| Part-Ⅰ Estrogen Metabolite2Methoxyestradiol Prevents Hypertension in Deoxycorticosterone Acetate-salt RatsPurpose:Our early work showed that the estrogen metabolite2Methoxyestradiol (2ME) inhibits proliferation of vascular smooth muscle cells (SMCs) and vascular contractility through an endothelium-dependent mechanism. The aim of this study was to examine whether2ME prevents the development of hypertension in rats.Methods:A hypertensive model was established in uninephrectomized rats using deoxycorticosterone acetate (DOCA)-salt. Blood pressure in response to2ME (treatment up to10weeks or single bolus) was monitored.Results:Our results showed that systolic blood pressure, as measured by tail-cuff plethysmography, was significantly increased in conscious rats treated with DOCA-salt for3-10weeks. Co-treatment with2ME (100-300μg/kg), but not dimethyl sulfoxide (DMSO), completely prevented the increase in blood pressure of DOCA-salt rats. After10-week treatment, the mean arterial blood pressure (MABP) of anesthetized rats measured using Power Lab Data Acquisition System was:84±16mmHg in normotensive control rats and150±9mmHg in DOCA-salt rats, which was similar to that of DMSO-treated rats. Treatment with2ME at low or high doses reduced MABP of DOCA-salt rats close to that of control normotensive rats. In addition, MABP of hypertensive DOCA-salt rats was significantly reduced inresponse to a single injection of2ME. Delayed administration of2ME reduced the further increase of blood pressure in DOCA-salt rats. However, inhibition of2ME production by entacapone did not significantly affect blood pressure in either control or DOCA-salt rats.Conclusions:2ME treatment prevents the development of hypertension in DOCA-salt rats, implicating a therapeutic potential of2ME in hypertension treatment. Part-II The Mechanism of Uridine Adenosine Tetraphosphate Induces Contraction of Circular and Longitudinal Gastric Smooth MusclePurpose:Extracellular nucleotides uridine-50-triphosphate (UTP) andadenosine triphosphate (ATP) induce contraction of gastricsmooth muscle (SM). The dinucleotide uridine adenosine tetraphosphate(Up4A), an endothelium-derived contraction factor, induces vascular SM contraction. Its effect on gastric SM contractions, however, is unknown. We addressed the hypothesis that Up4A induces gastric SM contraction via a mechanism that may differ between circular and longitudinal muscle(CM and LM, respectively).Methods:CM and LM were isolated from rat gastric fundus for the measurement of isometric tension.Up4A induced transient contractile responses in both CM and LM, which were similar to those induced by ATP and UTP.Results:Up4A failed to induce contraction of either LM or CM in the absence of extracellular Ca2+or in the presence of nimodipine,an inhibitor of voltage-gated Ca2+channels. P2X1,2,4,5and7and P2Y1,2,4and6receptor expression was detected in gastric SM by reverse transcription-polymerase chain reaction.IP5I (a P2X receptor antagonist) anda,p-methylene-ATP(a P2X receptor agonist) had no effect on Up4A-induced contractions of either LM or CM, and α,β-methylene-ATP alone failed to induce a contractile response in either tissue. Suramin(a P2Y receptor antagonist), on the other hand, significantly inhibited Up4A-induced contraction of CM, but not LM.Up4A-induced contraction of CM, but not LM, was also inhibited by pretreatment with Y-27632, an inhibitor of Rho-associated kinase.ConcIusions:We conclude that Up4A induces extracellular Ca2+-dependent contractions of rat gastric LM and CM, and Up4A-induced contraction of CM is mediated by suramin-sensitive P2Y receptors and subsequent activation of the Rho associated kinase pathway. |
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