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Characterization of a novel tetrandrine-induced contraction in rat tail artery

Achike FI, Kwan CY

Acta Pharmacol Sin, 2002 Aug;23(8):698-704.
PMID: 12147191

In an attempt to pharmacologically characterize the Chinese antihypertensive drug, tetrandrine, we observed in rat-tail arteries, an unusual contraction in tissues that were stimulated with high [KCl] and not those stimulated with phenylephrine. The characteristics of this contraction were studied.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
Goniothalamin induces apoptosis in vascular smooth muscle cells

Chan KM, Rajab NF, Ishak MH, Ali AM, Yusoff K, Din LB, et al.

Chem Biol Interact, 2006 Feb 1;159(2):129-40.
PMID: 16297902

Restenosis represents a major impediment to the success of coronary angioplasty. Abnormal proliferation of vascular smooth muscle cells (VSMCs) has been shown to be an important process in the pathogenesis of restenosis. A number of agents, particularly rapamycin and paclitaxel, have been shown to impact on this process. This study was carried out to determine the mechanisms of cytotoxicity of goniothalamin (GN) on VSMCs. Results from MTT cytotoxicity assay showed that the IC(50) for GN was 4.4 microg/ml (22 microM), which was lower compared to the clinically used rapamycin (IC(50) of 25 microg/ml [27.346 microM]). This was achieved primarily via apoptosis where up to 25.83 +/- 0.44% of apoptotic cells were detected after 72 h treatment with GN. In addition, GN demonstrated similar effects as rapamycin in inhibiting VSMCs proliferation using bromodeoxyuridine (BrdU) cell proliferation assay after 72 h treatment at IC(50) concentration (p > 0.05). In order to understand the mechanisms of GN, DNA damage detection using comet assay was determined at 2h post-treatment with GN. Our results showed that there was a concentration-dependent increase in DNA damage in VSMCs prior to cytotoxicity. Moreover, GN effects were comparable to rapamycin. In conclusion, our data show that GN initially induces DNA damage which subsequently leads to cytotoxicity primarily via apoptosis in VSMCs.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
Cardiovascular activity of the n-butanol fraction of the methanol extract of Loranthus ferrugineus Roxb

Ameer OZ, Salman IM, Siddiqui MJ, Yam MF, Sriramaneni RN, Sadikun A, et al.

Braz. J. Med. Biol. Res., 2010 Feb;43(2):186-94.
PMID: 20084331

We investigated the vascular responses and the blood pressure reducing effects of different fractions obtained from the methanol extract of Loranthus ferrugineus Roxb. (F. Loranthaceae). By means of solvent-solvent extraction, L. ferrugineus methanol extract (LFME) was successively fractionated with chloroform, ethyl acetate and n-butanol. The ability of these LFME fractions to relax vascular smooth muscle against phenylephrine (PE)- and KCl-induced contractions in isolated rat aortic rings was determined. In another set of experiments, LFME fractions were tested for blood pressure lowering activity in anesthetized adult male Sprague-Dawley rats (250-300 g, 14-18 weeks). The n-butanol fraction of LFME (NBF-LFME) produced a significant concentration-dependent inhibition of PE- and KCl-induced aortic ring contractions compared to other fractions. Moreover, NBF-LFME had a significantly higher relaxant effect against PE- than against high K+-induced contractions. In anesthetized Sprague-Dawley rats, NBF-LFME significantly lowered blood pressure in a dose-dependent manner and with a relatively longer duration of action compared to the other fractions. HPLC, UV and IR spectra suggested the presence of terpenoid constituents in both LFME and NBF-LFME. Accordingly, we conclude that NBF-LFME is the most potent fraction producing a concentration-dependent relaxation in vascular smooth muscle in vitro and a dose-dependent blood pressure lowering activity in vivo. The cardiovascular effects of NBF-LFME are most likely attributable to its terpenoid content.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
Fulltext Overview of Antagonists Used for Determining the Mechanisms of Action Employed by Potential Vasodilators with Their Suggested Signaling Pathways

