Extracellular pH is an important physiological determinant of vascular tone that is normally maintained within 7.35-7.45. Any change outside this range leads to severe pathological repercussions. We investigated the unknown effects of extracellular acidosis on relaxation in the superior mesenteric artery (SMA) of goat. SMA rings were employed to maintain isometric contractions at extracellular pH (pH) 7.4 and 6.8. We analyzed the effect of acidosis (pH 6.8) compared to physiological pH (pH 7.4) on three signaling mediators of endothelium-dependent hyperpolarization: nitric oxide (NO), prostaglandin I (PGI), and myoendothelial gap junctions (MEGJ). NO and cyclic guanosine monophosphate (cGMP) levels were compared between normal and acidic pH. Quantitative real-time PCR (qPCR) studies determined the change in expression of vascular connexin (Cx), Cx37, Cx40, and Cx43. Under acidosis, acetyl choline-induced relaxation was augmented in an endothelium-dependent manner via eNOS-NO-cGMP signaling. Conversely, at normal pH, acetyl choline-induced vasorelaxation was mediated primarily via COX-PGI pathway. The functional activity of MEGJ was increased under acidosis as evident from increased sensitivity of connexin blockers and upregulated gene and protein expression of connexins. In conclusion, acetyl choline-induced augmented vasorelaxation under acidosis is mediated by NOS-NO-cGMP, with a partial role of MEGJ as EDH mediators in the SMA. Present data suggest a novel role of connexin as therapeutic targets to attenuate the detrimental effect of acidosis on vascular tone.
Natural products like eugenol and curcumin have been reported to control hypertension. The purpose of our study was to examine the role of iNOS in eugenol/curcumin/nanocurcumin–induced vasorelaxation in the middle uterine artery (MUA) obtained from non-pregnant (NP) and pregnant (P) Capra hircus ( Ch). The MUA rings were mounted in an automatic organ bath attached to a powerlab data acquisition system. Vasorelaxation was induced by eugenol/curcumin/nanocurcumin in either the absence or presence of aminoguanidine in phenylephrine precontracted MUA rings. The vasorelaxation response was recorded isometrically by a highly sensitive isometric force transducer automatic organ bath connected to powerlab and analysed using Labchart 7.1.3 software. The maximal vasorelaxation (Rmax) obtained from eugenol, curcumin and nanocurcumin -induced concentration related contractile response elicited in PE- precontracted ED+ MUA rings was 49.5%, 42.6%, and 40.4% in NP, and 79.5%, 55.5%, and 44.1% in P Ch. Aminoguanidine attenuated the Rmax of eugenol, curcumin and nanocurcumin to 28.2%, 28.5%, and 16.4% in MUA of NP, and 57.2%, 57.4%, and 38.0% in MUA of P Ch, respectively. The results demonstrated that vasorelaxation to (i) Eugenol is partly mediated by partial activation of aminoguanidine-sensitive iNOS in the uterine artery and this pathway is augmented in pregnancy, (ii) Nanocurcumin is mediated by activation of aminoguanidine-sensitive iNOS in the uterine artery of NP, but not in P Ch and (iii) Curcumin is mediated by minimal activation of aminoguanidine sensitive iNOS only in the uterine artery of NP, but not in P Ch. In conclusion, eugenol and nanocurcumin possess a greater potential than curcumin in the control of hypertension due to partial activation of iNOS. These nutraceuticals could be useful to improve blood flow to the uterus to maintain oestrus cycle, maternal and fetal health.
Objective:The objective of this study was to characterize the α1-adrenoceptor (α1-AR) subtypes and evaluate the effect of acidosis on α1-AR function and expression in goat superior mesenteric artery (GSMA).Materials and Methods:GSMA rings were mounted in a thermostatically controlled (37.0°C ± 0.5°C) organ bath containing 20 ml of modified Krebs-Henseleit solution, maintained at pHo of 7.4, 6.8, 6.0, 5.5, 5.0, and 4.5. Noradrenaline (NA)- and phenylephrine (PE)-induced contractile response was elicited in the absence or presence of endothelium and prazosin at pHo of 7.4, 6.0, and 5.0. The responses were recorded isometrically by an automatic organ bath connected to PowerLab and analyzed using Labchart 7.1.3 software. Expression of α1D-AR was compared at physiological and acidic pHo using reverse transcription-polymerase chain reaction (RT-PCR).Results:NA- and PE-induced contractile responses were attenuated proportionately with a decrease in extracellular pH (pHo), i.e. 7.4 → 6.8 → 6.0 → 5.5 → 5.0 → 4.5. Endothelium denudation increased the contractile response at both normal and acidic pHo. Prazosin (1 nM, 10 nM, and 0.1 μM) inhibited the NA- and PE-induced contractile response at pHo 7.4 and the blocking effect of prazosin was potentiated at pHo of 6.0 and 5.0. RT-PCR analysis for α1D-AR in GSMA showed that the mRNA expression of α1D-AR was decreased under acidic pHo as compared to physiological pHo.Conclusion:(i) Adrenergic receptor mediates vasoconstriction in GSMA under normal physiological pHo, and α1D is the possible subtype involved in this event (ii) acidosis attenuates the vasocontractile response due to reduced function and expression of α1D-AR and also increased the release of endothelial-relaxing factors.
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