Vasorelaxant effects of biochemical constituents of various medicinal plants and their benefits in diabetes

Abstract

Endothelial function plays a pivotal role in cardiovascular health, and dysfunction in this context diminishes vasorelaxation concomitant with endothelial activity. The nitric oxide-cyclic guanosine monophosphate pathway, prostacyclin-cyclic adenosine monophosphate pathway, inhibition of phosphodiesterase, and the opening of potassium channels, coupled with the reduction of calcium levels in the cell, constitute critical mechanisms governing vasorelaxation. Cardiovascular disease stands as a significant contributor to morbidity and mortality among individuals with diabetes, with adults afflicted by diabetes exhibiting a heightened cardiovascular risk compared to their non-diabetic counterparts. A plethora of medicinal plants, characterized by potent pharmacological effects and minimal side effects, holds promise in addressing these concerns. In this review, we delineate various medicinal plants and their respective biochemical constituents, showcasing concurrent vasorelaxant and anti-diabetic activities.

Key Words: Medicinal plants; Vasorelaxation; Endothelium; Diabetes; Anti-diabetic

Core Tip: To the best of our knowledge, this study is pioneering, offering a unique perspective that addresses both vasorelaxation and diabetes concerning medicinal plants. The comprehensive collection of medicinal plant references presented in this study is anticipated to serve as a valuable resource, inspiring and guiding future investigations into cardiovascular diseases and diabetes.

INTRODUCTION

Cardiovascular diseases (CVDs), stemming from disorders affecting the heart and blood vessels, claim tens of millions of lives globally every year[1]. The cardiovascular system comprises the heart and three distinct types of blood vessels[2]. The inner surface of blood vessels is constituted by endothelial cells referred to as the tunica intima layer[3]. Endothelial cells envelop the interior of the vessel and establish interaction with the blood[2]. These cells function as a barrier between the vessel lumen and wall, preventing blood clotting, while mediators released from them exert vasoactive effects[4]. Impaired endothelial function and diminished endothelium-associated vasorelaxation contribute to the development of various cardiovascular disorders, including hypertension and diabetes[5]. Concurrently, diabetic vasculopathy manifests as endothelial dysfunction, characterized by endothelial injury and vascular wall thickening[6].

Hemodynamic forces, such as shear stress, impact endothelial cells, causing unidirectional deformation of endothelial cells[7]. The equilibrium between vasodilator and vasoconstrictor agents regulates vascular tone. Endothelial dysfunction further results in elevated vascular tone, leading to cardiovascular disorders such as hypertension[8]. Vasodilatory agents like endothelium-derived hyperpolarizing factor, nitric oxide (NO), and prostacyclin (PGI₂) are produced by the endothelium in response to increased shear stress[9]. Various mechanisms, including the NO- cyclic guanosine monophosphate (cGMP) pathway, PGI₂-cyclic adenosine monophosphate (cAMP) pathway, phosphodiesterase (PDE) inhibition, and the opening of K⁺ ion channels/reduction of intracellular Ca²⁺ levels, play crucial roles in vasorelaxation[10].

There are studies in the literature about the effects of medicinal plants on either vasorelaxation or diabetes. However, the absence of articles presenting the effects of medicinal plants on both vasorelaxation and diabetes necessitates the inclusion of this review in the literature. Addressing this gap will not only enhance our understanding but also aid in future studies on CVDs, as decreased vasorelaxation is a significant contributor to such conditions[11]. The mechanisms crucial for vasorelaxation are expounded upon in this review, along with accompanying figures. The review encompasses components and aspects of 85 medicinal plants, delineating their effects on vasorelaxation and diabetes in Table 1.

Table 1 Various medicinal plants with vasorelaxant activities and beneficial effects on diabetes.