Loh YC, Tan CS, Ch'ng YS, Ahmad M, Asmawi MZ, Yam MF

Molecules, 2016 Apr 15;21(4):495.
PMID: 27092479 DOI: 10.3390/molecules21040495

This paper is a review on the types of antagonists and the signaling mechanism pathways that have been used to determine the mechanisms of action employed for vasodilation by test compounds. Thus, we exhaustively reviewed and analyzed reports related to this topic published in PubMed between the years of 2010 till 2015. The aim of this paperis to suggest the most appropriate type of antagonists that correspond to receptors that would be involved during the mechanistic studies, as well as the latest signaling pathways trends that are being studied in order to determine the route(s) that atest compound employs for inducing vasodilation. The methods to perform the mechanism studies were included. Fundamentally, the affinity, specificity and selectivity of the antagonists to their receptors or enzymes were clearly elaborated as well as the solubility and reversibility. All the signaling pathways on the mechanisms of action involved in the vascular tone regulation have been well described in previous review articles. However, the most appropriate antagonists that should be utilized have never been suggested and elaborated before, hence the reason for this review.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
New therapies for erectile dysfunction

Tan HM

Int. J. Androl., 2000;23 Suppl 2:87-8.
PMID: 10849506

The quest for improving and maintaining sexual function has been going on since time immemorial. The advent of an effective oral drug, sildenafil, has brought about unprecedented open discussion on male erectile dysfunction, and gas accelerated the pace of development of new therapies for erectile dysfunction. New knowledge in the physiology of sexual function has enabled researchers to target drug treatment at the whole network of the central nervous system and the numerous cascadic enzymatic reactions leading to relaxation of the corporal smooth muscle. One of the brightest potential applications of future molecular technology in the study of erectile dysfuction is in the utilization of gene therapy.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Contractile function of smooth muscle retained after overnight storage

Loong BJ, Tan JH, Lim KH, Mbaki Y, Ting KN

Naunyn Schmiedebergs Arch Pharmacol, 2015 Oct;388(10):1061-7.
PMID: 26051407 DOI: 10.1007/s00210-015-1140-3

The functional responses of different overnight-stored in vitro tissues are not clearly described in any animal model. The influence of overnight storage in an animal model may vary between tissue types. We employed Sprague-Dawley rat as our animal model and investigated the functional changes of rat aorta, trachea, bronchus and bladder that were used (i) immediately after surgical removal (denoted as fresh) and (ii) after storage in aerated (95% O2, 5% CO2) Krebs-Ringer bicarbonate solution at 4 °C for 24 h (denoted as stored). The aorta ring was pre-contracted with phenylephrine, and the functional response of the tissue was investigated using isoprenaline, forskolin and carbachol. Carbachol was also used to increase the tone in trachea, bronchus rings and bladder strips. A clear reduced function of endothelium, with a minor if any effect in the smooth muscle function in rat aorta was observed after overnight storage. The contractile response of overnight-stored rat airway (trachea and bronchus) and bladder smooth muscles remained unchanged. Among all tested tissues, only bronchus showed a reduced response rate (only 40% responded) after storage. In vitro rat tissues that are stored in Krebs solution at 4 °C for 24 h can still be used to investigate smooth muscle responses, however, not endothelium-mediated responses for aorta. The influence of overnight storage on different tissues from an animal model (Sprague-Dawley rat in our study) also provides an insight in maximising the use of sacrificed animals.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
Dicentrine is preferentially antagonistic to rat aortic than splenic alpha 1-adrenoceptor stimulation

Mustafa MR, Achike FI

Acta Pharmacol Sin, 2000 Dec;21(12):1165-8.
PMID: 11603294

Dicentrine is a known alpha 1-adrenoceptor antagonist, but its alpha 1-adrenoceptor subtype selectivity has not yet been determined. We therefore, investigated the putative alpha 1-adrenoceptor subtype selectivity of this agent.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Fulltext "A Step and a Ceiling": mechanical properties of Ca2+ spark vasoregulation in resistance arteries by pressure-induced oxidative activation of PKG

Csato V, Kadir SZSA, Khavandi K, Bennett H, Sugden S, Gurney AM, et al.

