VASORELAXANT MECHANISM(S) OF CLERODENDRUM VOLUBILE ETHANOL LEAF EXTRACT IN NORMAL AND DOXORUBICIN-TREATED ENDOTHELIUM INTACT AORTIC RINGS

AKINYELE OLUBIYI AKINSOLA; ADEJUWON ADEWALE ADENEYE; OLUFUNKE ESAN OLORUNDARE; HUSSEIN MOYOSORE SALAHDEEN; BABATUNDE ADEKUNLE MURTALA; HASSAN MUKHTAR; RALPH M. ALBRECHT

doi:10.22159/ajpcr.2022.v15i7.44887

Authors

AKINYELE OLUBIYI AKINSOLA Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Kwara State, Nigeria.
ADEJUWON ADEWALE ADENEYE Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Clinical Sciences, Lagos State University College of Medicine, 1-5 Oba Akinjobi Way, G.R.A., Ikeja, Lagos State, Nigeria.
OLUFUNKE ESAN OLORUNDARE Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Kwara State, Nigeria.
HUSSEIN MOYOSORE SALAHDEEN Department of Physiology, Faculty of Basic Medical Sciences, Lagos State University College of Medicine, 1-5 Oba Akinjobi Way, G.R.A., Ikeja, Lagos State, Nigeria.
BABATUNDE ADEKUNLE MURTALA Department of Physiology, Faculty of Basic Medical Sciences, Lagos State University College of Medicine, 1-5 Oba Akinjobi Way, G.R.A., Ikeja, Lagos State, Nigeria.
HASSAN MUKHTAR Department of Dermatology, University of Wisconsin, Madison, Medical Science Center, 1300 University Avenue, Madison, WI 53706, USA.
RALPH M. ALBRECHT Animal Sciences Department, University of Wisconsin, Madison, 1675 Observatory Drive, Madison, WI 53706, USA.

DOI:

https://doi.org/10.22159/ajpcr.2022.v15i7.44887

Keywords:

Doxorubicin, Endothelium intact aortic rings, Vasorelaxant mechanisms, Clerodendrum volubile, Ethanol leaf extract

Abstract

Objectives: Doxorubicin (DOX) is a highly effective antibiotics anthracycline cytotoxic agent with a broad spectrum of activity in the treatment of solid and hematological malignancies. However, DOX is notorious for inducing cardiotoxicity and vascular dysfunction as its common off-target side effects. This study evaluated the possible vasorelaxant activity and mechanism(s) of action of Clerodendrum volubile ethanol leaf extract (CVE) in normal and DOX-pretreated endothelium intact aortic rings in Physiological Salt Solution (PSS) in vitro.

Methods: The responses were recorded isometrically by an organ bath connected to Data Capsule Acquisition System. Effects of CVE on phenylephrine-precontracted endothelium intact rat aortic rings and the influence of the respective blockers for adrenergic, cholinergic, calcium channel, and prostacyclin receptors were investigated to unveil the possible underlying vasorelaxant mechanism(s) of CVE.

Results: Our findings showed that CVE significantly induced vasorelaxation in phenylephrine hydrochloride (PE) and KCl precontracted endothelium intact aortic rings in a concentration-dependent manner. Furthermore, the CVE-induced vasorelaxation in PE- and KCl-precontracted aortic rings were inhibited by pre-incubation with atropine and indomethacin indicating that the vasorelaxant effect of CVE was profoundly mediated through cholinergic and prostacyclin mechanisms.

Conclusion: Overall, results of this study report for the first time the vasorelaxant effect of CVE in isolated endothelium-intact doxorubicin-treated aortic rings of normotensive rats which was probably cholinergic and prostacyclin-mediated. Thus, results of this study provide further insight into the cardioprotective mechanism of CVE in doxorubicin-induced cardiotoxicity beyond the antioxidant and anti-apoptosis mechanisms that have been previously reported.

Downloads

Download data is not yet available.

References

Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991;324:808-15.

Alkuraishy HM, Al-Gareeb AI, Al-Hussaniy HA. Doxorubicin-induced cardiotoxicity: Molecular mechanism and protection by conventional drugs and natural products. Int J Clin Oncol Cancer Res 2017;2:31-44.

Favreau-Lessard AJ, Sawyer DB, Francis SA. Anthracycline cardiomyopathy: The plot gets thinner. Circ Heart Fail 2018;11:e005194.

Zhao L, Zhang B. Doxorubicin induces cardiotoxicity through up-regulation of death receptors mediated apoptosis in cardiomyocytes. Sci Rep 2017;7:44735.

Nebigil CG, Désaubry L. Updates in anthracycline-mediated cardiotoxicity. Front Pharmacol 2018;9:1262.

Favreau-Lessard AJ, Blaszyk H, Jones MA, Sawyer DB, Pinz IM. Systemic and cardiac susceptibility of immune compromised mice to doxorubicin. Cardiooncology 2019;5:2.

Volkova M, Russell R 3rd, Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr Cardiol Rev 2011;7:214-20.

Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutics strategies. J Mol Cell Cardiol 2012;52:1213-25.

Diamanti J, Mezzetti B, Giampieri F, Alvarez-Suarezm JM, Quiles JL, Gonzáles-Alonso A, et al. Doxorubicin-induced oxidative stress in rats is efficiently counteracted by dietary anthocyanin differently enriched strawberry (Fragaria x ananassa Duch.). J Agric Food Chem 2014;62:3935-43.

Luu AZ, Chowdhury B, Al-Omran M, Teoh H, Hess DA, Verma S. Role of endothelium in doxorubicin-induced cardiomyopathy. JACC Basic Transl Sci 2018;3:861-70.

Chang WT, Li J, Huang HH, Liu H, Han M, Ramachandran S, et al. Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury and JNK activation. J Cell Biochem 2011;112:2873-81.

Kwatra M, Kumar V, Jangra A, Mishra M, Ahmed S, Ghosh P, et al. Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats. Pharm Biol 2016;54:637-47.

Chen T, Shen HM, Deng ZY, Yang ZZ, Zhao RL, Wang L, et al. A herbal formula, SYKT, reverses doxorubicin-induced myelosuppression and cardiotoxicity by inhibiting ROS-mediated apoptosis. Mol Med Rep 2017;15:2057-66.

Ojha S, Al Taee H, Goyal S, Mahajan UB, Patil CR, Arya D, et al. Cardioprotective potentials of plant-derived small molecules against doxorubicin associated cardiotoxicity. Oxid Med Cell Longev 2016;2016:5724973.

Afsar T, Razak S, Batoo KM, Khan MR. Acacia hydaspica R. Parker prevents doxorubicin-induced cardiac injury by attenuation of oxidative stress and structural cardiomyocyte alterations in rats. BMC Complement Altern Med 2017;17:554.

Adefegha SA, Oboh G. Antioxidant and inhibitory properties of Clerodendrum volubile leaf extracts on key enzymes relevant to non-insulin dependent diabetes mellitus and hypertension. J Taibah Univ Sci 2016;10:521-33.

Erukainure OL, Hafizur RM, Kabir N, Choudhary MI, Atolani O, Banerjee P, et al. Suppressive effects of Clerodendrum volubile P. Beauv. [Labiatae] methanolic extract and its fractions on type 2 diabetes and its complications. Front Pharmacol 2018;9:8.

Erukainure OL, Ebuehi OAT, Choudhary MI, Adhikari A, Hafizur RM, Perveen S, et al. Iridoid glycoside from the leaves of Clerodendrum volubile Beauv. Shows potent antioxidant activity against oxidative stress in rat brain and hepatic tissues. J Diet Suppl 2014;11:19-29.

Fred-Jaiyesimi A, Adekoya A. Pharmacognostic studies and anti-inflammatory activities of Clerodendrum volubile P Beauv leaf. Int J Phytomed 2012;4:414-8.