Plant	Vasorelaxation			Diabetes			1Ref.
	Component/extract	Part	Effect	Component/extract	Part	Effect
Securigera securidaca L.	Hydroalcoholic extract	Seed	Endothelium-dependent vasorelaxation in hyper-cholesterolemic rats	Hydroalcoholic extract	Seed	Anti-diabetic	[61,62]
Parkia biglobosa	Aqueous extract	Seed	Smooth muscle vasorelaxation via endothelium due to PGs	Hydromethanolic extract	Stem bark	Anti-diabetic	[63,64]
Orthosiphon stamineus	Eupatorin	-	Endothelium-intact aortic ring vasorelaxation on contraction by KCl and endothelium-denuded aortic ring vasorelaxation on contraction by PE	Water extract, methanolic extract	Aerial parts	Anti-diabetic	[65,66]
Rosa damascena Mill.	2-phenyl ethyl alcohol	Spent flower	Vasorelaxation on rat aorta and mesenteric artery without vascular endothelium effect	Methanolic extract	Flower	α-glucosidase inhibitor	[67,68]
Eruca sativa Mill.	Crude extract, fractions	-	Endothelium-dependent vasorelaxation on aortic rings of normotensive rats and endothelium-independent vasorelaxation on aortic rings of hypertensive rats	Hexane fraction and its fatty acid-rich fraction	Leaf	Anti-diabetic	[69,70]
Echinodorus grandiflorus	Ethanolic extract and its butanol fraction	Leaf	Vasorelaxation on resistance vessels by releasing PGI2 and NO through B2-bradykininergic and endothelial M3- muscarinic receptors and then activating K+ channels in vascular smooth muscle	Ethanolic extract	Leaf	Antiglycation	[52,71]
Gynura procumbens	Aqueous extract, methanolic extract	Leaf	Vasorelaxation by activating muscarinic M3 receptors in the existence of endothelium and vasorelaxation on rat thoracic aorta through cholinergic pathway	Leaf extract	Leaf	Anti-diabetic	[52,72]
Garcinia cowa	Leaf extract	Leaf	Vasorelaxation by activating KATP and generating prostanoids and NO	Compounds 4 and 8	Leaf	α-glucosidase inhibitor	[73,74]
Bauhinia forficata Link	Ethyl-acetate plus butanol fraction, kaempferitrin, kaempferol	Leaf	Vasorelaxation on the thoracic aorta of hypertensive and normotensive rats	Methanolic extract	Leaf, stem	Hypoglycemic	[39,75]
Nelumbo nucifera	Extracts of spornioderm	Spornioderm	Endothelium-dependent vasorelaxation by activating PI3K-eNOS-sGC pathway	Seed extract	Seed	Hypoglycemic	[76,77]
Cimicifuga racemosa	Black cohosh extract		Vasorelaxation by way of endothelium-dependent and -independent mechanisms on pre-contracted rat thoracic aortic rings by NE	Extract Ze 450		Decreasing plasma glucose in ob/ob mice with diabetes	[78,79]
Crocus sativus L.	Crocetin		Endothelium-dependent vasorelaxation through endothelial NO	Crocins	Stigma	Decreasing levels of glucose and increasing expression of insulin in zebrafish embryo	[80,81]
Morus alba	Root bark extract	Root bark	Endothelium-dependent vasorelaxation partially via NO-cGMP pathway containing TEA sensitive K+ channels activation	Kuwanon H, morin, morusin, oxyresveratrol, kuwanon G	Root bark	α-glucosidase inhibitor	[46,82]
Erigeron breviscapus Hand Mazz.	Scutellarin		Endothelium-independent vasorelaxation on thoracic artery rings by blocking the influx of extracellular Ca2+ as independent from VDCCs	Scutellarin		Induces autophagy signal pathway by upregulating autophagy-related factors and blocks apoptotic signal pathway by downregulating apoptosis-related factors, and consequently relief of type 2 DC	[83,84]
Vernonia amygdalina	Ethanolic extract	Leaf	Vasorelaxation by upregulating NO/cGMP and PGI2 signalization pathways and modulating muscarinic and β2-adrenergic receptor levels, and Ca2+/K+ channels	Leaf extracts	Leaf	α-amylase inhibitor	[54,85]
Glycyrrhiza uralensis	50% ethanolic extract		Vasorelaxation in endothelium-intact aortic rings pre-contracted with PE and KCl	Glycyrrhiza flavonoids	Root	α-glucosidase inhibitor	[86,87]
Salvia miltiorrhiza	S. miltiorrhiza extract		Vasorelaxation of renal, mesenteric, and femoral arteries at low extract concentration and vasorelaxation of coronary arteries at all extract concentrations tested	S. miltiorrhiza extract	Root	Hypoglycemic	[88,89]
Sophora alopecuroides	Oxysophoridine		Vasorelaxation on thoracic aorta rings by being related to KATP and KV channels	Aloperine	Aerial parts	Hypoglycemic	[90,91]
Coriandrum sativum	Coriander crude extract		Vasorelaxation on contracted rabbit aorta with PE and K+ (80 mM)	Aqueous extract	Leaf, stem	α-glucosidase inhibitor	[53,92]
Ligusticum chuanxiong Hort.	Ethanolic extract	Rhizome	Induction of eNOS-derived NO production	Ethanolic extract	Rhizome	Amelioration of diabetic nephropathy	[58,93]
Sorbus commixta Hedl.	Methanolic extract	Cortex	Vasorelaxation on vascular smooth muscle through NO-cGMP pathway	Lupenone, lupeol	Stem bark	PTP1B inhibitor	[94,95]
Aronia melanocarpa	Conjugated cyanidins, chlorogenic acids	Juice	Inducing endothelial NO production in a coronary artery by getting eNOS phosphorylation due to redox-sensitive activation of the Src/PI3-kinase/Akt pathway		Juice	Hypoglycemic	[96,97]
Annona squamosa	Esquamosan	Leaf	Endothelium-independent vasorelaxation on isolated rat aorta via prevention of intracellular Ca2+ increasing by blocking VDCCs and intracellular storage channels in VSMCs	Hexane extract		Hypoglycemic	[98,99]
Artemisia herba alba	Aqueous extract		Vasorelaxation through endothelial NO production	Aqueous extract	Leaf or bark	Lowering blood glucose levels	[100,101]
Ajuga iva (L.) Schreber (Labiatae)	Aqueous extract		In vitro, NO-mediated and NO-independent vasorelaxation; ex vivo, endothelium-independent vasorelaxation	Lyophilized aqueous extract	Whole plant	Hypoglycemic	[102,103]
Mansoa hirsuta D.C.	Ethanolic extract	Leaf	Endothelium-dependent vasorelaxation	Fraction		α-amylase inhibitor	[104,105]
Mentha longifolia	N-butanol fraction	Aerial parts	Endothelium-independent relaxation owing to increase of cAMP and cGMP levels by blocking diverse PDEs			Anti-diabetic	[40,106]
Euphorbia humifusa Willd.	Total flavonoids of E. humifusa		Vasorelaxation on rat thoracic aorta with endothelium-dependent NO-cGMP signaling by inducing PI3K/Akt-and Ca2+-eNOS-NO signaling pathway; relaxation of VSMCs by stimulating NO-sGC-cGMP-protein kinase G signaling via L-type Ca2+ channel activity inhibition	Vitexin and astragalin	Whole plant	Anti-diabetic	[42,107]
Sophora flavescens	Ethanolic extract	Root	Relaxation of vascular smooth muscle via the endothelium-dependent NO-sGC-cGMP signaling pathway	Four minor flavonoids (1-4)	Root	α-glucosidase inhibitor	[108,109]
