NANOCURCUMIN SELECTIVELY ACTIVATES ENDOTHELIAL NITRIC OXIDE IN MIDDLE UTERINE ARTERY OF GOAT (CAPRA HIRCUS)

NANOCURCUMIN SELECTIVELY ACTIVATES ENDOTHELIAL NITRIC OXIDE IN MIDDLE UTERINE ARTERY OF GOAT (CAPRA HIRCUS)

Harithalakshmi Jandhyam ¹, Prakash Chandra Behera ² and Subas Chandra Parija ^{* 1}

Department of Pharmacology and Toxicology ¹, Department of Veterinary Biochemistry ²,  College of Veterinary Science and Animal Husbandry, Orissa University of Agriculture and Technology, Bhubaneswar - 751003, Odisha, India.

ABSTRACT: Objective: The present study is designed to investigate vasorelaxation mechanisms of Nanocurcumin in the middle uterine artery (MUA) of both non-pregnant (NP) and pregnant (P) Capra hircus (Ch). Methods: MUA rings were mounted in an automatic organ bath and the contractile response was recorded isometrically by highly sensitive force transducer connected to a power lab data acquisition system. Nanocurcumin (1 pM-100 µM) vasorelaxation response (NCVR) was elicited in PE-precontracted rings either in the absence or presence of different blockers. Results: The maximal vasorelaxation (R_max) to Nanocurcumin in phenylephrine-precontracted endothelium intact MUA rings of NP (40.36 ± 2.38%) and of P (44.09 ± 3.41%) was reduced to 22.93 ± 0.80% and 25.37 ± 2.2% in endothelium-denuded MUA rings of NP and P Ch. L-NAME, Indomethacin and L-NAME + Indomethacin inhibited NCVR by significantly decreasing the R_max to 17.65%, 28.42%, 17.95% in NP and to 27.34%, 39.06%, 24.50% in P Ch. The ODQ and carbenoxolone/18β Glycyrrhetinic acid did not inhibit the R_max of NCVR. Conclusion: Nanocurcumin potentially dilates the MUA of both NP and PCh. The endothelial L-NAME sensitive eNOS is activated by Nanocurcumin and it has the potential to increase blood flow to the uterus and fetus. Additionally, it could also be useful in the effective treatment of hypertensive disorders such as pre-eclampsia.

Nanocurcumin, Uterine artery, Vasorelaxation, Nitric oxide, Pregnancy

INTRODUCTION: Hypertension is the most common health disorder of pregnancy and is reported to complicate up to 10% of pregnancies and is associated with increased maternal and neonatal morbidity and mortality ¹. NO maintains vascular tone by relaxing vascular smooth muscle cells ².

Myo-endothelial gap junctions connect endothelial cells and smooth muscle cells. The hyper-polarization in smooth muscle cells is basically conducted from the endothelial cells through myoendothelial gap junctions since smooth muscle and endothelial cells are coupled ³.

Connexins play specific roles in estradiol-17β-treatment-regulated uterine function and in placental development during early gestation ⁴. During normal pregnancy, there is an increased production of NO, PGI₂ and EDHF but in preeclampsia, there is increased release of placental cytokines that inhibit the production of endothelium-derived relaxing factors and thereby decrease smooth muscle relaxation ⁵. Curcumin, a hydrophobic polyphenol extracted from the rhizomes of Curcuma longa (Zingiberaceae). Curcumin has been used as traditional medicine, beauty aid, cooking spice, and a coloring agent for centuries in India ⁶. Several studies have demonstrated the beneficial effects of Curcumin, including antidepressant, antioxidant, anti-inflammatory, antibacterial, and anti-cancer activities ⁷. Curcumin shows to improve endothelial function and also been reported to have numerous therapeutic effects in the treatment of cardiovascular diseases ⁸. The pleiotropic effects of Curcumin are dependent on its capacity of interacting and regulation of multiple molecular targets. Due to its efficacy and regulation of multiple targets as well as its safety for human use, Curcumin has received considerable interest as a potential therapeutic agent for the prevention and treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease and alternative therapy for uterine leiomyoma ^9-11.

