatonin lowered blood pressure and reduced to serve as control. Both drugs were given with norepinephrine blood levels in SHR 6-8 . intraperitoneal injection in 18:00 every day. All In vitro , melatonin attenuated constriction of animals were housed at a temperature of 23±1°C aortic ring in SHR were demonstrated to inhibit in individual cages and freely fed a regular pellet phospholipase-C cascade independently on mela - diet ad libitum. All rats were subjected to alter - tonin receptor or α1- adrenoceptor blockade and nate 12 h periods of dark and light (lights on 6:00 prevent excess oxidative load related with the an - a.m.-6:00 p.m.). tioxidant enzyme superoxide dismutase 9. Melatonin secretion decreased in fructose fed Blood Pressure Measurements rats, an animal model of the metabolic syndrome, Systolic blood pressure (SBP) was determined that developed hypertension and the administra - weekly in conscious restrained rats by tail-cuff tion of melatonin blunted this blood pressure plethysmography at 9:00 a.m. and at 9:00 p.m.. rise 10 . Before the beginning of the experiments, rats The plasma half-life of melatonin is only 35 to were conditioned three to four times to the proce - 50 minutes. Attempts have been made to remedy dure and when blood pressure was determined, this problem via a controlled-release formulation the reported values represented the mean of three of melatonin and by developing various indolic to four separate determinations. After five weeks and non-indolic melatonergic agonists. of treatment, blood pressure was determined by Piromelatine (former name is Neu-P11) is a direct puncture of the carotid. Body weights melatonin agonist, serotonin 5-HT-1A and 5-HT- (BW) and food consumption were measured 1D agonist and serotonin 5-HT2B antagonist. once a week. Piromelatine is a multimodal agent with sleep promoting, anti-diabetic, analgesic, anti-neurode - Biochemical Parameters generative, anxiolytic and antidepressant poten - Plasma was separated by centrifugation (12,000 tial, currently in development for the treatment of rpm, 4 min) and stored at –80 °C. Glucose was de - insomnia. termined by a chemical colorimetric method Recent studies have shown that piromelatine (BioAssay Systems, Hayward, CA, USA). Plasma promoted sleep 11 , exerts antidepressant and anxi - insulin and adiponectin were determined by olytic activities in rodent models 12 and inhibited ELISA (Biocompare, San Francisco, CA, USA. weight gain and improved insulin sensitivity in Plasma triglycerides (TG), total Cholesterol (TC), high-fat/high-sucrose-fed rats 13 . In the present high-density lipoprotein (HDL) and low-density study we investigated the potential effects of lipoprotein/very low-density lipoprotein piromelatine and melatonin on blood pressure (LDL/VLDL) cholesterol were determined by and metabolic profiles of SHR with established commercially available enzymatic methods hypertension. (BioAssay Systems, Hayward, CA, USA). 2450 Blood pressure reducing effects of piromelatine and melatonin in spontaneously hypertensive rats - n Statistical Analysis a a a a a a a a a a n o g ) 9 1 8 5 9 5 1 4 8 1 i . c k g n + 2 5 3 3 3 3 3 2 3 4 All quantitative data are expressed as mean ± / n Y o H g i ± ± ± ± ± ± ± ± ± ± t K a m 8 3 2 4 3 5 4 9 2 2 m SD. One-way ANOVA test was used to analyze d l . e W 6 8 7 3 4 1 0 8 0 9 e m 0 n ( 2 2 2 2 2 2 2 1 2 1 i the significance of differences between mean val - 1 m 1 1 1 1 1 1 1 1 1 1 m r ues. A level of p < 0.05 was considered statisti - e e t a a a a a a a a a n e g ) 3 9 6 2 2 9 4 5 4 8 i . d k cally significant. t g + 3 2 3 4 4 2 3 2 3 3 / a s l Y H g ± ± ± ± ± ± ± ± ± ± a e K m 1 3 9 3 1 5 1 1 5 7 m w . m W 5 7 2 5 2 0 3 4 0 8 ) m 0 o ( 2 2 2 2 2 2 2 2 2 1 r P 5 i 1 1 1 1 1 1 1 1 1 1 B Results p S ( e e r a a a a a a a a a a n g u ) 4 8 9 8 6 5 7 4 9 1 i .
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