Physiol Rep, 2019 Nov;7(22):e14260.
PMID: 31782255 DOI: 10.14814/phy2.14260

We investigated the biomechanical relationship between intraluminal pressure within small mesenteric resistance arteries, oxidant activation of PKG, Ca2+ sparks, and BK channel vasoregulation. Mesenteric resistance arteries from wild type (WT) and genetically modified mice with PKG resistance to oxidative activation were studied using wire and pressure myography. Ca2+ sparks and Ca2+ transients within vascular smooth muscle cells of intact arteries were characterized using high-speed confocal microscopy of intact arteries. Arteries were studied under conditions of varying intraluminal pressure and oxidation. Intraluminal pressure specifically, rather than the generic stretch of the artery, was necessary to activate the oxidative pathway. We demonstrated a graded step activation profile for the generation of Ca2+ sparks and also a functional "ceiling" for this pressure --sensitive oxidative pathway. During steady state pressure - induced constriction, any additional Ca2+ sensitive-K+ channel functional availability was independent of oxidant activated PKG. There was an increase in the amplitude, but not the Area under the Curve (AUC) of the caffeine-induced Ca2+ transient in pressurized arteries from mice with oxidant-resistant PKG compared with wild type. Overall, we surmise that intraluminal pressure within resistance arteries controls Ca2+ spark vasoregulation through a tightly controlled pathway with a graded onset switch. The pathway, underpinned by oxidant activation of PKG, cannot be further boosted by additional pressure or oxidation once active. We propose that these restrictive characteristics of pressure-induced Ca2+ spark vasoregulation confer stability for the artery in order to provide a constant flow independent of additional pressure fluctuations or exogenous oxidants.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
The effects of palm oil tocotrienol-rich fraction supplementation on biochemical parameters, oxidative stress and the vascular wall of streptozotocin-induced diabetic rats

Budin SB, Othman F, Louis SR, Bakar MA, Das S, Mohamed J

Clinics (Sao Paulo), 2009;64(3):235-44.
PMID: 19330251

OBJECTIVE: This study examined the effects of palm oil tocotrienol-rich fractions on streptozotocin-induced diabetic rats.
METHODS: Animals were divided into three groups: (i) normal non-diabetic (NDM), (ii) diabetic treated (tocotrienol-rich fractions - TRF) and (iii) diabetic untreated (non-TRF). The treatment group received oral administration of tocotrienol-rich fractions (200 mg/kg body weight) daily for eight weeks. The normal non-diabetic and the diabetic untreated groups were fed standard rat feed. Blood glucose and lipid profiles, oxidative stress markers and morphological changes of the thoracic aorta were evaluated.
RESULTS: Tocotrienol-rich fractions treatment reduced serum glucose and glycated hemoglobin concentrations. The tocotrienol-rich fractions group also showed significantly lower levels of plasma total cholesterol, low-density lipoprotein cholesterol, and triglyceride, as compared to the untreated group. The tocotrienol-rich fractions group had higher levels of high-density lipoprotein cholesterol, as compared to the untreated group. Superoxide dismutase activity and levels of vitamin C in plasma were increased in tocotrienol-rich fractions-treated rats. The levels of plasma and aorta malondealdehyde + 4-hydroxynonenal (MDA + 4-HNE) and oxidative DNA damage were significant following tocotrienol-rich fractions treatment. Electron microscopic examination showed that the normal morphology of the thoracic aorta was disrupted in STZ-diabetic rats. Tocotrienol-rich fractions supplementation resulted in a protective effect on the vessel wall.
CONCLUSION: These results show that tocotrienol-rich fractions lowers the blood glucose level and improves dyslipidemia. Levels of oxidative stress markers were also reduced by administration of tocotrienol-rich fractions. Vessel wall integrity was maintained due to the positive effects mediated by tocotrienol-rich fractions.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Fulltext Goniothalamin induces coronary artery smooth muscle cells apoptosis: the p53-dependent caspase-2 activation pathway

