• The Korean Journal of Physiology and Pharmacology
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• 제20권6호
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• pp.641-647
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• 2016

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling of pulmonary arteries (PAs) and increased vascular resistance in the lung. Monocrotaline (MCT), a toxic alkaloid, is widely used for developing rat models of PAH caused by injury to pulmonary endothelial cells; however, characteristics of vascular functions in MCT-induced PAH vary and are not fully understood. Here, we investigated hypoxic pulmonary vasoconstriction (HPV) responses and effects of various vasoconstrictors with isolated/perfused lungs of MCT-induced PAH (PAH-MCT) rats. Using hematoxylin and eosin staining, we confirmed vascular remodeling (i.e., medial thickening of PA) and right ventricle hypertrophy in PAH-MCT rats. The basal pulmonary arterial pressure (PAP) and PAP increase by a raised flow rate (40 mL/min) were higher in the PAH-MCT than in the control rats. In addition, both high $K^+$ (40 mM KCl)- and angiotensin II-induced PAP increases were higher in the PAH-MCT than in the control rats. Surprisingly, application of a nitric oxide synthase inhibitor, L-$N^G$-Nitroarginine methyl ester (L-NAME), induced a marked PAP increase in the PAH-MCT rats, suggesting that endothelial functions were recovered in the three-week PAH-MCT rats. In addition, the medial thickening of the PA was similar to that in chronic hypoxia-induced PAH (PAH-CH) rats. However, the HPV response (i.e., PAP increased by acute hypoxia) was not affected in the MCT rats, whereas HPV disappeared in the PAH-CH rats. These results showed that vascular contractility and HPV remain robust in the MCT-induced PAH rat model with vascular remodeling.

• Molecular & Cellular Toxicology
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• 제4권1호
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• pp.72-77
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• 2008

The present study was undertaken to determine whether pioglitazone treatment influences on the agonist-induced vascular smooth muscle contraction and, if so, to investigate the related mechanism. The measurement of isometric contractions using a computerized data acquisition system was combined with molecular experiments. Pioglitazone decreased Rho-kinase activating agonist-induced contraction but not phorbol ester-induced contraction suggesting the least involvement of $Ca^{2+}$-independent thin filament regulation of contractility. Furthermore, pioglitazone decreased thromboxane $A_2$ mimeticinduced phosphorylation of MYPT1 at Thr855, the newly-highlighted site, instead of Thr696. In conclusion, this study provides the evidence and possible related mechanism concerning the vasorelaxing effect of pioglitazone as an antihypertensive on the agonist-induced contraction in rat aortic rings regardless of endothelial function.

• 약학회지
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• 제56권3호
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• pp.180-185
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• 2012

The aim of present study was to investigate the possible influence and related mechanism of alcohol on the arterial contraction. Vascular contraction involves the activation of thick or thin filament pathway. However, there are no reports addressing the question whether this pathway is involved in alcohol-induced regulation. We hypothesized that alcohol plays a role in vascular contraction evoked by a vasoconstrictor in rat aortae regardless of endothelial function. Denuded arterial rings from male rats were used and isometric contractions were recorded using a computerized data acquisition system. Interestingly, alcohol at a low concentration (3% v/v) inhibited thromboxane $A_2$ or phorbol ester-induced contraction with endothelial function but at a high concentration (10%) didn't inhibit and rather increased the contraction in the denuded muscle. Therefore, alcohol at a low concentration decreases the contraction and alcohol at a high concentration increases the contraction suggesting that additional pathways different from endothelial nitric oxide synthesis might be involved in the regulation of contractility. In conclusion, alcohol has some effect on the regulation of contractility regardless of endothelial function.

• Biomolecules & Therapeutics
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• 제26권2호
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• pp.139-145
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• 2018

The present study was undertaken to investigate the influence of hypothermia on endothelium-independent vascular smooth muscle contractility and to determine the mechanism underlying the relaxation. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Hypothermia significantly inhibited fluoride-, thromboxane $A_{2-}$, phenylephrine-, and phorbol ester-induced vascular contractions regardless of endothelial nitric oxide synthesis, suggesting that another pathway had a direct effect on vascular smooth muscle. Hypothermia significantly inhibited the fluoride-induced increase in pMYPT1 level and phorbol ester-induced increase in pERK1/2 level, suggesting inhibition of Rho-kinase and MEK activity and subsequent phosphorylation of MYPT1 and ERK1/2. These results suggest that the relaxing effect of moderate hypothermia on agonist-induced vascular contraction regardless of endothelial function involves inhibition of Rho-kinase and MEK activities.