Kaempferia parviflora	Ethanolic extract	Rhizome	Vasorelaxation in a dose-dependent manner on aortic rings pre-contracted with PE			Anti-diabetic	[19,110]
Angelica decursiva	70% ethanolic extract	Root	Endothelium-independent vasorelaxation via KATP channels as well as blocking of Ca2+ influx through VDCCs and ROCCs	Coumarins 1-6		α-glucosidase inhibitor, PTP1B inhibitor	[111,112]
Hintonia latiflora	H. latiflora extract, neoflavonoid coutareagenin	Bark	Vasorelaxation on aortic rings pre-contracted with NE	H. latiflora extract, neoflavonoid coutareagenin	Bark	Diminishing blood glucose	[113,114]
Kaempferia galanga L.	Ethyl-p-methoxycinnamate	Rhizome	Endothelium-independent but K+ channel-dependent vasorelaxation	Novel K. galanga rhizome essential oil rich in ethyl p-methoxy cinnamate	Rhizome	Anti-diabetic	[115,116]
Prunus mume Sieb. et Zucc.	70% ethanolic extract	Bark	Endothelium-dependent vasorelaxation on isolated rat aortic rings through NO/sGC/cGMP and PGI2 pathway; vasorelaxation partially via KCa, KATP, KV, and Kir channels	70% ethanolic extract	Leaf	Anti-diabetic	[116,117]
Bacopa monnieri	Saponins (bacoside A and bacopaside I), flavonoids (luteolin and apigenin)		Endothelium-intact vasorelaxation and endothelium-denuded vasorelaxation	Bacosine		Antihyperglycemic	[118,119]
Haloxylon scoparium	Aqueous extract		Vasorelaxation via Ca2+ channels blockade	Decoctate, methanolic extract, macerated methanol, ethyl; acetate extract	Aerial part	A-glucosidase inhibitor, a-amylase inhibitor, ß-asides inhibitor	[56,120]
Swietenia macrophylla King	50% ethanolic extract	Seed	Inhibiting IP3R, blocking VOCC and activating K+ channels; vasorelaxation via β2-adrenergic pathway and NO/sGC/cGMP signaling pathways	Limonoids	Fruit	Anti-diabetic	[48,121]
Eucalyptus globulus	Aqueous extract	Leaf	Dose-dependent vasorelaxation on aortic rings by inducing NO production			Amelioration of hyperglycemia	[122,123]
Plumeria rubra	Aqueous-methanolic extract	Leaf	Concentration-dependent vasorelaxation on PE-induced spastic contractions and K+ (80 mM)-induced spastic contractions	Compounds 1-4, 7, 8, and 16	Flower	α-glucosidase inhibitor, PTP1B inhibitor	[41,124]
Prunus persica	P. persica extract	Branch	Endothelium-dependent vasorelaxation via NO-sGC-cGMP, vascular PGI2, and muscarinic receptor transduction pathways; vasorelaxation partially through KATP, BKCa, and KV channels			Anti-diabetic	[19,125]
Prunus yedoensis Matsum.	Methanolic extract	Bark	Vasorelaxation due to activation of NO production through L-Arg and NO-cGMP pathways; vasorelaxation through blockade of extracellular Ca2+ channels	P. yedoensis extract	Leaf	Antihyperglycemic	[126,127]
Xanthoceras sorbifolia Bunge	Ethanolic extract	Leaf	Vasorelaxation on vascular smooth muscle through Akt- and SOCE-eNOS-sGC pathways		Wood	α-glucosidase inhibitor	[128,129]
Passiflora edulis	Hydroethanolic extract	Fruit peel	Vasorelaxation on mesenteric artery rings via activation of K+ channels	Aqueous extract	Fruit peel	Anti-diabetic	[129,130]
Apium graveolens L.	Seed extract	Seed	Vasorelaxation through inhibition of ROCCs and VDCCs, the release of EDHF, and activation of Kv channels	Leaf extract	Leaf	Reducing pre-prandial blood glucose levels and post-prandial blood glucose levels in pre-diabetic elderly patients	[60,131]
Phyllanthus niruri L.	Methyl brevifolincarboxylate	Leaf	Inhibition of NE-induced vasoconstriction via ROCCs partially mediated by (Ca2+)i decrease	Aqueous extract, ethanolic extract	Aerial part	α-glucosidase inhibitor	[132,133]
Marrubium vulgare	Crude extracts	Aerial part	Inhibiting KCl-induced contraction on the rat aorta	Aqueous extract		Anti-diabetic	[134,135]
Psoralea corylifolia L.	P. corylifolia extract, bakuchiol, isobavachalcone, isopsoralen, psoralen	Seed	Endothelium-dependent vasorelaxation through NO-cGMP pathway; attenuating PE-induced vasoconstriction by inhibiting TRPC3 channels in a dose-dependent manner	Compounds 1, 2, 3, 6, 8	Seed	DGAT1 inhibitor, α-glucosidase inhibitor	[57,136]
Ginkgo biloba	Terpenoids (bilobalide, ginkgolides A, B, and C) and flavonoids (quercetin and rutin)		Concentration-dependent vasorelaxation	G. biloba extract		Antihyperglycemic	[137,138]
Rubus chingii	Ethanolic extract	Dried fruit	Vasorelaxation via Ca2+-eNOS-NO signaling in endothelial cells and later NO-sGC-cGMP-KV channel signaling in VSMCs	Ursane-type triterpenes	Fruit	PTP1B inhibitor	[55,139]
Bidens pilosa	Neutral extract	Leaf	Vasorelaxation and behaving as a Ca2+ antagonist	B. pilosa formulation		Anti-diabetic	[140,141]
Allium sativum	L-arginine in aged garlic extract		Endothelium-dependent vasorelaxation on the aorta by inducing NO formation	Silver nanoparticles	Bulb	Anti-diabetic	[142,143]
Petroselinum crispum	Aqueous extract	Aerial part	Vasorelaxation via VOCCs and ROCCs	P. crispum extract	Leaf	Decreasing blood glucose	[144,145]
Curcuma longa	Curcubisabolanin A	Rhizome	Partially endothelium-dependent vasorelaxation by regulating NO production in vascular endothelial cells via the PI3K/Akt/eNOS signaling pathway			Enhancing postprandial serum insulin levels with ingestion of 6 g of C. longa	[146,147]
Allium cepa	A. cepa peel hydroalcoholic extract	Peel	Decreasing aortic contractions probably through depression of Ca2+ influx from extracellular to intracellular, without including endothelium, NO, cGMP, and PGs			Diminishing blood glucose	[148,149]
Alpinia zerumbet	Essential oil	Leaf	Vasorelaxation by inhibiting both Ca2+ influx and Ca2+ release from intracellular storage; vasorelaxant effect via NOS/sGC pathway	Labdadiene	Rhizome	Antiglycation	[43,150]
Paeonia suffruticosa Andr.	1,2,3,4,6-penta-O-galloyl-beta-d-glucose	Root cortex	Concentration-dependent vasorelaxation on rat aorta pre-contracted with PE	Extract of moutan cortex	Root	Improving inflammation in AGEs-induced mesangial cell dysfunction and high-glucose-fat diet and STZ-induced DN rats	[151,152]
Nigella sativa	Seed extract	Seed	Endothelium-independent vasorelaxation on contraction stimulated by PE and KCl via inhibition of extracellular Ca2+ influx, KATP channels, and IP3-mediated receptors	Crude aqueous extract	Seed	In vitro, suppressing electrogenic intestinal absorption of glucose directly; in vivo, ameliorating both body weight and glucose tolerance after chronic oral administration in rats	[153,154]