Chan KM, Rajab NF, Siegel D, Din LB, Ross D, Inayat-Hussain SH

Toxicol. Sci., 2010 Aug;116(2):533-48.
PMID: 20498002 DOI: 10.1093/toxsci/kfq151

Goniothalamin (GN), a styryl-lactone isolated from Goniothalamus andersonii, has been demonstrated to possess antirestenostic properties by inducing apoptosis on coronary artery smooth muscle cells (CASMCs). In this study, the molecular mechanisms of GN-induced CASMCs apoptosis were further elucidated. Apoptosis assessment based on the externalization of phosphatidylserine demonstrated that GN induces CASMCs apoptosis in a concentration-dependent manner. The GN-induced DNA damage occurred with concomitant elevation of p53 as early as 2 h, demonstrating an upstream signal for apoptosis. However, the p53 elevation in GN-treated CASMCs was independent of NAD(P)H: quinone oxidoreductase 1 and Mdm-2 expression. An increase in hydrogen peroxide and reduction in free thiols confirmed the role for oxidative stress in GN treatment. Pretreatment with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK) that significantly abrogated GN-induced CASMCs apoptosis suggested the involvement of caspase(s). The role of apical caspase-2, -8, and -9 was then investigated, and sequential activation of caspase-2 and -9 but not caspase-8 leading to downstream caspase-3 cleavage was observed in GN-treated CASMCs. Reduction of ATP level and decrease in oxygen consumption further confirmed the role of mitochondria in GN-induced apoptosis in CASMCs. The mitochondrial release of cytochrome c was seen without mitochondrial membrane potential loss and was independent of cardiolipin. These data provide insight into the mechanisms of GN-induced apoptosis, which may have important implications in the development of drug-eluting stents.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
Effect of alpha lipoic acid on oxidative stress and vascular wall of diabetic rats

Balkis Budin S, Othman F, Louis SR, Abu Bakar M, Radzi M, Osman K, et al.

Rom J Morphol Embryol, 2009;50(1):23-30.
PMID: 19221642

PREMISES AND OBJECTIVES: Antioxidant plays an important role in preventing the progression of diabetes mellitus (DM) complications. The aim of the present study was to investigate the effect of alpha lipoic acid (ALA) supplementation on plasma lipid, oxidative stress and vascular changes in diabetic rats.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Reduced nitric oxide-mediated relaxation and endothelial nitric oxide synthase expression in the tail arteries of streptozotocin-induced diabetic rats

Mokhtar SS, Vanhoutte PM, Leung SW, Suppian R, Yusof MI, Rasool AH

Eur J Pharmacol, 2016 Feb 15;773:78-84.
PMID: 26825543 DOI: 10.1016/j.ejphar.2016.01.013

Diabetes is associated with endothelial dysfunction, which is characterized by impaired endothelium-dependent relaxations. The present study aimed to examine the role of nitric oxide (NO), prostacyclin and endothelium-dependent hyperpolarization (EDH), in the relaxation of ventral tail arteries of rats under diabetic conditions. Relaxations of tail arteries of control and diabetic rats were studied in wire myograph. Western blotting and immunostaining were used to determine the presence of proteins. Acetylcholine-induced relaxations were significantly smaller in arteries of diabetic compared to control rats (Rmax; 70.81 ± 2.48% versus 85.05 ± 3.15%). Incubation with the combination of non-selective cyclooxygenase (COX) inhibitor, indomethacin and potassium channel blockers, TRAM 34 and UCL 1684, demonstrated that NO-mediated relaxation was attenuated significantly in diabetic compared to control rats (Rmax; 48.47 ± 5.84% versus 68.39 ± 6.34%). EDH-type (in the presence of indomethacin and NO synthase inhibitor, LNAME) and prostacyclin-mediated (in the presence of LNAME plus TRAM 34 and UCL 1684) relaxations were not significantly reduced in arteries of diabetic compared to control rats [Rmax: (EDH; 17.81 ± 6.74% versus 34.16 ± 4.59%) (prostacyclin; 15.85 ± 3.27% versus 17.23 ± 3.75%)]. Endothelium-independent relaxations to sodium nitroprusside, salbutamol and prostacyclin were comparable in the two types of preparations. Western blotting and immunostaining indicated that diabetes diminished the expression of endothelial NO synthase (eNOS), while increasing those of COX-1 and COX-2. Thus, since acetylcholine-induced NO-mediated relaxation was impaired in diabetes because of reduced eNOS protein expression, pharmacological intervention improving NO bioavailability could be useful in the management of diabetic endothelial dysfunction.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Effects of flavonoids on vascular smooth muscle of the isolated rat thoracic aorta

Ajay M, Gilani AU, Mustafa MR

Life Sci, 2003 Dec 19;74(5):603-12.
PMID: 14623031

The potency, structure-activity relationship, and mechanism of vasorelaxation of a series of flavonoids, representing different subclasses (flavonols: fisetin, rutin, quercetin; flavones: chrysin, flavone, baicalein; flavanones: naringenin, naringin; isoflavones: diadzein and flavanes: epigallo catechin gallate), were examined in the isolated rat aorta. Most of the flavonoids tested showed concentration dependent relaxant effects against K+ (80 mM) and phenylephrine (PE, 0.1 microM)-induced contractions with a greater inhibition of the responses to the alpha1-adrenoceptor agonist. The relaxant effects of most of the flavonoids involve in part the release of nitric oxide and prostaglandins from the endothelium as pretreatment with L-NAME and indomethacin attenuated the responses. In addition, the relaxant action of the flavonoids includes inhibition of Ca+2 influx and release of Ca+2 from intracellular stores. A structure-activity relationship amongst the flavonoids was suggested.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
Direct effects of quercetin on impaired reactivity of spontaneously hypertensive rat aortae: comparative study with ascorbic acid

Ajay M, Achike FI, Mustafa AM, Mustafa MR

Clin Exp Pharmacol Physiol, 2006 Apr;33(4):345-50.
PMID: 16620299

1. There is a growing interest in the anti-oxidant characteristics and use of flavonoids in the management of cardiovascular diseases. The cardiovascular mechanism of action of these plant derivatives remains controversial. This study compared the effects of the flavonoid quercetin with those of the anti-oxidant vitamin ascorbic acid (vitamin C) on the reactivity of aortic rings from spontaneously hypertensive rats (SHR). 2. The phenylephrine (PE)-induced contractile and the endothelium-dependent and independent relaxant responses of aortic rings from 21 to 22 week old SHR and age-matched normotensive Wistar (WKY) rats were observed in the presence of quercetin or ascorbic acid. All the experiments were performed in the presence of the cyclooxygenase inhibitor, indomethacin (10 micromol/L). 3. The endothelium-dependent and independent relaxations to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were significantly lesser in the SHR compared to the WKY tissues whereas the contractile responses to PE were similar in both tissues. Pretreatment of WKY rings with quercetin or ascorbic acid had no effect on the responses to ACh or PE. In the SHR tissues, however, quercetin or ascorbic acid significantly improved the relaxation responses to ACh and reduced the contractions to PE with greater potency for quercetin. Both compounds lacked any effects on the responses to SNP in either aortic ring types. N(omega)-nitro-L-arginine methyl ester (l-NAME, 10 micromol/L) significantly attenuated the vasodepressor effects of quercetin and ascorbic acid, raising the responses to PE to a level similar to that observed in the control SHR tissues. In l-NAME pretreated aortic rings, quercetin and ascorbic acid inhibited the contractile responses to PE with the same magnitude in WKY and SHR tissues. 4. The present results suggest that acute exposure to quercetin improves endothelium-dependent relaxation and reduces the contractile responses of hypertensive aortae with a greater potency than ascorbic acid. This suggests a better vascular protection with this flavonoid than ascorbic acid in the SHR model of hypertension and possibly in human cardiovascular diseases.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle

Rostam MA, Kamato D, Piva TJ, Zheng W, Little PJ, Osman N

Cell Signal, 2016 08;28(8):956-66.
PMID: 27153775 DOI: 10.1016/j.cellsig.2016.05.002

Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atherosclerosis. In human vascular smooth muscle, transforming growth factor-β (TGF-β) regulates glycosaminoglycan chain hyperelongation via ERK and p38 as well as Smad2 linker region (Smad2L) phosphorylation. In this study, we identified the involvement of TGF-β receptor, intracellular serine/threonine kinases and specific residues on transcription factor Smad2L that regulate glycosaminoglycan synthesizing enzymes. Of six glycosaminoglycan synthesizing enzymes, xylosyltransferase-1, chondroitin sulfate synthase-1, and chondroitin sulfotransferase-1 were regulated by TGF-β. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four individual residues in the TGF-β receptor mediator Smad2L can be phosphorylated by these kinases and in turn regulate the synthesis and activity of glycosaminoglycan synthesizing enzymes. Smad2L Thr220 was phosphorylated by CDKs and Smad2L Ser250 by ERK. p38 selectively signalled via Smad2L Ser245. Phosphorylation of Smad2L serine residues induced glycosaminoglycan synthesizing enzymes associated with glycosaminoglycan chain elongation. Phosphorylation of Smad2L Thr220 was associated with XT-1 enzyme regulation, a critical enzyme in chain initiation. These findings provide a deeper understanding of the complex signalling pathways that contribute to glycosaminoglycan chain modification that could be targeted using pharmacological agents to inhibit the development of atherosclerosis.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Modulation of vascular reactivity in normal, hypertensive and diabetic rat aortae by a non-antioxidant flavonoid

Ajay M, Achike FI, Mustafa MR

Pharmacol Res, 2007 May;55(5):385-91.
PMID: 17317209

In this study, we report the effects of a non-antioxidant flavonoid flavone on vascular reactivity in Wistar-Kyoto (WKY) rat isolated aortae. Whether flavone directly modulates vascular reactivity in spontaneously hypertensive rat (SHR) and streptozotocin-induced diabetic-WKY rat isolated aortae was also determined. Thoracic aortic rings were mounted in organ chambers and exposed to various drug treatments in the presence of flavone (10 microM) or its vehicle (DMSO), which served as control. Pretreatment with flavone enhanced relaxant effects to endothelium-dependent vasodilator acetylcholine (ACh) and attenuated contractile effects to alpha(1)-receptor agonist phenylephrine (PE) in WKY aortae compared to those observed in control aortic rings. Flavone had no effect on relaxations to ACh in WKY aortae incubated with either L-NAME or methylene blue, but enhanced relaxations to ACh in WKY aortae incubated with indomethacin or partially depolarized with KCl. Relaxations to ACh are totally abolished in both control or flavone pretreated endothelium-denuded WKY aortae. Flavone attenuated the inhibition by beta-NADH of ACh-induced relaxation in WKY aortae, but it had no significant effect on the transient contractions induced by beta-NADH nor the pyrogallol-induced abolishment of ACh-induced relaxation in WKY aortae. Flavone enhanced endothelium-independent relaxation to sodium nitroprusside (SNP) in both endothelium-intact and -denuded WKY aortae. Flavone enhanced relaxation to ACh and SNP as well as attenuated contractile effects to PE in SHR and diabetic aortae, a finding similar to that observed in normal WKY aortae. From these results, we conclude that flavone modulates vascular reactivity in normal as well as hypertensive and diabetic aortae. These effects of flavone results probably through enhanced bioactivity of nitric oxide released from the endothelium.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Vasodilation and Antihypertensive Activities of Swietenia macrophylla (Mahogany) Seed Extract

Ch'ng YS, Loh YC, Tan CS, Ahmad M, Asmawi MZ, Wan Omar WM, et al.

J Med Food, 2018 Mar;21(3):289-301.
PMID: 29420109 DOI: 10.1089/jmf.2017.4008

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.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Fulltext Carbon Monoxide Suppresses Neointima Formation in Transplant Arteriosclerosis by Inhibiting Vascular Progenitor Cell Differentiation

Sakihama H, Lee GR, Chin BY, Csizmadia E, Gallo D, Qi Y, et al.

Arterioscler Thromb Vasc Biol, 2021 Jun;41(6):1915-1927.
PMID: 33853347 DOI: 10.1161/ATVBAHA.120.315558

[Figure: see text].

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects*
The contribution of adrenoceptor subtype(s) in the renal vasculature of diabetic spontaneously hypertensive rats

Armenia A, Munavvar AS, Abdullah NA, Helmi A, Johns EJ

Br J Pharmacol, 2004 Jun;142(4):719-26.
PMID: 15172958

1. Diabetes and hypertension are both associated with an increased risk of renal disease and are associated with neuropathies, which can cause defective autonomic control of major organs including the kidney. This study aimed to examine the alpha(1)-adrenoceptor subtype(s) involved in mediating adrenergically induced renal vasoconstriction in a rat model of diabetes and hypertension. 2. Male spontaneously hypertensive rats (SHR), 220-280 g, were anaesthetized with sodium pentobarbitone 7-day poststreptozotocin (55 mg x kg(-1) i.p.) treatment. The reductions in renal blood flow (RBF) induced by increasing frequencies of electrical renal nerve stimulation (RNS), close intrarenal bolus doses of noradrenaline (NA), phenylephrine (PE) or methoxamine were determined before and after administration of nitrendipine (Nit), 5-methylurapidil (5-MeU), chloroethylclonidine (CEC) and BMY 7378. 3. In the nondiabetic SHR group, mean arterial pressure (MAP) was 146+/-6 mmHg, RBF was 28.0+/-1.4 ml x min(-1) x kg(-1) and blood glucose was 112.3+/-4.7 mg x dl(-1), and in the diabetic SHR Group, MAP was 144+/-3 mmHg, RBF 26.9+/-1.3 ml(-1) min x kg(-1) and blood glucose 316.2+/-10.5 mg x dl(-1). Nit, 5-MeU and BMY 7378 blunted all the adrenergically induced renal vasoconstrictor responses in SHR and diabetic SHR by 25-35% (all P<0.05), but in diabetic rats the responses induced by RNS and NA treated with 5-MeU were not changed. By contrast, during the administration of CEC, vasoconstrictor responses to all agonists were enhanced by 20-25% (all P<0.05) in both the SHR and diabetic SHR. 4. These findings suggest that alpha(1A) and alpha(1D)-adrenoceptor subtypes contribute in mediating the adrenergically induced constriction of the renal vasculature in both the SHR and diabetic SHR. There was also an indication of a greater contribution of presynaptic adrenoceptors, that is, alpha(1B)-, and/or alpha(2)-subtypes.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects
Fulltext Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells

Kimura TE, Duggirala A, Hindmarch CC, Hewer RC, Cui MZ, Newby AC, et al.

J Mol Cell Cardiol, 2014 Jul;72(100):9-19.
PMID: 24534707 DOI: 10.1016/j.yjmcc.2014.02.001

AIMS: Cyclic AMP inhibits vascular smooth muscle cell (VSMC) proliferation which is important in the aetiology of numerous vascular diseases. The anti-mitogenic properties of cAMP in VSMC are dependent on activation of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), but the mechanisms are unclear.
METHODS AND RESULTS: Selective agonists of PKA and EPAC synergistically inhibited Egr1 expression, which was essential for VSMC proliferation. Forskolin, adenosine, A2B receptor agonist BAY60-6583 and Cicaprost also inhibited Egr1 expression in VSMC but not in endothelial cells. Inhibition of Egr1 by cAMP was independent of cAMP response element binding protein (CREB) activity but dependent on inhibition of serum response element (SRE) activity. SRF binding to the Egr1 promoter was not modulated by cAMP stimulation. However, Egr1 expression was dependent on the SRF co-factors Elk1 and 4 but independent of MAL. Inhibition of SRE-dependent Egr1 expression was due to synergistic inhibition of Rac1 activity by PKA and EPAC, resulting in rapid cytoskeleton remodelling and nuclear export of ERK1/2. This was associated with de-phosphorylation of the SRF co-factor Elk1.
CONCLUSION: cAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. This occurs, at least in part, via inhibition of Rac1 activity leading to rapid actin-cytoskeleton remodelling, nuclear export of ERK1/2, impaired Elk1-phosphorylation and inhibition of SRE activity. This identifies one of the earliest mechanisms underlying the anti-mitogenic effects of cAMP in VSMC but not in endothelial cells, making it an attractive target for selective inhibition of VSMC proliferation.

Matched MeSH terms: Muscle, Smooth, Vascular/drug effects

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