• 한국생물물리학회:학술대회논문집
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• 한국생물물리학회 2001년도 학술 발표회 진행표 및 논문초록
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• pp.24-24
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• 2001

The present study was undertaken to determine whether p38 mitogen-activated protein kinase participates in the regulation of vascular smooth muscle contraction by endothelin-I (ET-1) in rat thoracic aorta. ET-1 induced a sustained contraction. In contrast, both the intracellular Ca$\^$2＋/ and myosin light chain (MLC) phosphorylations were not sustained.(omitted)

• 약학회지
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• 제58권4호
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• pp.223-228
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• 2014

The present study was undertaken to investigate the influence of sulforaphane on vascular smooth muscle contractility and to determine the mechanism involved. We hypothesized that sulforaphane, the primary ingredient of broccoli of cruciferous vegetables, plays a role in vascular relaxation through inhibition of Rho-kinase in rat aortae. Intact of denuded arterial rings from male Sprague-Dawley rats were used and isometric tensions were recorded using a computerized data acquisition system. Interestingly, sulforaphane significantly inhibited fluoride, phorbol ester or thromboxane $A_2$ mimetic-induced contraction in denuded muscles suggesting that additional pathways different from endothelial nitric oxide synthesis such as inhibition of Rho-kinase or MEK might be involved in the vasorelaxation. Furthermore, sulforaphane inhibited thromboxane $A_2$-induced increases in pERK1/2 levels suggesting the mechanism including inhibition of thromboxane $A_2$-induced increases in ERK1/2 phosphorylation. This study provides evidence that sulforaphane induces vascular relaxation through inhibition of Rho-kinase or MEK in rat aortae.

• 약학회지
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• 제57권5호
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• pp.376-381
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• 2013

The present study was undertaken to investigate the influence of curcumin on vascular smooth muscle contractility and to determine the mechanism involved. We hypothesized that curcumin, the primary ingredient of Curcuma longa, plays a role in vascular relaxation through inhibition of Rho-kinase in rat aortae. Denuded arterial rings from male Sprague-Dawley rats were used and isometric tensions were recorded using a computerized data acquisition system. Interestingly, curcumin inhibited fluoride-induced contraction but didn't inhibit phorbol ester-induced contraction suggesting that additional pathways different from endothelial nitric oxide synthesis might be involved in the vasorelaxation. Furthermore, curcumin significantly inhibited fluoride-induced increases in pMYPT1 levels. On the other hand, it didn't significantly inhibit phorbol ester-induced increases in pERK1/2 levels suggesting the mechanism involving inhibition of fluoride-induced MYPT1 phosphorylation. This study provides evidence that curcumin induces vascular relaxation through inhibition of Rho-kinase in rat aortae.

• The Korean Journal of Physiology
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• 제29권2호
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• pp.279-289
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• 1995

This study was designed 1) to develop a hypertensive animal model in which the blood pressures (BPs) of symmetric regions (right and left upper extremities) are significantly different and 2) to test the effect of BP per se on the contractility and endothelium-dependent relaxation of vascular smooth muscle. Rabbits were anesthetized with sodium pentobarbital and ventilated with room air via animal respirator. The transverse aorta was exposed through the left second intercostal space and the lumen of the aorta was narrowed partially by ligation using 3-0 silk and a probe at a point between the origins of the brachiocephalic trunk and the left subclavian artery. Four to eight weeks postoperatively, BPs were measured in the carotid artery as the high BP area (proximal to coactation site) and in the femoral artery as the low BP area (distal to coarctation site). In the animal model, pressure-overload hypertension was developed and the BP of the right subclavian artery was higher than that of the left subclavian artery. The concentrations of circulating epinephrine, norepinephrine, angiotensin I, and angiotensin II were measured. The right and left subclavian arteries and their branches were used for isometric tension recording in organ baths and their responsiveness to phenylephrine, serotonin, acetylcholine, and sodium nitroprusside were examined. The BPs of carotid and femoral artery in control animals were $116{\pm} 12/75{\pm}9\;mmHg (mean ${\pm}SEM$) and $130{\pm}16/68{\pm}9\;mmHg$ respectively, while those of carotid and femoral artery in the hypetensive animals were $172{\pm}6/111{\pm}10\;mmHg$ and 136{\pm} 4/100 {\pm}9\;mmHg$ respectively. There were no significant differences in the concentrations of circulating epinephrine, norepinephrine, angiotensin I, and angiotensin II between controls and the animal models. No significant differences were found in the vascular sensitivities to phenylephrine and serotonin between the high pressure-exposed vessels and the low pressure-exposed vessels. However, the endothelium-dependent relaxation to acetylcholine and nitroprusside-induced relaxation showed significant differences between the high pressure-exposed and the low pressure-exposed subclavian arteries. From the above results, we suggest that the contractility of vascular smooth muscle is unchanged by the elevated pressure per se. However, the endothelium-dependent relaxation to acetylcholine and the nitroprusside-induced relaxation are attenuated by pressure.