Myrciaria cauliflora Berg	Hydroalcoholic extract	Fruit peel	Endothelium-dependent vasorelaxation via NO/sGC/cGMP pathway	M. cauliflora extract	Lyophilized fruit	Hypoglycemic	[155,156]
Morus bombycis Koidzumi	100% ethanolic extract	Root bark	Vasorelaxation on isolated rat aortic preparations	2,5-dihydroxy-4,3-di(beta-D-glucopyranosyloxy)-trans-stilbene	Root	Hypoglycemic	[157,158]
Humulus lupulus L.	Aqueous hop extract		Vasorelaxation through NOS activation, COX products, and Ca2+ pathways in both male and female rats	Xanthohumol		α-glucosidase inhibitor	[159]
Sesamum indicum L.	Petroleum ether soluble fraction of root extract	Root	Endothelium-dependent vasorelaxation			Decreasing fasting blood sugar	[160,161]
Hibiscus sabdariffa	Hibiscus acid		Vasorelaxation by depression of intracellular Ca2+ influx through VDCCs	Ethyl acetate extract, ethanolic extract, aqueous extract	Flower	Anti-diabetic	[162,163]
Jasminum sambac	Hydroalcoholic leaf extract	Leaf	Vasorelaxation completely on endothelium-intact rabbit aorta contracted with PE; vasorelaxation partially on endothelium-intact rabbit aorta contracted with NE	Polyphenol extract	Leaf	Preventing and having a therapeutic effect on DC	[59,164]
Hancornia speciosa Gomes	Ethanolic extract	Leaf	NO- and endothelium-dependent vasorelaxation on rat aortic preparations through PI3K activation	Aqueous extract	Latex	Hypoglycemic	[165,166]
Pseuderanthemum palatiferum	Water extract	Leaf	Vasorelaxation via partially vascular endothelium not with NO production and muscarinic receptor activation	80% ethanolic leaf extract	Leaf	Hypoglycemic	[167,168]
Terminalia superba	Methylene chloride extract, methylene chloride-methanol extract	Stem bark	Vasorelaxation partially via depression of extracellular Ca2+ influx and/or suppression of intracellular Ca2+ releasing in VSMCs; vasorelaxation via endothelial NO	Methylene chloride-methanol extract	Leaf	Anti-diabetic	[49,169]
Guazuma ulmifolia	Procyanidin fraction	Bark	Vasorelaxation through endothelium-related factors, including NO	Aqueous extract		Anti-diabetic	[170,171]
Persea americana Mill.	Aqueous leaf extract	Leaf	Vasorelaxation through endothelial NO production and releasing	Hydroalcoholic extract	Leaf	Anti-diabetic	[172,173]
Capparis aphylla	Crude extract	Aerial part	Endothelium-dependent vasorelaxation partially via atropine-sensitive NO pathway; endothelium-independent vasorelaxation partially via the Ca2+ channel blocking activity	Methanolic extract, active fraction	Stem	Decreasing blood glucose levels	[174,175]
Rheum undulatum	Piceatannol in rhizome extract	Rhizome	Vasorelaxation through endothelium-dependent NO signaling pathway	E-viniferin, piceatannol, and δ-viniferin in methanolic extract	Rhizome	PTP1B inhibitor	[176,177]
Globularia alypum	G. alypum extract		Vasorelaxation due to EDHF via endothelial muscarinic receptor activation	Methanolic extract, water extract	Leaf	Reducing fasting blood glucose	[178,179]
Gmelina arborea	Hexane extract	Leaf	Concentration-dependent vasorelaxation on isolated rat aorta	Aqueous extract	Bark	Antihyperglycemic	[50,180]
Coscinium fenestratum	C. fenestratum extract		Endothelium-dependent and -independent vasorelaxation on isolated aortic rings precontracted with PE and KCl	Alcoholic stem extract	Stem	Anti-diabetic	[181,182]
Myrtus communis L.	Crude methanolic extract	Aerial part	Vasorelaxation on isolated rabbit aorta preparations contracted with PE and K+	Volatile oil		Hypoglycaemic	[183,184]
Thymus linearis Benth.	N-butanolic fraction	Aerial part	Endothelium-independent vasorelaxation due to increase in cAMP and cGMP via inhibition of several PDEs	Ethyl acetate extract, combined extract	Aerial part	Α-amylase inhibitor	[185,186]
Vitex agnus-castus	V. agnus-castus extract	Fruit	Endothelium-dependent vasorelaxation via NO/cGMP and PGs production in the aorta	Hydroalcoholic extract	Desiccated fruit	Hypoglycemic	[51,187]
Anogeissus leiocarpus	Aqueous extract	Trunk bark	Endothelium-dependent NO-mediated vasorelaxation on porcine coronary arteries via redox-sensitive Src/PI3-kinase/Akt pathway-dependent activation of eNOS	Supernatant fraction, total extract	Root	Anti-diabetic	[188,189]
Zanthoxylum armatum DC	Tambulin in methanolic extract	Fruit	Influencing directly vascular smooth muscle through cAMP and/or cGMP-related relaxing pathways	Fruit, bark, and leaf extracts	Fruit, bark, and leaf	Anti-diabetic	[190,191]
Cymbopogon martinii	Crude methanolic extract	Leaf	Partial vasorelaxation on isolated rabbit aortic preparations contracted with PE and K+			Α-glucosidase inhibitor	[192,193]
Moringa oleifera	M. oleifera leaf extract	Leaf	Endothelium-dependent vasorelaxation through EDHF-mediated hyperpolarization; endothelium-independent vasorelaxation due to inhibition of extracellular Ca2+ influx through VOCCs and ROCCs and suppression of sarcolemmal Ca2+ releasing through IP3R Ca2+ channels	Methanolic extract	Pods	Anti-diabetic	[194,195]
Dalbergia odorifera T. Chen	Butein		Vasorelaxation on rat aorta; the novel cAMP-specific PDE inhibitor; vasorelaxant action related intact endothelium	Compounds in ethyl acetate soluble fraction	Heartwood	α-glucosidase inhibitor	[196,197]
Coptis chinensis	Berberine		Decreasing expression of miR-133a; enhancing BH4 levels and production of NO	Polysaccharide		Anti-diabetic	[38,198]
Angelica keiskei	Xanthoangelol, 4-hydroxyderricin, xanthoangelol E and F in EtOAc-soluble fraction, xanthoangelol B in EtOAc-soluble fraction	Root	Blocking PE-induced vasoconstriction through EDRF/NO synthesis and/or attenuation of PE-induced (Ca2+)i increase; blocking PE-induced vasoconstriction by reducing (Ca2+)i increase and directly inhibiting smooth muscle contraction	Flavonoid-rich ethanolic extract	Leaf	Hypoglycemia	[199,200]
Scutellaria baicalensis Georgi	Baicalin		Vasorelaxation on the mesenteric artery by stimulating BKCa channels and blocking VDCCs with endothelium-independent mechanisms, moreover by inducing cGMP/PKG and cAMP/PKA pathways	Root polysaccharide	Root	α-amylase inhibitor, α-glucosidase inhibitor	[201,202]
Ocimum gratissimum	Essential oil		Dose-dependent vasorelaxation on resistance blood vessels of rat mesenteric vascular beds completely via NO; dose-dependent vasorelaxation on rat aorta partially mediated by NO	Chicoric acid in leaf extract	Leaf	Hypoglycemic	[203,204]