Despite its enormous curative potential, low water-solubility, chemical instability, rapid metabolism, short half-life, and poor oral bioavailability are some of the major factors which restrict the utilization of Curcumin ¹². However, to improve its bioavailability, the nano-formulation of Curcumin is an emerging novel substitute. The different types of nano-carriers were utilized for Curcumin nano-particle formulation. Nanoparticles (10-200 nm), can improve the circulation time of the loaded therapeutic molecule and improve its residence at the pathological site by enhancing permeation and retention (EPR) effect ¹³. Recent reports suggested that nano-curcumin as a chemopreventive agent against malignant tumor proliferation in different organs ¹⁴. It may be a promising lead in reducing hypertension. Administration of nano-curcumin in proper doses can reduce hypertension during pregnancy, and this could be one of the potential adjuncts for the treatment of pre-eclampsia.

Information on the vasodilator role of nano-curcumin is lacking in the uterine artery of any species. Our present research would explore the relative potential of nano-curcumin to cause vasodilatation in MUA of non-pregnant and pregnant goat model. Further, the functional involvement of eNOS-NO-cGMP, COX-PGI₂, sGC, and hyperpolarizing factors were examined to establish the mechanism of vasorelaxation to nano-curcumin in MUA of NP and P Ch.

MATERIALS AND METHODS:

Ethical Approval: This work has been approved by the institutional animal ethical committee (Registration No: 433/CPCSEA/CVS vide ID.No. 1586(6)/CVS/dt.03.05.2016 for conducting randomized ex-vivo animal tissue experiments.

Chemicals: Nanocurcumin (Gifted by Dr. B.P. Mohanty, CIFRI, ICAR, India), 18 β Glychrrhetinic Acid (MP Biochemicals, India), N^G –nitro-L-arginine methyl ester (L-NAME), 1H-[1, 2, 4] oxadiazolo [4, 3-a] quinoxaline-1one (Cayman Chemical, USA) and Carbenoxolone (Sigma, USA) were employed in this study. All the solutions were prepared fresh in triple-distilled water except for 18βGA, ODQ which were dissolved in dimethyl sulfoxide (DMSO) and indomethacin, which was dissolved in ethanol. Nanocurcumin was prepared in 0.5 N NaOH and PBS.

Middle Uterine Artery Preparation: Both non-pregnant and pregnant uterus with broad ligament intact along with uterine artery were obtained in an aerated ice-cold (4-6 °C) Modified Krebs-Henseleit Saline (MKHS) solution to the laboratory. Secondary branches of uterine artery supplied to the uterine horn carefully cleared of fascia and connective tissue were cut into segments of circular rings measuring 1.5-2 mm in length.

The arterial rings were then mounted between two fine stainless steel L-shaped hooks and kept under a resting tension of 1.5 gm in a thermostatically controlled (37.0 ± 0.5 ºC) automatic organ bath (Pan Lab) of 20 mL capacity bubbled with carbogen (95% O₂ + 5% CO₂). Endothelium denuded (ED-) rings were prepared by the cotton swab method. The change of isometric tension was measured by a highly sensitive isometric force transducer (Model: MLT0201, AD instrument, Australia) and analyzed using chart 7.1.3 software.

Nanocurcumin- Induced Concentration Related Response in PE-Precontracted ED +/ ED- MUA Rings: After obtaining a plateau tension induced by PE (10 µM), Nanocurcumin (1 pM-100 µM) was added to bath cumulatively with an increment of 1.0 log unit at 4 min interval. Net tension (gm) at each concentration of nano-curcumin was recorded. The concentration-related response curves of nano-curcumin were elicited and the shift of the CRCs was compared between ED + and ED - groups. Rmax/R_Bmax, mean threshold concentration, and pIC₅₀, were calculated for MUA rings for non-pregnant and pregnant groups.

Nanocurcumin-Induced Vasorelaxation in Presence of L-NAME or Indomethacin or L-NAME and Indomethacin or ODQ or Carbeno-xolone or 18 β Glycyrrhetinic Acid in PE-Precontracted MUA Rings: In order to examine nano-curcumin (1 pM-100 µM) induced vaso-relaxation involving EDRF and EDHF pathways, the arterial rings were pre-incubated with 10 µ of L-NAME or Indomethacin or L-NAME and Indomethacin or ODQ for a period of 15 min and Carbenoxolone or 18 β Glycyrrhetinic acid for a period of 30 min prior to PE pre contraction.

Curcumin was added with an increment of 1.0 log unit in a cumulative manner into the bath at 4 min interval after attaining a plateau contraction induced by PE. The concentration-related response curves of nano-curcumin were elicited and the shift of the CRCs was compared with non-treated control. Rmax/R_Bmax, mean threshold concen-tration, and pIC₅₀, were calculated for MUA rings of NP and P Ch.