• Journal of Chest Surgery
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• 제43권4호
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• pp.345-355
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• 2010

산성화를 초래하는 Hypoxia 등 여러 가지 조건에서 변화하는 세포외 pH 변화는 궁극적으로 세포내 pH 변화를 유발하며 세포 내외 pH 변화는 혈관평활근 수축성 변화를 유발한다. 이러한 세포 내외 pH 변화에 의한 혈관 수축성 변화 기전을 규명하고자, pH 변화가 혈관수축인자들에 의한 혈관평활근 수축, 혈관평활근세포내 $Ca^{2+}$ 농도, 그리고 혈관평활근의 $Ca^{2+}$에 대한 민감도에 미치는 영향을 알아보고자 하였다. 대상 및 방법: 쥐에서 분리한 상장간막동맥과 그 분지에서 등장성 수축을 기록하였으며 배양한 상장간막동맥 세포에서 세포내 $Ca^{2+}$ 변화를 측정하였다. 세포외 pH는 정상인 7.4에서 6.4, 6.9 혹은 7.8로 변화시켰으며, 세포내 pH 변화는 propionic acid나 $NH_4$를 투여하거나 ${\beta}$-escin으로 세포막의 투과성을 증가시켜 세포외 용액의 pH 변화로 유발시켰다. 결과: 세포외 pH를 7.4에서 6.9, 6.4로 감소시키면 노에피네프린과 세로토닌에 의한 용량-반응 곡선이 우측 이동하였으며 최대 수축력의 50% 수축력을 유발하는 농도(half maximal effective concentration)가 증가하였고, pH를 7.8로 증가시키면 그 반대 현상이 일어났다. 노에피네프린은 배양한 혈관평활근세포에서 세포내 $Ca^{2+}$ 농도를 증가시켰으며, 이 세포내 $Ca^{2+}$ 증가는 세포외 pH 감소에 의하여 억제되었으며 세포외 pH 증가에 의하여 증가하였다. 노에피네프린에 의한 수축은 세포내 pH를 감소시키는 $NH_4$에 의하여 억제된 반면, 안정 장력은 $NH_4$과 propionic acid에 의하여 증가하였다. ${\beta}$-escin으로 세포막의 투과도를 증가시킨 후 세포외 용액의 $Ca^{2+}$ 농도를 증가시켜 수축을 유발시킨 후 세포외 용액의 pH를 변화시키면 pH 감소에 의하여 수축력이 감소하였으며 증가에 의하여 수축력이 증가하였다. 결론: 세포외 pH의 감소는 혈관평활근의 수축성을 감소시키는데 이는 세포외 pH 감소에 의한 혈관평활근의 혈관수축물질에 대한 반응성 감소, 혈관평활근 세포내 $Ca^{2+}$ 유입 억제 그리고 $Ca^{2+}$에 대한 혈관평활근의 민감성 감소에 의하여 일어난 것으로 추정할 수 있었다.

• Journal of Chest Surgery
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• 제28권12호
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• pp.1079-1095
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• 1995

Recently endogenous digitalis-like substances were found in the blood of various cardiovascular diseases and they have been considered one of the causes of evoking hypertension. However, the mechanism of endogenous digitalis-like substances-induced hypertension is not clarified yet. Therefore, the effects of Na-K pump inhibition on the contractility of vascular smooth muscle[conduit and resistant artery were investigated, using organ bath and bioassay experiment. Aortic and carotid arterial rings[conduit artery and the branches of brachial and superior mesenteric artery[resistant artery were used to find the effect of Na-K pump inhibition. The results obtained were as followes;The magnitudes of contractions induced by norepinephrine, serotonin, or acetylcholine in all these arteries were significantly increased by the inhibition of Na-K pump. The increased contractile responses to these agonists, especially to serotonin, were much more prominant in resistant arteries. Nitroprusside-induced relaxations were attenuated by Na-K pump inhibition and there were no significant differences in the effects of Na-K pump inhibition on nitroprusside-induced relaxations of these blood vessels. Endothelium-dependent relaxation was suppressed by the inhibition of Na-K pump, especially by the administration of ouabain, and this inhibitory effect was much more prominent in the branches of superior mesenteric artery, compared with other arteries. In the branches of superior mesenteric arteries, endothelium-dependent relaxation was completely blocked by ouabain. The release of EDRF was partially suppressed by Na-K pump inhibition.From the above results, it is suggested that the hypertension due to the increase in vascular resistance can be evoked by the inhibition of Na-K pump and endogenous digitalis-like substances induce hypertension through this mechanism.