¹The first reference is associated with vasorelaxation and the second with diabetes.

ACh: Acetycholine; AGEs: Advanced glycation end-products; BH4: Tetrahydrobipterin; BK_Ca channel: Large-conductance Ca²⁺-activated K⁺ channel; COX: Cyclooxygenase; DGAT1 inhibitor: Diacylglycerol acyltransferase-1 inhibitor; DC: Diabetic cardiomyopathy; DN: Diabetic nephropathy; eNOS: Endothelial nitric oxide synthase; EDHF: Endothelium-derived hyperpolarizing factor; EDRF: Endothelium-derived relaxing factor; EtOAc: Ethyl acetate; IP₃R: Inositol triphosphate receptor; K_ATP channel: ATP-sensitive K⁺ channel; K_Ca channel: Ca²⁺ activated K⁺ channel; K_ir channel: Inward rectifier-type K⁺ channel; K_v channel: Voltage-sensitive K⁺ channel; NO: Nitric oxide; NE: Norepinephrine; PDE: Phosphodiesterase; PE: Phenylephrine; PG: Prostaglandin; PGI₂: Prostacyclin; PI3K: Phosphatidyl-inositol 3-kinase; PKA: Protein kinase A; PKG: Protein kinase G; PTP1B inhibitor: Protein tyrosine phosphatase 1B inhibitor; ROCC: Receptor-operated Ca²⁺ channel; sGC: Soluble guanylate cyclase; SOCE: Store-operated Ca²⁺ entry; STZ: Streptozotocin; TEA: Tetraethylammonium; TRPC3 channel: Transient receptor potential canonical 3 channel; VDCC: Voltage-dependent Ca²⁺ channel; VOCC: Voltage-operated Ca²⁺ channel; VSMC: Vascular smooth muscle cell.

Several articles investigating the effects of plants on vasorelaxation are outlined below: Luna-Vázquez et al[12] identified 19 compounds isolated from 10 plants used in traditional Mexican medicine that can alter arterial smooth muscle tone. Guerrero et al[13] illustrated that different fractions obtained from two Latin American plants used in Amerindian traditional medicine possess vasorelaxation effects. Luna-Vázquez et al[14] elucidated the mechanism of action of 207 vasorelaxant metabolites. Capettini et al[15] discovered that xanthones derived from Brazilian medicinal plants exhibit vasorelaxant and antioxidant properties. Tang et al[16] highlighted traditional medicinal plants with the potential to prevent and treat hypertension, cardiovascular, and cerebrovascular diseases. Malekmohammad et al[17] reported on metabolites of medicinal plants that stimulate critical vasorelaxation mechanisms.

Additionally, numerous articles explore the effects of plants on diabetes: Kadir et al[18] documented an ethnobotanical survey on antidiabetic plants used in traditional Bangladeshi medicine. Salehi et al[19] identified numerous plants and their components effective against diabetes. Trojan-Rodrigues et al[20] identified plant species widely used in diabetes treatment in the state of Rio Grande do Sul in southern Brazil. Garima et al[21] conducted an ethnobotanical survey on anticancer and antidiabetic plants used by local tribes in Mizoram, Northeast India.

NO-CYCLIC GUANOSINE 3’, 5’-MONOPHOSPHATE GUANOSINE PATHWAY

Vascular smooth muscle cell (VSMC) is stimulated by NO that is produced in a catalyzed reaction, formed citrulline amino acid from arginine amino acid, by endothelial nitric oxide synthase (eNOS)[22]. The soluble guanylate cyclase receptor found in adjacent cells is activated by NO[23]. Thus, it is occurred to rise the level of cGMP, which forms vasodilation[10] (Figure 1).

Figure 1 Vasorelaxation effect of nitric oxide-cyclic guanosine monophosphate pathway. cGMP: Cyclic guanosine monophosphate; EC: Endothelial cell; eNOS: Endothelial nitric oxide synthase; NO: Nitric oxide; sGC: Soluble guanylate cyclase; VSMC: Vascular smooth muscle cell.

PGI₂-CYCLIC ADENOSINE MONOPHOSPHATE PATHWAY

PGI₂, which activates the prostacyclin receptor included in the G protein-coupled receptor (GPCR), functions as a vasorelaxant factor[24]. The enzyme cyclooxygenase catalyzes arachidonic acid as a substrate, forming prostaglandin H₂, the precursor of PGI₂[25]. Additionally, prostacyclin synthase generates PGI₂, a lipid, when stimulated by various factors such as shear stress, cytokines, thrombin, and growth factors. The concentration of cAMP increases through the induction of adenylyl cyclase by PGI₂[25]. Consequently, this leads to a vasorelaxation impact on VSMCs[26] (Figure 2).

Figure 2 Vasorelaxation effect of PGI₂-cyclic adenosine monophosphate pathway. AC: Adenylyl cyclase; ARA: Arachidonic acid; cAMP: Cyclic adenosine monophosphate; COX: Cyclooxygenase; EC: Endothelial cell; PGI₂: Prostacyclin; IP: Prostacyclin receptor; PGIS: Prostacyclin synthase; PGH₂: Prostaglandin H₂; VSMC: Vascular smooth muscle cell.