Data Analysis: The data was expressed as a percentage of the maximum relaxation to agonist obtained in the absence of antagonist (control) and analyzed by the interactive non-linear regression through the computer program Graph Pad Prism (GraphPad Prism Software, San Diego, CA, USA). Rmax/R_Bmax, mean threshold concentration and –logIC₅₀/pIC₅₀ were calculated through GraphPad Prism. GraphPad Quick Calcs ‘t’ test was used to calculate the P-value to determine the level of significance and to analyze the data. A ‘p’ value < 0.05 and <0.001 were considered statistically significant.

RESULTS AND DISCUSSION: Table 1 presents the R_max and pIC₅₀ of nanocurcumin in MUA of NP and P Ch. Nanocurcumin inhibited PE- induced sustained contraction in both NP and P Ch in a concentration-dependent manner. NCVR curve (R_max 40.36 ± 2.38%; pIC₅₀ 8.83 ± 0.12) elicited in ED + rings was shifted to right with significant (p<0.001) decrease in R_max (22.93 ± 0.80%) and significant (p<0.05) decrease in pIC₅₀ (8.08 ± 0.20) in ED- rings of NP Ch Fig. 1A. In MUA of P Ch, NCVR curve (R_max 44.09 ± 3.41%; pIC₅₀ 6.05 ± 0.09) elicited in ED + rings was shifted to right with significant (p<0.05) decrease in R_max (25.37 ± 2.20%) and significant (p<0.001) increase pIC₅₀ (7.76 ± 0.18) in ED-MUA rings Fig. 1B.

FIG. 1: NANO CURCUMIN (1PM-100 μM)-INDUCED CONCENTRATION RESPONSE CURVE ELICITED IN ED+/- MUA RING OF A) NP Ch AND B) P Ch

L-NAME, eNOS inhibitor and Indomethacin, a COX inhibitor and both attenuated nanocurcumin vasorelaxation in PE precontracted MUA rings Table 1. NCVR curve was shifted right with significant (p<0.001) decrease in R_Bmax (17.66 ± 0.45%) and pIC₅₀ (7.02 ± 0.11) in presence of L-NAME, with significant (p<0.05) decrease in R_Bmax (28.42 ± 2.02%) and increase in pIC₅₀ (9.38 ± 0.18) in presence of Indomethacin. In presence of both L-NAME and Indomethacin, the NCVR curve was also shifted to the right with significant (p<0.001) decrease in R_Bmax (17.95 ± 1.43%) and pIC₅₀ (7.04 ± 0.12) Fig. 2A. In MUA of P Ch, NCVR curve was shifted to right with significant (p<0.05) decrease in R_Bmax (27.34 ± 0.93%) and increase in pIC₅₀ (6.75 ± 0.17) in presence of L-NAME, with non-significant decrease in R_Bmax (39.06 ± 1.80%) and significant (p<0.001) increase in pIC₅₀ (10.81 ± 0.15) in presence of Indomethacin. In presence of L-NAME and Indomethacin, the NCVR curve was shifted to the right with significant (p<0.001) decrease in R_Bmax (24.50 ± 1.68%) and increase in pIC₅₀ (9.28 ± 0.14) Fig. 2B.

FIG. 2: NANOCURCUMIN (1PM-100 μM)-INDUCED CONCENTRATION RESPONSE CURVE ELICITED IN ABSENCE (CONTROL) OR IN PRESENCE OF L-NAME (10 μM) OR INDOMETHACIN (INDO, 10 μM) OR L-NAME AND INDOMETHACIN (L-NAME +INDO, 10 μM) IN MUA RING OF A) NP Ch AND B) P Ch

In presence of ODQ (sGC inhibitor, 10 μM), NCVR curve showed a non-significant decrease in R_Bmax (35.48 ± 1.29%) and a significant decrease (p<0.001) in pIC₅₀ (6.79 ± 0.12) as compared to NP control Fig. 3A. In MUA of P Ch, NCVR curve was unaltered with a non-significant decrease in R_Bmax (50.54 ± 0.29) and significant (p<0.001) increase in pIC₅₀ (7.85 ± 0.14) as compared to P control Fig. 3B.

