• The Korean Journal of Physiology and Pharmacology
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• 제4권3호
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• pp.263-270
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• 2000

To evaluate the involvement of nitric oxide production on the endothelium-dependent relaxation in diabetes, we have measured vascular and endothelial function and nitric oxide concentration, and the expression level of endothelial nitric oxide synthase in the streptozotocin-induced diabetic rats. Diabetic rats were induced by the injection of streptozotocin (50 mg/kg i.v.) in the Sprague-Dawley rats. Vasoconstrictor responses to norepinephrine (NE) showed that maximal contraction to norepinephrine $(10^{-5}\;M)$ was significantly enhanced in the aorta of diabetic rats. Endothelium-dependent relaxation induced by acetylcholine was markedly impaired in the aorta of diabetic rats, these responses were little improved by the pretreatment with indomethacin. However, endothelium-independent relaxation induced by nitroprusside was not altered in the diabetic rats. Plasma nitrite and nitrate $(NO_2/_3)$ levels in diabetic rats were significantly lower than in non-diabetic rats. Western blot analysis using a monoclonal antibody against endothelial cell nitric oxide synthase (eNOS) revealed that the protein level was lower in the aorta of diabetic rats than in non-diabetic rats. These data indicate that nitric oxide formation and eNOS expression is reduced in diabetes, and this would, in part, account for the impaired endothelium-dependent relaxation in the aorta of streptozotocin-induced diabetic rats.

• 대한수의학회지
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• 제43권4호
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• pp.597-606
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• 2003

Although the antidepressant effects of imipramine (IMI) have been well known in several studies, the effects on cardiovascular system, particularly the vasorelaxant effects, have not known clearly. We hypothesis that IMI-induced vasorelaxation involves NO (nitrie oxide), activation of guanylate cyclase (GC) and $Ca^{2+}$ channel. The possible roles of the endothelium and $Ca^{2+}$ in IMI-induced responses were investigated using isolated rings of rat thoracic aorta and anesthesized rats. In KCl-precontracted rings. IMI produces endothelium-dependent and endothelium-independent relaxations in intact (+E) as well as endothelium-denuded (-E) rat aorta in a concentration-dependent manner. In phenylephrine (PE)-precontracted rings, the IMI-induced relaxation was significantly greater in +E rings. The IMI-induced relaxations were suppressed by nitric oxide synthase (NOS) inhibitors, N(G)-nitro-L-arginine (L-NNA), N(omega)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine, a non-selective GC inhibitor, methylene blue, $Na^+$ channel blockers, lidocaine and procaine, or $Ca^{2+}$ channel blockers, nifedipine and verapamil, in PE-precontracted +E rings, but not in PE-precontracted -E rings. These relaxations were also suppressed by lidocaine or procaine in -E aortic rings. However, IMI-induced relaxations were not inhibited by a PLC inhibitor 2-nitro-4-carboxyphenyl-n,n-diphenylcarbamate (NCDC), an inositol monophosphatase inhibitor, lithium, indomethacin and dexamethasone in +E and -E rings. In vivo, infusion of IMI elicited significant decrease in arterial blood pressure. After intravenous injection of saponin, NOS inhibitors. MB and nifedipine, infusion of IMI inhibited the IMI-lowered blood pressure markedly. These findings suggest that the endothelium-dependent relaxation induced by IMI is mediated by activation of NO/cGMP signaling cascade or inhibition of $Ca^{2+}$ entry through voltage-gated channel, and this mechanism may contribute to the hypotensive effects of IMI in rats.