PDE INHIBITION

cGMP and cAMP, serving as second messengers in the cell, are hydrolyzed by cyclic nucleotide PDEs[27]. In this manner, PDE enzymes facilitate the breakdown of cAMP into 5’-AMP and cGMP into 5’-GMP. Preventing PDE activation results in heightened concentrations of cyclic nucleotides, such as cAMP and cGMP, promoting vasorelaxation[28] (Figure 3).

Figure 3 Vasorelaxation effect of phosphodiesterases inhibition. cGMP: Cyclic guanosine monophosphate; EC: Endothelial cell; eNOS: Endothelial nitric oxide synthase; 5’-GMP: 5’-Guanylic acid; NO: Nitric oxide; PDE: Phosphodiesterase; sGC: Soluble guanylate cyclase; VSMC: Vascular smooth muscle cell.

OPENING K⁺ ION CHANNELS AND REDUCING CA²⁺ LEVELS IN CELLS

VSMCs harbor different K⁺ channels, including voltage-sensitive K⁺ (K_V) channels, inward rectifier-type K⁺ (K_ir) channels, ATP-sensitive K⁺ (K_ATP) channels, and Ca²⁺-activated K⁺ (K_Ca) channels[29]. Activation of K⁺ channels induces membrane hyperpolarization, leading to the cessation of voltage-dependent Ca²⁺ channels’ (VDCCs) activity, blocking the entry of Ca²⁺ into the cell, and ultimately resulting in vasorelaxation[30]. Additionally, the relaxation of VSMCs occurs when receptor-operated Ca²⁺ channels or VDCCs, responsible for intracellular calcium ion procurement, are blocked[31].

Diabetes mellitus (DM), a metabolic disease, affected 425 million patients in 2017. The World Health Organization predicts that diabetes will become the seventh leading cause of death by 2030[32]. The major cause of morbidity and mortality in people with diabetes is CVDs. Adults with diabetes face a 2-4 times higher cardiovascular risk compared to those without diabetes[33]. Type 1 DM, characterized by beta cell failure in pancreatic islets and decreased insulin release, is prevalent among teenagers and children[34]. On the other hand, type 2 DM (T2DM), defined by insulin resistance and hyperglycemia, is non-insulin dependent[35]. While T2DM is predominantly observed in adults, there is an increasing incidence among children due to the rising prevalence of obesity[36].

Throughout history, numerous drugs have been derived from the use of medicinal plants. Plants exhibiting effective pharmacological effects with minimal side reactions are preferred for various diseases due to advantages such as economic feasibility and accessibility[37]. This review article highlights medicinal plants’ effectiveness on vasorelaxation and diabetes, emphasizing their potential benefits for CVDs. Given the lack of existing literature on medicinal plants’ impact on vasorelaxation and diabetes, this review aims to address this knowledge gap[38] (Figure 4).

Figure 4 Vasorelaxation effect of opening K⁺ ion channels/reduction of Ca²⁺ levels in the cell. EC: Endothelial cell; MH: Membrane hyperpolarization; VSMC: Vascular smooth muscle cell.

MEDICINAL PLANTS AND THEIR FORMATIONS WITH BOTH VASORELAXANT ACTIONS AND AFFIRMATIVE EFFECTS ON DIABETES

This section focuses on medicinal plants related to vasorelaxation and diabetes, as presented in Table 1. Each herb, identified by its binomial name, categorizes its effects concerning vasorelaxation and diabetes. Formations such as extracts, fractions, compounds, flavonoids, oils, formulations, and polysaccharides obtained from each medicinal plant are detailed in the table. Examples include the methanolic extract from Bauhinia forficata Link[39], n-butanol fraction from Mentha longifolia[40], compounds 1-4, 7, 8, and 16 from Plumeria rubra[41], total flavonoids from Euphorbia humifusa Willd[42], essential oil from Alpinia zerumbet[43], formulation from Bidens Pilosa[44], and polysaccharide from Coptis chinensis[38].

The table indicates whether vasorelaxation is linked to the endothelium or not, and pathways and channels are also highlighted, such as Gynura procumbens[45], Morus alba[46], Prunus mume Sieb. et Zucc[47], Swietenia macrophylla King[48].

Moreover, medicinal plants exhibit diverse specialties in diabetes (Table 1). Examples include anti-diabetic effects with Terminalia superba[49], anti-hyperglycemic effects with Gmelina arborea[50], hypoglycemic effects with Vitex agnus-castus[51], anti-glycation effects with Echinodorus grandifloras[52], α-glucosidase inhibitor activity with Coriandrum sativum[53], α-amylase inhibitor activity with Vernonia amygdalina[54], protein tyrosine phosphatase 1B (PTP1B) inhibition with Rubus chingii[55], ß-galactosidase inhibition with Haloxylon scoparium[56], and diacylglycerol acyltransferase-1 (DGAT1) inhibitory effects with Psoralea corylifolia L[57].

In addition, Table 1 demonstrates that medicinal herbs possess desirable efficacies on diabetic nephropathy, diabetic cardiomyopathy, and prediabetes, exemplified by Ligusticum chuanxiong Hort[58], Jasminum sambac[59], and Apium graveolens L[60], respectively (Table 1[61-204]).

CONCLUSION

This review article delves into the intersection of vasorelaxation and diabetes within the realm of medicinal plants. Each medicinal herb examined here is intricately connected with both topics, with the overarching aim of providing a promising perspective on cardiovascular disorders. The study reports on various vasorelaxant action mechanisms, encompassing endothelium-dependent and -independent vasorelaxation, observed in various experimental studies in conjunction with medicinal plants.

The review highlights that several medicinal herbs can mitigate the undesirable effects of diabetes, drawing upon extensive literature scans. These herbs exhibit a spectrum of properties, including being anti-diabetic, anti-hyperglycemic, hypoglycemic, promoting insulin expression, anti-glycation, alpha-glucosidase inhibition, α-amylase inhibition, PTP1B inhibition, ß-galactosidase inhibition, and DGAT1 inhibition. Furthermore, the study underscores the influence of medicinal plants on affirmative outcomes in diabetic nephropathy, diabetic cardiomyopathy, and pre-diabetic conditions. In studies focusing on the anti-diabetic activity of medicinal plants, an effectiveness rate of 81% is observed when plant selection is based on ethnobotanical records and traditional folk use. However, this rate decreases to 47% in the case of random plant selection[205]. Most studies investigating the efficacy of medicinal plants on diabetes reveal that total plant extract is more effective than pure secondary metabolites in the extract composition[206].

The reported effects on vasorelaxation and diabetes encompass a wide array of plant components, such as extracts, compounds, fractions, oils, formulations, flavonoids, and polysaccharides, derived from various parts of these plants. To the best of our knowledge, this study is pioneering, offering a unique perspective that addresses both vasorelaxation and diabetes concerning medicinal plants. The comprehensive collection of medicinal plant references presented in this study is anticipated to serve as a valuable resource, inspiring and guiding future investigations into CVDs and diabetes.

In this study, 85 species from 79 genera across 41 plant families were investigated. The majority of the medicinal plants examined belong to families such as Lamiaceae, Fabaceae, Rosaceae, Apiaceae, and Asteraceae, implying a potentially higher therapeutic efficacy in treating and preventing cardiovascular diseases compared to other families. Moreover, employing species from these families in cardiovascular disease studies could result in cost and time savings. The plant species and their respective families are presented in Table 2 for reference.

Table 2 Familial classification of various medicinal plants with vasorelaxant activities and beneficial effects on diabetes.

Fabaceae	Lamiaceae	Rosaceae	Brassicaceae	Myrtaceae
Securigera securidaca L.; Parkia biglobosa; Bauhinia forficata Link; Dalbergia odorifera T. Chen; Glycyrrhiza uralensis; Sophora alopecuroides; Sophora flavescensi; Psoralea corylifolia L.	Orthosiphon stamineus; Thymus linearis Benth; Gmelina arborea; Vitex agnus-castus; Ocimum gratissimum; Marrubium vulgare; Salvia miltiorrhiza; Mentha longifolia; Scutellaria baicalensis Georgi; Ajuga iva (L.) Schreber	Rosa damascena Mill.; Sorbus commixta Hedl.; Aronia melanocarpa; P. mume Sieb. et Zucc.; Prunus persica; P. yedoensis Matsum.; Rubus chingii	Eruca sativa Mill.	Eucalyptus globulus; Myrciaria cauliflora Berg; Myrtus communis L.
Alismataceae	Asteraceae	Nelumbonaceae	Clusiaceae	Apocynaceae
Echinodorus grandiflorus	Gynura procumbens; E. breviscapus Hand Mazz.; Vernonia amygdalina; Artemisia herba alba; Bidens pilosa	Nelumbo nucifera	Garcinia cowa	Plumeria rubra; Hancornia speciosa Gomes
Iridaceae	Moraceae	Apiaceae	Annonaceae	Sapindaceae
Crocus sativus L.	Morus alba; Morus bombycis Koidzumi	Coriandrum sativum; Angelica decursiva; Apium graveolens L.; Petroselinum crispum; L. chuanxiong Hort.; Angelica keiskei	Annona squamosal	Xanthoceras sorbifolia Bunge
Poaceae	Bignoniaceae	Euphorbiaceae	Zingiberaceae	Passifloraceae
Cymbopogon martinii	Mansoa hirsuta D.C.	E. humifusa Willd.	Kaempferia parviflora; Kaempferia galanga L.; Curcuma longa; Alpinia zerumbet	Passiflora edulis
Rubiaceae	Plantaginaceae	Amaranthaceae	Meliaceae	Phyllanthaceae
Hintonia latiflora	Bacopa monnieri; Globularia alypum	Haloxylon scoparium	S. macrophylla King	Phyllanthus niruri L.
Moringaceae	Ginkgoaceae	Amaryllidaceae	Paeoniaceae	Ranunculaceae
Moringa oleifera	Ginkgo biloba	Allium sativum; Allium cepa	P. suffruticosa Andr.	Nigella sativa; Coptis chinensis; Cimicifuga racemosa
Cannabaceae	Pedaliaceae	Malvaceae	Oleaceae	Acanthaceae
Humulus lupulus L.	Sesamum indicum L.	Hibiscus sabdariffa; Guazuma ulmifolia	Jasminum sambac	P. palatiferum
Combretaceae	Lauraceae	Capparaceae	Polygonaceae	Menispermaceae
Terminalia superba; Anogeissus leiocarpus	Persea americana Mill.	Capparis aphylla	Rheum undulatum	Coscinium fenestratum
Rutaceae
Z. armatum DC