FIG. 3: NANOCURCUMIN (1PM-100 μM)-INDUCED CONCENTRATION RESPONSE CURVE ELICITED IN ABSENCE (CONTROL) OR IN PRESENCE OF ODQ (10 μM) IN MUA OF A) NP Ch AND B) P Ch

Gap junction uncouplers like Carbenoxolone/18β glycyrrhetinic acid did not alter NCVR significantly in MUA rings of both NP and P Ch Table 1. Carbenoxolone (10 μM), caused a non-significant decrease in R_Bmax (34.15 ± 1.30%) and significant (p<0.001) decrease pIC₅₀ (7.86 ± 0.14) of NCVR curve. Similarly, 18β Glycyrrhetinic acid (10 μM) inhibited NCVR with significant (p<0.05) increase in R_Bmax (51.91 ± 3.0 %) and decrease in pIC₅₀ (8.13 ± 0.13) in MUA of NP Ch Fig. 4A. In MUA of P Ch, NCVR curve was shifted with a non-significant decrease in R_Bmax (40.21 ± 0.63%) and significant (p<0.001) increase in pIC₅₀ (9.21 ± 0.15) in presence carbenoxolone. In the presence of 18 β-glycyrrhetinic acid NCVR curve showed a non-significant decrease in R_Bmax (41.41 ± 3.25%) and significant (p<0.001) increase in pIC₅₀ (7.87 ± 0.16) Fig. 4B.

FIG. 4: NANOCURCUMIN (1PM-100 μM)-INDUCED CONCENTRATION RESPONSE CURVE ELICITED IN ABSENCE (CONTROL) OR PRESENCE OF CARBENOXOLONE (CARBENOX, 10 μM) OR 18β GLYCYRRHETINIC ACID (18β GA, 10 μM), IN MUA RING OF A) NP Ch AND B) P Ch

The major findings are i) The maximal vasorelaxation obtained from the NCVR curve elicited in PE- precontracted ED+ MUA rings were almost identical in P (44.09%) than NP Ch (40.36%). Endothelium removal decreased the maximal NCVR to 22.93% and 25.37% in MUA of NP and P Ch, respectively. In MUA rings of NP and P Ch, NCVR is mediated by an identical endothelium-dependent component. ii) L-NAME, Indomethacin, L-NAME + Indomethacin decreased the maximal NCVR to 17.66%, 28.42%, 17.95% in MUA ring of NP and 27.34%, 39.06%, 24.50% in MUA ring of P Ch, respectively. iii) In presence of ODQ, the maximal CVR was inhibited to 35.48% in NP but augmented to 50.54% in MUA ring of P Ch. iv) Carbenoxolone did not alter NCVR in both MUA of NP (34.15%) and P (40.21%) Ch. 18β glycyrrhetinic acid augmented NCVR to 51.91% in MUA of NP but did not attenuate in MUA of P (41.41%) Ch.

Cumulative addition of graded concentration of Nanocurcumin to the PE-precontracted MUA rings of NP or P Ch resulted in vasorelaxation response. Nanocurcumin-induced vasorelaxation response (NCVR) in ED+ MUA of NP (40.36%) was slightly increased in P (44.09%) Ch. Removal of endothelium did significantly decrease the R_max of NCVR curve to 22.93% and 25.37% in P Ch demonstrating that about 17% and 19% of NCVR is endothelium-dependent in MUA of NP and P Ch, respectively. This clearly demonstrates that vasorelaxation to nano-curcumin is mediated by endothelium-dependent and independent component in MUA of NP and P Ch. Curcumin –induced vasorelaxation has been reported in rat aorta ¹⁵, porcine coronary arteries ¹⁶, rabbit basilar arteries ¹⁷, rat mesenteric arteries ¹⁸, goat ruminal artery ^19, and uterine artery ²⁰.

The information on the vasorelaxation effect of nano-curcumin in any arterial model is almost lacking. So, we have discussed several aspects of the mechanism of action of nano-curcumin vasorelaxation on the basis of its targets of action. L-NAME, Indomethacin, L-NAME + Indo-methacin decreased significantly the maximal NCVR to 17.66%, 28.42%, and 17.95% in MUA ring of NP Ch, respectively. Hence, 22%, 12% and 22% of NCVR are mediated by endothelium-dependent eNOS-NO and COX-PGI₂ pathways. In conclusion, Nanocurcumin activates predominantly the L-NAME-sensitive eNOS and secondarily Indomethacin COX-PGI₂. In MUA of P Ch, the R_Bmax obtained from the NCVR curve in the presence of L-NAME, and L-NAME + Indomethacin decreased significantly to 27.34% and 24.50%.