• 대한약리학회지
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• 제26권2호
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• pp.135-144
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• 1990

Propylthiouracil(PTU)을 4주 및 12주간 투여한 흰쥐의 대동맥을 적출하여 혈관수축제와 이완제에 대한 반응을 관찰하여 다음과 같은 결과를 얻었다. PTU를 처치한 실험군에서는 대조군에 비해 현저한 체중저하와 혈중 갑상선호르몬의 감소를 보였다. PTU를 처치한 흰쥐의 대동맥에 대한 norepinephrine (NE)과, calcium및 potassium 이온에 의한 최대수축 반응은 대조군에 비하여 유의하게 감소되었다. 그러나 NE에 대한 중간유효량은 증가되었으나, calcium이온에 대한 중간 유효량은 유의한 차이가 없었다. 그리고 acetylcholine, histamine, isoproterenol 및 nitroprusside에 의한 대동맥의 이완작용은 대조군에 비해 증가된 경향을 보였다. PTU를 12주간 처치한 군에 있어서 acetylcholine에 의한 최대 이완반응은 대조군에 비해 유의하게 증가되었지만 다른 이완제에 의해서는 유의한 차이가 없었다. PTU를 4주간 처치한 군에 있어서는 대조군에 비하여 혈관이완제에 대한 중간억제량은 유의한 차이가 없었지만, 12주 처치군에 있어서는 isoproterenol 및 nitroprusside에 대한 중간억제량은 감소 되었으나 acetylcholine 및 histamine에 대한 중간억제량은 유의한 차이가 없었다. 이상의 결과로 미루어 보아 PTU-처치에 의한 혈관 반응성의 변화는 혈관 내피세포보다는 혈관 평활근세포자체의 변화에 기인되며, 이러한 세포내의 변화는 갑상선 기능이 저하된 후에도 계속되고 있음을 알 수 있었다.

• 대한약리학회지
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• 제27권2호
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• pp.125-133
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• 1991

내피세포가 제거된 토끼의 적출 장간막 동맥에서 토끼의 대동맥 내피세포로 부터 A23187과 acetylcholine은 NO와 유사한 혈관 이완성 물질 (EDRF)을 유리한다. 이에 첨가하여 A23187은 acetylcholine과는 달리 superoxide anion에 의하여 파괴되지 않는 EDRF도 유리시킴을 확인하고 이의 특성에 대하여 연구하였다. 정상적인 생리영양액에서는 A23187과 acetylcholine의 용량-반응 곡선은 내피세포에 의존하지 않는 sodium nitroprusside의 곡선과 유사하였다. 이들은 methylene blue에 의하여 억제되었다. Hypoxanthine (HX)과 xanthine oxidase (XO)를 bath내로 투여시 phenylephrine에 의한 수축이 일과성으로 증가한 후 지속적으로 이완되었다. HX-XO 반응중에는 A23187은 장간막 동맥을 즉각적으로 이완시켰으나 acetylcholine의 이완작용은 소실되었다. A23187에 의하여 야기되는 장간막동맥의 이완은 50 mM $K^+-PSS$로 수축을 야기시켰을 때에는 나타나지 아니하였다. Superoxide dismutase를 전처치하였을 때는 HX-XO 반응중에도 acetylcholine 뿐만아니라 A23187에 의한 장간막 동맥의 수축은 이완되었다. 한편, acetylcholine에 의하여 야기되는 장간막 동맥의 이완은 A23187에 의하여 야기되는 이완에 비하여 phorbol 12-myristate 13-acetate (PMA)에 훨씬 더 민감하게 억제되었다. 내피세포의 기능과는 무관한 sodium nitroprusside에 의하여 야기되는 이완은 PMA에 의하여 영향을 받지 아니하였다. 이상의 결과로 미루어 볼때, A23187과 acetylcholine은 methylene blue에 의하여 억제되는 내피세포 의존성 이완을 야기시키고, 첨가하여 A23187은 어떤 병적 환경 아래서는 superoxide anion과 PMA에 저항성을 지닌 혈관이완성 물질을 유리하는 것으로 사료된다. 앞으로 A23187에 의하여 유리되는 혈관 이완성 물질이 superoxide anion에 의존하여 생성된 것인지에 대하여는 추후의 연구과제이다.

