• Title/Summary/Keyword: Endothelium-independent relaxation

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Mechanism of the relaxant action of imipramine in isolated rat aorta (흰쥐 대동맥에서 imipramine의 혈관이완 작용기전)

  • Kang, Hyung-sub;Lee, Sang-woo;Baek, Sung-su;Joe, Sung-gun;Kim, Jin-shang
    • Korean Journal of Veterinary Research
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    • v.43 no.4
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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.

The Relaxant Effect of Propofol on Isolated Rat Intrapulmonary Arteries

  • Zhang, Guangyan;Cui, Jianxiu;Chen, Yijing;Ma, Jue
    • The Korean Journal of Physiology and Pharmacology
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    • v.18 no.5
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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).

Vasorelaxant and hypotensive effects of trazodone in Guinea pig (기니픽에서 trazodone의 혈관 이완 및 혈압 하강 효과)

  • Kim, Shang-Jin;Kang, Hyung-Sub;Kim, Jin-Shang
    • Korean Journal of Veterinary Research
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    • v.45 no.4
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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.

Vasorelaxant properties of cyclic nucleotide phosphodiesterase inhibitors in rat aorta (흰쥐 대동맥에서 cyclic nucleotide phosphodiesterase 억제제들의 혈관 이완 특성)

  • Kang, Hyung-sub;Choi, Cheol-ho;Kim, Jin-shang
    • Korean Journal of Veterinary Research
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    • v.43 no.4
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    • pp.615-624
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    • 2003
  • Vascular smooth muscle relaxation is modulated by an increase in cGMP subsequent to nitric oxide (NO) production by endothelial cells. The effects of cAMP and cGMP phosphodiesterase (PDE) inhibitors were investigated in phenylephrine-precontracted rat aorta rings by using the specific inhibitors of PDE I, III, IV and V as relaxing agents (calmodulin-activated PDE inhibitors, IBMX and $W_7$, type I; cAMP-specific PDE inhibitors, milrinone, type IV; Ro 20-1724, type III and cGMP-specific PDE inhibitor, zaprinast, type V). All the PDE inhibitors produced a concentration-dependent relaxation in the ring with intact endothelium (+E). Except for milrinone, all the PDE inhibitors-induced relaxations were inhibited by removal of extracellular $Ca^{2+}$, $N^G$-nitro-L-arginine, $N^G$-nitro-L-arginine methyl ester, methylene blue (MS) or nifedipine. The specific PDE I and PDE IV inhibitors both produced endothelium-independent relaxations which were inhibited by MS in -E rings. However, zaprinast had no effect in -E rings. Except for milrinone, sodium nitroprusside (a NO donor)-induced relaxation was significantly augmented by all PDE inhibitors in +E rings. The results suggest that I) the vasorelaxant properties of IBMX, $W_7$, Ro 20-1724 and zaprinast are dependent on endothelium or on interaction with $Ca^{2+}$ regulation, 2) each PDE is differently distributed in vascular tissues (endothelial and smooth muscle cells), 3) the vasodilations of PDE inhibitors are due to the increase of cAMP and cGMP formation through inhibition of cAMP- and cGMP-PDE and 4) the vasodilation action of milrinone does not involve in endothelial-cyclic nucleotide system.

Vasodilation of Ethanol Extract of Cinnamomi Ramulus via Voltage Dependent $Ca^{2+}$ Channel Blockage (전압의존성 $Ca^{2+}$ 통로 억제를 통한 계지(桂枝) 에탄올 추출물의 혈관이완 효능)

  • Kim, Jong-Bong;Shin, Heung-Mook
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.24 no.4
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    • pp.592-597
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    • 2010
  • Cinnamomi Ramulus is one of the medicinal plants that have been used to improve various diseases caused by insufficient blood circulation. This study was performed for the investigation of vasodilation efficacy ethanol extract of Cinnamomi Ramulus (CR). CR exhibited vascular relaxation against phenylephrine (PE, $10^{-6}M$)-, KCl- and NaF-induced contraction in rat thoracic aorta. In addition, its relaxation was endothelium-independent. Treatment of potassium channel blockers such as gilbenclamide (Gli, $10^{-5}M$), tetraethylammonium (TEA, 1 mM) and 4-aminopyridine (4-AP, 0.2 mM) did not effect on the relaxation of CR. The relaxant effects were also not inhibited by pre-treatment of rat aorta with L-NAME ($10^{-4}M$), methylene blue ($10^{-5}M$), indomethacin ($10^{-5}M$), and atropine ($10^{-6}M$). However, nifedipine ($10^{-5}M$), L-type $Ca^{2+}$ channel blocker, in part attenuated the relaxation of CR ($0.2\;mg/m{\ell}$), but SK&F96365 ($3{\times}10^{-5}M$), receptor activated $Ca^{2+}$ channel blocker and 2-APB ($10^{-4}M$), store operated $Ca^{2+}$ channel blocker did not affact dilation of CR. These findings suggest that the endothelium-independent relaxation effect of CR is partly related with inhibition of $Ca^{2+}$ influx via voltage dependent $Ca^{2+}$ channel.

Endothelium Independent Effect of Pelargonidin on Vasoconstriction in Rat Aorta

  • Min, Young Sil;Yoon, Hyuk-Jun;Je, Hyun Dong;Lee, Jong Hyuk;Yoo, Seong Su;Shim, Hyun Sub;Lee, Hak Yeong;La, Hyen-Oh;Sohn, Uy Dong
    • Biomolecules & Therapeutics
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    • v.26 no.4
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    • pp.374-379
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    • 2018
  • In this study, we investigated the effects of pelargonidin, an anthocyanidin found in many fruits and vegetables, on endothelium-independent vascular contractility to determine the underlying mechanism of relaxation. Isometric contractions of denuded aortic muscles from male rats were recorded, and the data were combined with those obtained in western blot analysis. Pelargonidin significantly inhibited fluoride-, thromboxane A2-, and phorbol ester-induced vascular contractions, regardless of the presence or absence of endothelium, suggesting a direct effect of the compound on vascular smooth muscles via a different pathway. Pelargonidin significantly inhibited the fluoride-dependent increase in the level of myosin phosphatase target subunit 1 (MYPT1) phosphorylation at Thr-855 and the phorbol 12,13-dibutyrate-dependent increase in the level of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation at Thr202/Tyr204, suggesting the inhibition of Rho-kinase and mitogen-activated protein kinase kinase (MEK) activities and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxation effect of pelargonidin on agonist-dependent vascular contractions includes inhibition of Rho-kinase and MEK activities, independent of the endothelial function.

Potentiation of endothelium-dependent vasorelaxation of mesenteric arteries from spontaneously hypertensive rats by gemigliptin, a dipeptidyl peptidase-4 inhibitor class of antidiabetic drug

  • Kim, Hae Jin;Baek, Eun Bok;Kim, Sung Joon
    • The Korean Journal of Physiology and Pharmacology
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    • v.22 no.6
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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.

Signaling Mechanisms on the Vascular Relaxation of HMC05 (HMC05의 혈관이완 활성과 신호전달 작용기전)

  • Moon, Kug-Jin;Jang, Hyo-Oil;Kim, Gil-When;Shin, Heung-Mook
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.22 no.2
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    • pp.315-320
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    • 2008
  • This study investigated the signaling mechanisms contributed to the vasodilatory effects of HMC05, a herbal prescription. HMC05 acted in an endothelium-independent manner. To elucidate the fundamental mechanisms of its vascular actions, we focused on the signaling molecules involved in actin-myosin filament regulation including 20 kDa myosin light chains (LC20), Rho-associated kinase (ROCK), PKC, JNK and extracellular signal-regulated protein kinase (ERK) in the endothelium-denuded thoracic aorta or isolated smooth muscle cells (SMCs). It lowered the phosphorylation level of LC20 and showed that ROCK, ERK, JNK and $PKC{\alpha}$ pathways played important roles in the effects, as confirmed by the observations with a specific inhibition or activation, and with the activity and the subcellular localization of these molecules. In particular, HMC05 dramatically inhibited the activity of ERK and the downstream signaling of ROCK. It also changed the subcellular localization of the phophorylated $PKC{\alpha}$ as well as the amount of phosphorylation. Taken together, these data indicate that the vascular relaxation effects of HMC05 are attributed to the regulation of these signaling mechanisms.