Indomethacin did not reduce the NCVR. These findings clearly show that endothelium-dependent and L-NAME sensitive eNOS is exclusively sensitive to Nanocurcumin in MUA ring of P Ch. In conclusion, Nanocurcumin activates exclusively L-NAME –sensitive eNOS and mediates endothelium-dependent vaso-relaxation involving eNOS-NO-cGMP pathways similar to the endothelial mechanism of vasorelaxation of curcumin observed in porcine coronary arterial rings and goat uterine artery ^{16, 20}.

In the presence of ODQ, the maximal NCVR was non-significantly inhibited to 35.48% in NP and augmented to 50.54% in the MUA ring of P Ch suggesting that nano curcumin-induced vaso-relaxation did not activate directly sGC. In goat ruminal artery, the mechanism of vasorelaxation to curcumin via activation of sGC-cGMP pathways- with opening of K⁺ ion channels ¹⁹ does not appear to involve in the mechanism of NCVR in MUA ring of Ch. On the other hand, our previous studies showed that nano-curcumin directly activates the K_V, KCa, Kir channels in NP Ch, and opens KC_a and K_V channels in P Ch to cause hyperpolarization in vascular smooth muscle membrane and vaso-relaxation in goat uterine artery ²¹.

In order to examine the effect of NC on MEGJ, NCVR was elicited in the presence of uncouplers of GJ like Carbenoxolone and 18β glycyrrhetinic acid. NCVR was not attenuated in MUA of NP and P Ch in presence of GJ uncouplers suggesting that NC has no modulatory effect at myoendothelial gap junction in MUA of Ch. on contrast the modulatory effect of Curcumin on gap junctions has been reported in astrocyte cells of SD rats ²² and crypt cells of Azoxymethane (AOM)-induced colon carcinogenesis in mice ²³. This result clearly demonstrates that nanoformulation of Curcumin does not activate MEGJ in goat uterine blood vessels as that of Curcumin.

TABLE 1: R_max AND PIC₅₀ OF NANO CURCUMIN (1 PM-100 μM) IN ENDOTHELIUM INTACT (ED+)  OR IN ENDOTHELIUM DENUDED (ED-) OR  IN ABSENCE (R_MAX) OR IN PRESENCE (R_BMAX) OF  L-NAME (10 μM) OR INDOMETHACIN (10 μM) OR  L-NAME (10 μM) AND INDOMETHACIN (L-NAME + INDO, 10 μM) OR ODQ (10 μM) OR CARBENOXOLONE (10 ΜM) OR 18β GLYCYRRHETINIC ACID (18βGA, 10 μM) IN PE (10 μM)-PRECONTRACTED MUA RINGS OF NP AND P Ch

a (p<0.001), b (p<0.05) represents a level of significance between the rows within each column. The values are expressed as Mean ± SEM. N value = Total number of MUA rings used in the experiments

CONCLUSION: Nanocurcumin potently dilates the middle uterine artery of P Ch than that of NP Ch. Nanocurcumin selectively increases the NO turnover via activation of eNOS in MUA of P Ch without the involvement of sGC and myo-endothelial gap junctions.

It is possible that the NO thus produced by nano-curcumin in the endothelium diffused to vascular smooth muscles to activate K⁺-channels to cause hyperpolarisation and vasorelaxation. These studies clearly support that nano curcumin exhibits a precise signaling target in the endothelium with better vasodilator effect than curcumin, which acts at multiple sites. Nanocurcumin has the potential to revolutionize the health industry, especially in the therapeutic management of hypertensive disorders in pregnancy, such as preeclampsia.

ACKNOWLEDGEMENT: The authors are grateful to the UGC, GOI, for providing student fellowship grant (NFO-2015-17-OBC-AND-33897) during the research work of one of the authors Harithalakshmi Jandhyam.

We also would like to thank OUAT, Odisha, India for providing the infrastructure facility to carry out this study.

CONFLICTS OF INTEREST: The authors declare that there are no conflicts of interest.

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    How to cite this article:

    Jandhyam H, Behera PC and Parija CS: Nanocurcumin selectively activates endothelial nitric oxide in middle uterine artery of goat (Capra hircus). Int J Pharm Sci & Res 2020; 11(7): 3306-12. doi: 10.13040/IJPSR.0975-8232.11(7).3306-12.

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