Age-Specific Influences of Chronic Administration of the Fatty Acid

Pharmacological Reports 68 (2016) 363–369

Contents lists available at ScienceDirect

Pharmacological Reports

jou rnal homepage: www.elsevier.com/locate/pharep

Original research article

Age-speciﬁc inﬂuences of chronic administration of the fatty acid

amide hydrolase inhibitor URB597 on cardiovascular parameters and

organ hypertrophy in DOCA-salt hypertensive rats

Marek Toczek, Marta Baranowska-Kuczko, Emilia Grze˛da, Anna Pe˛dzin´ ska-Betiuk,

Jolanta Weresa, Barbara Malinowska *

Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland

A R T I C L E I N F O A B S T R A C T

Article history: Background: The endocannabinoid system has been suggested to be up-regulated in hypertension. Fatty

Received 13 April 2015

acid amide hydrolase (FAAH) is the main hydrolytic enzyme for the encocannabinoid anandamide. The

Received in revised form 8 October 2015

aim of our study was to examine the age-speciﬁc inﬂuence of the chronic administration of the FAAH

Accepted 9 October 2015

inhibitor URB597 on blood pressure (BP), heart rate (HR) and cardiac and renal hypertrophy in

Available online 24 October 2015

hypertensive rats during two critical periods for the development of hypertension.

Methods: Experiments were performed on uninephrectomised 4 (younger) and 6–7 (older) weeks old

Keywords:

rats rendered hypertensive by a high salt diet and deoxycorticosterone acetate (DOCA) injections and on

Age-speciﬁc

normotensive animals (unilateral nephrectomy only). URB597 1 mg/kg or its vehicle were injected twice

Anandamide

daily for 2 weeks.

DOCA-salt hypertension

Results: The DOCA-salt procedure caused comparable increases in BP (but not HR) in both age groups

Endocannabinoid system

URB597 and more strongly increased cardiac and renal hypertrophic indices in younger than in older animals.

Chronic URB597 administration reduced BP and HR in older but not in younger rats. In contrast, the

inhibitor diminished the cardiac and renal hypertrophy in younger but not in older animals. URB597 did

not affect body weight gain, and food and water intake in normotensive or hypertensive rats.

Conclusion: Two weeks of URB597 administration to DOCA-salt hypertensive rats caused an age-speciﬁc

reduction in BP, HR and cardiac and renal hypertrophy and did not affect the body weight, and water and

food intake. Thus, caution should be taken during studies of FAAH inhibitors because of their potential

age-speciﬁc effects.

ß 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights

reserved.

Introduction [6]. Similarly, anandamide and its stable analogue methananda-

mide stimulated stronger hypotension in anaesthetised SHR

Hypertension is a major cause of cardiovascular diseases that compared with normotensive controls [7,8]. In conscious animals,

leads to development and progression of heart hypertrophy, they decreased BP in SHR and in angiotensin II (Ang II) and

chronic renal failure and, ultimately, to death. The endocannabi- vasopressin-induced hypertension but increased BP in normoten-

noid system has been suggested to be up-regulated in hypertensive rats [7,9]. The higher concentrations of anandamide and fatty

sion, thus buffering increases in blood pressure (BP) [1–3]. The acid amide hydrolase (FAAH; an enzyme responsible for the

plasma level of the best known endocannabinoid anandamide was anandamide degradation) have been demonstrated in myocardial

higher in hypertensive patients [4,5], in spontaneously hyperten- biopsies from patients with myocardial hypertrophy [10]. More-

sive rats (SHR) and in 2 kidney 1 clip hypertensive rats [4]. The over, anandamide and methanandamide attenuated hypertrophy

decreases in BP after D -tetrahydrocannabinol inhalation were of neonatal rat cardiomyocytes acting via cannabinoid CB1 and CB2

more pronounced in hypertensive open-angle glaucoma patients receptors [11], while antagonists of CB1 receptors reduced the

hypertrophy of human proximal tubular (HK2) cells [12] and renal

hypertrophy in obese Zucker rats [13].

A salt-rich diet in conjunction with stress is one of the main

* Corresponding author.

E-mail address: [email protected] (B. Malinowska). lifestyle factors leading to hypertension. Three weeks of high

http://dx.doi.org/10.1016/j.pharep.2015.10.004

364 M. Toczek et al. / Pharmacological Reports 68 (2016) 363–369

sodium intake increased BP and plasma anandamide levels in rats Materials and methods

[14]. Among animal models, the deoxycorticosterone acetate

(DOCA)-salt hypertension, which is connected with pronounced Animals

cardiac and renal hypertrophy, is the appropriate model for

evaluating the role of sodium in hypertension [15,16]. We have All surgical procedures and experimental protocols were

recently demonstrated the enhanced function of inhibitory performed in accordance with the European and Polish legislation

presynaptic cannabinoid CB1 receptors on sympathetic nerves in and were approved by the local Animal Ethics Committee in

DOCA-salt hypertensive rats, which may play a protective role in Białystok (Poland). Rats had free access to food pellets and water

hypertension [17]. and were maintained under a 12/12 h light/dark cycle.

The FAAH inhibitors increase cerebral and peripheral levels of

anandamide [18]. They constitute an attractive therapeutic DOCA-salt hypertension and URB597 administration

approach to the treatment of pain, inﬂammation and central

nervous system disorders [2,19] and are postulated to be potential We used two groups of male Wistar rats younger and older, i.e.

antihypertensive agents [8,20]. The defective gene variant FAAH 4 weeks old and 6–7 weeks old before nephrectomy, respectively.

129T is associated with lower BP in young males [21]. Acute The experimental protocol is shown in Fig. 1. Rats were

injection of the FAAH inhibitors URB597 [8] and AM3506 [20] anaesthetised by intraperitoneal (ip) injection of pentobarbitone

reduced BP in hypertensive (but not in normotensive) anaesthe- sodium [(Biowet, Puławy, Poland; 70 mg/kg (i.e. 300 mmol/kg)].

tised SHR and/or in rats with Ang II-induced hypertension. The right kidney was removed in all rats via a right lateral

However, the potential antihypertensive properties of chronic abdominal incision. After a 1-week recovery period, hypertension

administration of FAAH inhibitors have not been examined, yet. was induced by subcutaneous injections of 11-deoxycorticoster-

Thus, the main aim of our study was to examine the inﬂuence of one acetate [(DOCA; Sigma–Aldrich, Steinheim, Germany); 25 mg/

the chronic, 2-week administration of the FAAH inhibitor URB597 kg (i.e. 67 mmol/kg); 0.4 ml/kg)] twice weekly for 6 weeks, and

on blood pressure, heart rate and heart and renal hypertrophy in replacement of drinking water with 1% NaCl solution. Control rats

conscious DOCA-salt hypertensive rats. received vehicle for DOCA (N,N-dimethylformamide; Steinheim,

Evidence from human and rodents clearly indicate that Germany) twice weekly and drank tap water. Five weeks after

components of the endocannabinoid system both in the brain unilateral nephrectomy, a part of hypertensive and normotensive

0 0

and in peripheral tissues undergo age-speciﬁc changes, suggest- rats was injected ip with URB597 [(3 -(aminocarbonyl)[1,1 -

ing that the effectiveness of endocannabinoid-based therapeutic biphenyl]-3-yl)-cyclohexylcarbamate; Cayman Chemical Compa-

might be dependent on the patient age [22]. Thus, the rat brain ny (Ann Arbour, MI, USA); 1 mg/kg (i.e. 3 mmol/kg); 1 ml/kg] and

FAAH activity was reported to decrease between postnatal days the second part of each group with the solvent for URB597 [a

25–35 and to increase between postnatal days 45–70 [23]. More- mixture of DMSO, Tween 80 (Sigma–Aldrich, Steinheim, Germany)

over, the most potent effect of the CB1 receptor antagonist and saline (1:2:7)] for 14 days twice daily. URB597 is usually

rimonabant on food intake was observed in 18 and 28 days old rats applied at a dose of 0.3 mg/kg [18]. However, chronic administra-

in comparison with 60 days old animals [24]. Weaning (until the tion of this dose of URB597 sometimes failed to mimic/enhance the

age of 28 days) and prepubertal rats (up to the age of 40–45 days) endocannabinoid-mediated responses [e.g. 27]. On the other hand,

are more susceptible to various forms of experimental salt- URB597 at 1 mg/kg injected every 2nd day increased brain

induced hypertension than adult animals [16]. Interestingly, anandamide levels and exerted anti-inﬂammatory effects in the

different mechanisms are responsible for the maintenance of high rat hippocampus [28]. The same dose of URB597 given once a day

BP in weaning and prepubertal DOCA-salt hypertensive rats, for 6 days maintained antinociceptive and anxiolytic-like activity

namely sympathetic nervous system is decisive in the former and of its acute administration [29]. However, the relatively short half-

pressor effects of Ang II and vasopressin in the latter life of this compound [18] has often limited its chronic use [30]. For

[16,25,26]. Therefore, we decided to compare potential age- this reason, a 2-week URB597 administration twice daily

speciﬁc cardiovascular effects of URB597 in younger (4-week) and signiﬁcantly diminished arthritis severity, whereas its injections

older (6–7-week) rats. once daily only partially blocked these ailments [31]. Taking the

Fig. 1. Experimental protocol used to examine the inﬂuence of URB597 on blood pressure (BP), heart rate (HR) and organ hypertrophy in deoxycorticosterone (DOCA)-salt

hypertensive younger (Y) and older (O) rats. All animals underwent unilateral nephrectomy. After a 1-week recovery period, hypertension was induced by 6-week

subcutaneous (sc) injections of DOCA and replacement of drinking water with 1% NaCl solution. Control rats received vehicle for DOCA and drank tap water. BP and HR were

measured just before the ﬁrst dose of DOCA or its solvent (day 0) and then again after 4–6 weeks. From the 5th week, URB597 or its vehicle were injected intraperitoneally (ip)

for 14 days. Rats were sacriﬁced 12 h after the ﬁnal dose of URB597 (or its vehicle). Download English Version: https://daneshyari.com/en/article/2011644

Download Persian Version:

https://daneshyari.com/article/2011644

Daneshyari.com