• The Korean Journal of Physiology and Pharmacology
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• 제24권4호
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• pp.339-348
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• 2020

We aimed to characterize the participation of rapid non-genomic and delayed non-genomic/genomic or genomic mechanisms in vasoactive effects to triiodothyronine (T3), emphasizing functional analysis of the involvement of these mechanisms in the genesis of nitric oxide (NO) of endothelial or muscular origin. Influences of in vitro and in vivo T3 treatments on contractile and relaxant responsiveness of isolated rat aortas were studied. In vivo T3-treatment was 500 ㎍·kg^-1·d^-1, subcutaneous injection, for 1 (T3_1d) and 3 (T3_3d) days. In experiments with endothelium-intact aortic rings contracted with phenylephrine, increasing concentrations of T3 did not alter contractility. Likewise, in vitro T3 did not modify relaxant responses induced by acetylcholine or sodium nitroprusside (SNP) nor contractile responses elicited by phenylephrine or angiotensin II in endothelium-intact aortas. Concentration-response curves (CRCs) to acetylcholine and SNP in endothelium-intact aortic rings from T3_1d and T3_3d rats were unmodified. T3_3d, but not T3_1d, treatment diminished CRCs to phenylephrine in endothelium-intact aortic rings. CRCs to phenylephrine remained significantly depressed in both endothelium-denuded and endothelium-intact, nitric oxide synthase inhibitor-treated, aortas of T3_3d rats. In endothelium-denuded aortas of T3_3d rats, CRCs to angiotensin II, and high K⁺ contractures, were decreased. Thus, in vitro T3 neither modified phenylephrine-induced active tonus nor CRCs to relaxant and contractile agonists in endothelium-intact aortas, discarding rapid non-genomic actions of this hormone in smooth muscle and endothelial cells. Otherwise, T3_3d-treatment inhibited aortic smooth muscle capacity to contract, but not to relax, in an endothelium- and NO-independent manner. This effect may be mediated by delayed non-genomic/genomic or genomic mechanisms.

• 대한수의학회지
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• 제43권4호
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• pp.573-578
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• 2003

The effects of removing the endothelium on the vasodilatory response to substance P, calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) was examined in the isolated rabbit renal artery. The vasodilator response to substance P ($0.1{\mu}M$) was completely absent in vessels in which the endothelium had previously been removed. There was no significant difference in the vasodilatation produced in response to CGRP ($0.1{\mu}M$), or VIP ($0.1{\mu}M$) in the intact and removed-endothelium rabbit renal artery segments. L-NAME ($100{\mu}M$) significantly reduced the vasodilatory response to substance P ($0.1{\mu}M$). This inhibition was significantly attenuated when L-arginine (10 mM) was also present in the organ bath along with L-NAME ($100{\mu}M$). Indomethacin ($1{\mu}M$) did not significantly affect the vasodilatation produced in response to substance P ($0.1{\mu}M$). The inhibitory effect of L-NAME ($100{\mu}M$) and indomethacin ($1{\mu}M$) on the vasodilatory response to substance P ($0.1{\mu}M$) was not significantly different from that produced by L-NAME ($100{\mu}M$) alone. This study indicates that substance P induced vasodilatation via an endothelium-dependent mechanism in the isolated rabbit renal artery. It also established that CGRP and VIP induced vasodilatation by an endothelium-independent mechanism and substance P-induced vasodilatation is at least partially via NO.

• The Korean Journal of Physiology and Pharmacology
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• 제18권5호
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• pp.377-381
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• 2014

Propofol is a widely used anesthetic. Many studies have shown that propofol has direct effects on blood vessels, but the precise mechanism is not fully understood. Secondary intrapulmonary artery rings from male rats were prepared and mounted in a Multi Myograph System. The following constrictors were used to induce contractions in isolated artery rings: high $K^+$ solution (60 mmol/L); U46619 solution (100 nmol/L); 5-hydroxytryptamine (5-HT; $3{\mu}mol/L$); or phenylephrine (Phe; $1{\mu}mol/L$). The relaxation effects of propofol were tested on high $K^+$ or U46619 precontracted rings. Propofol also was added to induce relaxation of rings preconstricted by U46619 after pretreatment with the nitric oxide synthase inhibitor $N^G$-nitro-L-arginine methyl ester (L-NAME). The effects of propofol on $Ca^{2+}$ influx via the L-type $Ca^{2+}$ channels were evaluated by examining contraction-dependent responses to $CaCl_2$ in the absence or presence of propofol (10 to $300{\mu}mol/L$). High $K^+$ solution and U46619 induced remarkable contractions of the rings, whereas contractions induced by 5-HT and Phe were weak. Propofol induced dose-dependent relaxation of artery rings precontracted by the high $K^+$ solution. Propofol also induced relaxation of rings precontracted by U46619 in an endothelium-independent way. Propofol at different concentrations significantly inhibited the $Ca^{2+}$-induced contractions of pulmonary rings exposed to high $K^+$-containing and $Ca^{2+}$-free solution in a dose-dependent manner. Propofol relaxed vessels precontracted by the high $K^+$ solution and U46619 in an endothelium-independent way. The mechanism for this effect may involve inhibition of calcium influx through voltage-operated calcium channels (VOCCs) and receptor-operated calcium channels (ROCCs).