Erukainure OL, Zaruwa MZ, Choudhary MI, Naqvi SA, Ashraf N, Hafizur RM, et al. Dietary fatty acids from leaves of Clerodendrum volubile induce cell cycle arrest, down regulate matrix metalloproteinase-9 expression, and modulate redox status in human breast cancer. Nutr Cancer 2016;68:634-45.

Erukainure OL, Mesaik MA, Atolani O, Muhammad A, Chukwuma CI, Islam MS. Pectolinarigenin from the leaves of Clerodendrum volubile shows potent immunomodulatory activity by inhibiting T-cell proliferation and modulating respiratory oxidative burst in phagocytes. Biomed Pharmacother 2017;93:529-35.

Afolabi S, Olorundare O, Gyebi G, Syed DN, Mukhtar H, Albrecht R, et al. Cytotoxic potentials of Clerodendrum volubile against prostate cancer cells and its possible proteomic targets. J Clin Nutr Food Sci 2019;2:46-53.

Oboh G, Ogunruku OO, Oyeleye SI, Olasehinde TA, Ademosun AO, Boligun AA. Phenolic extracts from Clerodendrum volubile leaves inhibit cholinergic and monoaminergic enzymes relevant to the management of some neurodegenerative diseases. J Diet Suppl 2017;14:358-71.

Senjobi CT, Fasola TR, Aziba PI. Phytochemical and analgesic evaluation of methanol leaf extract of Clerodendrum volubile Linn. Ife J Sci 2017;19:1-5.

Ajao AA, Oseni OM, Oladipo OT, Adams YA, Mukaila YO, Ajao AA. Clerodendrum volubile P. Beauv (Lamiaceae), an underutilized indigenous vegetable of utmost nutritive and pharmacological importance. BJBAS 2018;7:606-11.

Olorundare OE, Adeneye AA, Akinsola AO, Sanni DA, Koketsu M, Mukhtar H. Clerodendrum volubile ethanol leaf extract: A potential antidote to doxorubicin-induced cardiotoxicity in rats. J Toxicol 2020;2020:8859716.

Adeneye AA, Olorundare OE, Akinsola AO, Sanni DA, Ntambi JM, Mukhtar H. Ameliorative potential of Clerodendrum volubile ethanol leaf extract on doxorubicin-induced hepatorenal toxicities in rats. PHATOXNATMED 2021;1:1-13.

United States National Institutes for Health publication, 1985;85:23.

Salahdeen HM, Idowu GO, Murtala BA. Endothelium-dependent and independent vasorelaxant effects of aqueous extract of Tridax procumbens Lin. leaf in rat aortic rings. Indian J Exp Biol 2012;50:883-8.

Wilkinson EL, Sidaway JE, Cross MJ. Cardiotoxic drugs, Herceptin and doxorubicin, inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability. Biol Open 2016;5:1362-70.

An T, Zhang Y, Huang Y, Zhang R, Yin S, Guo X, et al. Neuregulin-1 protects against doxorubicin-induced apoptosis in cardiomyocytes through an Akt-dependent pathway. Physiol Res 2013;62:379-85.

El-Boghdady NA. Increased cardiac endothelin-1 and nitric oxide in adriamycin-induced acute cardiotoxicity: Protective effect of Ginkgo biloba extract. Indian J Biochem Biophys 2013;50:202-9.

Wojcik T, Buczek E, Majzner K, Kolodziejczyk A, Miszczyk J, Kaczara P, et al. Comparative endothelial profiling of doxorubicin and daunorubicin in cultured endothelial cells. Toxicol In vitro 2015;29:512-21.

Chaosuwannakit N, D’Agostino R Jr., Hamilton CA, Lane KS, Ntim WO, Lawrence J, et al. Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol 2010;28:166-72.

Du H, Wang X, Wu J, Qian Q. Phenylephrine induces elevated RhoA activation and smooth muscle α-actin expression in Pkd2+/-vascular smooth muscle cells. Hypertens Res 2010;33:37-42.

Mohanty I, Suklabaidya S, Panja SC. Acidosis reduces the function and expression of α1D-adrenoceptor in superior mesenteric artery of Capra hircus. Indian J Pharmacol 2016;48:399-406.

Jin H, Liu X, Tang Y, Tang L, Wang Y, Du C. Effects of total flavones from Dendranthema morifolium on vasocontraction and proliferation of vascular smooth muscle cells. Mol Med Rep 2016;13:989-93.

Arce C, Vicente D, Segura V, Flacco N, Montó F, Almenar L, et al. Activation of α1A‐adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing. Br J Pharmacol 2017;174:2015-30.

Ratz PH, Berg KM, Urban NH, Miner AS. Regulation of smooth muscle calcium sensitivity: KCl as a calcium-sensitizing stimulus. Am J Physiol Cell Physiol 2005;288:C769-83.

Patai Z, Guttman A, Mikus EG. Potential L-type voltage-operated calcium channel blocking effect of drotaverine on functional models. J Pharmacol Exp Ther 2016;359:442-51.

Godfraind T. Discovery and development of calcium channel blockers. Front Pharmacol 2017;8:286.

Hottinger DG, Beebe DS, Kozhimannil T, Prielipp RC, Kumar G, Belani KG. Sodium nitroprusside in 2014: A clinical concepts review. J Anaesthesiol Clin Pharmacol 2014;30:462-71.

Liu T, Zhang M, Mukosera GT, Borchardt D, Li Q, Tipple TE, et al. L-NAME releases nitric oxide and potentiates subsequent nitroglycerin-mediated vasodilation. Redox Biol 2019;26:101238.

Bower EA, Law AC. The effects of Nw-nitro-L-arginine methyl ester, sodium nitroprusside and noradrenaline on venous return in the anaesthetized cat. Br J Pharmacol 1993;108:933-40.

McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr 2012;95:454-64.

Albuquerque JG, Assis VL, Almeida AJ, Basílio IJ, Luciano MN, Meireles BR, et al. Antioxidant and vasorelaxant activities induced by northeastern Brazilian fermented grape skins. BMC Complement Altern Med 2017;17:376.

Grosso G, Micek A, Godo J, Pajak A, Sciacca S, Galvano F, et al. Dietary flavonoid and lignan intake and mortality in prospective cohort studies: Systematic review and dose-response meta-analysis. Am J Epidemiol 2017;185:1304-16.

Basri DF, Heng KY, Meng CK, Ghazali AR. Screening of antioxidant phytoextracts of Canarium odontophyllum (Miq.) leaves in vitro. IOSR J Pharm 2014;4:1-6.

Basri DN, Rahman NS, Ali SS, Zainalabidin S. The vasorelaxant effect of Canarium odontophyllum Miq. (Dabai) extract in rat thoracic aorta. Egypt J Basic Appl Sci 2018;5:75-9.

Sarr M, Ngom S, Kane MO, Wele A, Diop D, Sarr B, et al. In vitro vasorelaxation mechanisms of bioactive compounds extracted from Hibiscus sabdariffa on rat thoracic aorta. Nutr Metab 2009;6:45.

Satoh H. Comparative effects of anthocyanins (Cassis and bilberry) on arteriosclerotic parameters: Analysis from human pressure pulse wave and arterial stiffness. Food Funct 2013;11:2-8.

Bogaki T, Mitani K, Oura Y, Ozeki K. Effects of ethyl-α-d-glucoside on human dermal fibroblasts. Biosci Biotechnol Biochem 2017;81:1706-11.

Wang N, Kuczmanski A, Dubrovska G, Gollasch M. Palmitic acid methyl ester and its relation to control of tone of human visceral arteries and rat aortas by perivascular adipose tissue. Front Physiol 2018;9:583.

Rasheed HM, Khan T, Wahid F, Khan R, Shah AJ. Chemical composition and vasorelaxant and antispasmodic effects of essential oil from Rosa indica L. petals. eCAM 2015;2015:279247.

Lee YC, Cheng HH, Liu CH, Chen MF, Chen PY, Kuo JS, et al. Methyl palmitate: A potent vasodilator released in the retina. Invest Ophthalmol Vis Sci 2001;51:4746-53.