Effects of Cnidium officinale, Petasites japonicus, Coptis chinensis Extract Mixture on Vasodilation (천궁(川芎), 머위, 황련(黃連) 추출물 조성의 $Ca^{2+}$ 유입 억제를 통한 혈관이완 효능)

  • Kim, Sang-Dae;김길훤, Gil-Whon;Shin, Heung-Mook
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.20 no.6
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    • pp.1620-1624
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    • 2006
  • This study was performed to investigate a vasodilatory efficacy and its underlying mechanisms of the mixture of Cnidium officinale, Petasites japonicus and Coptis chinensis (CPC), CPC relaxed rat aortic vascular strips in endothelium-independant manner precontracted with phenylephrine or KCI(50mM), but the magnitude of relaxation was greater in KCI induced contraction. L-NAME, iNOS inhibitor, and methylen blue(MB), cGMP inhibitor, did not attenuate the relaxation responses of CPC. Furthermore, the contraction by increaseing $Ca^{2+}$ concentration (0.3-10.0mM) to a $Ca^{2+}$-free high $K^+$ (60mM) was significantly reduced by CPC pretreatment. These results suggest that the relaxation effect of CPC is related with the block of $Ca^{2+}$ influx via $Ca^{2+}$ channel.

Effects of Sunghyangchungisan on contractile Reactivity of Isolated Rabbit Carotid Artery (성향정기산(星香正氣散)이 가토(家?)의 경동맥(頸動脈) 평활근(平滑筋) 긴장도(緊張度) 조절(調節)에 미치는 영향(影響))

  • Kim, Young-Kyun;Ko, Woo-Shin;Kim, Jong-Hoon
    • The Journal of Korean Medicine
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    • v.19 no.2
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    • pp.228-243
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    • 1998
  • This study was undertaken to evaluate the effect of Sunghyangchungisan (SHCS) on the regulation of vascular tone. Vascular rings isolated from rabbit carotid artery were myographed isometrically in isolated organ baths and the effect of SHCS on contractile activities were determined. SHCS relaxed the arterial rings which were pre-contracted by phenylephrine(PE). The responses to SHCS were partially dose-dependent at concentrations lower than 0.5 mg/ml. When SHCS was applied prior to the exposure to PE, it inhibited the PE-induced contraction by a similar magnitude which was comparable to the relaxation of pre-contracted arterial rings. Washout of SHCS after observing its relaxant effect resulted in a full recovery of PE-induced contractions, indicating that the action mechanism is reversible. The observation that SHCS did not change the $ED_{50}$ of PE on its dose-response curve ruled out the possible interaction of SHCS and ${\alpha}-receptor$. The relaxant effect of SHCS was not affected by removal of endothelium, and pretreatment of the arterial rings with methylene blue or nitro-L-arginine. This results suggest that the action of SHCS is not mediated by endothelium nor soluble guanylate cyclase. SHCS relaxed high $K^{+}-induced$ contractions as well, whereas it failed to relax phorbol ester-induced contractions. When contraction was induced by additive application of $Ca^{2+}$ in arterial rings which were pre-depolarized by high $K^+$ in a $Ca^{2+}-free$ solution, the relaxant effect of SHCS was attenuated by increasing the $Ca^{2+}$ concentration. SHCS, when applied to the arterial rings pre-contracted by PE and then relaxed by nifedipine, a $Ca^{2+}$ channel blocker, did not show additive relaxation. From above results, it is suggested that SHCS relax PE-induced contraction of rabbit carotid artery in an endothelium-independent manner, and inhibition of $Ca^{2+}$ influx may contribute to the underling mechanism.

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