• 대한수의학회지
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• 제57권3호
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• pp.181-187
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• 2017

Antihypertensive effects of ethanol extracts of Aralia elata (Miq.) Seem. (AE) were investigated in spontaneously hypertensive rats (SHR). SHR aged 14 weeks were treated for 8 weeks with AE (10 or 50 mg/kg/day) or amlodipine besylate (Am; 10 mg/kg/day) orally. Hypertension results in injury to several organs and can produce a significant increase in malondialdehyde (MDA) content as a result of lipid peroxidation and endothelial dysfunction. In this study, oral administration of AE and Am significantly reduced systolic blood pressure, organ weight index, and MDA content in tissues but increased significantly the plasma nitrite and nitrate concentrations. The endothelium-dependent relaxant activities of acetylcholine ($10^{-10}-10^{-3}M$) in norepinephrine (NE)-precontracted aorta were increased in AE- and Am-treated rats. Particularly strong endothelium-dependent relaxant activities were observed in AE-treated (50 mg/kg) rats. The endothelium-independent relaxant activities of sodium nitroprusside ($10^{-10}-10^{-3}M$) in NE-precontracted aorta were not changed. The results of this study suggest that AE has both antihypertensive and end-organ protective effects in SHR.

• 대한수의학회지
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• 제45권4호
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• pp.485-493
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• 2005

We studied the effects of trazodone on arterial blood pressure in anesthesized guinea pigs, and on vascular responses in isolated thoracic aorta. Trazodone produced a concentration-dependent relaxation in phenylephrine-precontracted endothelium intact (+E) rings, but not in a KCl-precontracted aortic rings. These relaxant effects of trazodone on +E rings were significantly greater than those on denuded (-E) rings. The trazodone-induced relaxation was suppressed by glibenclamide and tetrabutylammonium, but not by N(G)-nitro-L-arginine (L-NNA), N(omega)-nitro-L-arginine methyl ester (L-NAME), methylene blue (MB), nifedipine, indomethacin, 2-nitro-4-carboxyphenyl-n,n-diphenylcarbamate (NCDC) and clotrimazole. In vivo, infusion of trazodone elicited a significant decrease in arterial blood pressure. Trazodone-induced blood pressure lowering was markedly inhibited by intravenous pretreatment of prazosin but not by pretreatment of saponin, L-NNA, L-NAME, MB, nifedipine, glibenclamide, clotrimazole and NCDC. In addition, trazodone produced an increase in twitch force of isolated papillary muscle and left ventricular pressure of perfused heart. These findings suggest that the endothelium-independent vasorelaxant effect of trazodone may be explained by activation of $Ca^{2+}$-activated and ATP-sensitive $K^+$ channels, and the hypotensive effect of trazodone is not associated with cardiac contraction.

• The Korean Journal of Physiology and Pharmacology
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• 제22권6호
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• pp.713-719
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• 2018

Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are antidiabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by $1{\mu}M$ gemigliptin while not by saxagliptin and sitagliptin up to $10{\mu}M$. The ACh-EDR of SHR MA was also improved by $1{\mu}M$ gemigliptin while similar recovery was observed with higher concentration ($10{\mu}M$) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L-NAME. In the endothelium-denuded MA of SHR, sodium nitroprusside induced dose-dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with $30{\mu}M$ pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism.