• The Korean Journal of Physiology and Pharmacology
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• 제5권1호
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• pp.47-53
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• 2001

Drinking excessive alcohol has been recognized as a risk factor for hypertension. However, the mechanism by which alcohol intake causes hypertension still remains elusive. We tested the hypothesis that ethanol itself acts as a stress factor on vasculature and indirectly modulates vascular contractility. After end of exposure to 1, 2.5 and 5% ethanol for 45 min, rat aortic strips were subjected to contractile responses, immunoblot for Hsp70 and the measurement of levels of myosin light chain phosphorylation. Exposure to 5% ethanol not only augmented contractions to KCl or phenylephrine, but also increased expression of Hsp70 and the levels of myosin light chain phosphorylation. There were no significant differences in contractions produced by $1\;{\mu}mol/L$ phorbol 12,13-dibutyrate, a protein kinase C activator, whether the tissues were exposed to 5% ethanol or not. This is the first report to show that even short exposure to ethanol has a delayed effect to increase vascular smooth muscle contractility through a modulation of thick filament regulation. It may be a mechanism by which ingestion of alcohol induces hypertension.

• Experimental and Molecular Medicine
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• 제50권12호
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• pp.11.1-11.9
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• 2018

Estrogen has diverse effects on cardiovascular function, including regulation of the contractile response to vasoactive substances such as serotonin. The serotonin system recently emerged as an important player in the regulation of vascular tone in humans. However, hyperreactivity to serotonin appears to be a critical factor for the pathophysiology of hypertension. In this study, we examined the modulatory mechanisms of estrogen in serotonin-induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. $17{\beta}$-Estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aortic strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes are not mediated by estrogen receptor. Patch-clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which was significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK293T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerts vasodilatory effects on serotonin-precontracted arteries via Src, implying a critical role for estrogen in the prevention of vascular hyperreactivity to serotonin.

• Molecules and Cells
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• 제23권2호
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• pp.175-181
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• 2007

The present study was undertaken to determine whether $SM22{\alpha}$ participates in the regulation of vascular smooth muscle contractility using $SM22{\alpha}$ knockout mice and, if so, to investigate the mechanisms involved. Aortic ring preparations were mounted and equilibrated in organ baths for 60 min before observing contractile responses to 50 mM KCl, and then exposed to contractile agents such as phenylephrine and phorbol ester. Measurement of isometric contractions using a computerized data acquisition system was combined with molecular or cellular experiments. Interestingly, the aortas from $SM22{\alpha}$-deficient mice ($SM22^{-/-LacZ}$) displayed an almost three-fold increase in the level of $SM22{\beta}$ protein compared to wild-type mice, but no change in the levels of caldesmon, actin, desmin or calponin. $Ca^{2+}$-independent contraction in response to phenylephrine or phorbol ester was significantly decreased in the $SM22{\alpha}$-deficient mice, whereas in the presence of $Ca^{2+}$ neither contraction nor subcellular translocation of myosin light chain kinase (MLCK) in response to phenylephrine or 50 mM KCl was significantly affected. A decrease in phosphorylation of extracellular signal regulated kinase (ERK) 1/2 was observed in the $SM22{\alpha}$-deficient mice and this may be related to the decreased vascular contractility. Taken together, this study provides evidence for a pivotal role of $SM22{\alpha}$ in the regulation of $Ca^{2+}$-independent vascular contractility.

• Journal of Yeungnam Medical Science
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• 제23권1호
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• pp.36-44
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• 2006

진통과 해열작용을 가진 NSAIDs는 소화기계에 대한 부작용 때문에 COX-2 선택성 억제제로 대체되고 있다. 그러나 COX-2 선택적 억제제는 심혈관계에 대한 부작용이 보고되고 있어 혈관 평활근에 대한 직접적인 연구가 필요하다. 이에 본 연구에서는 혈관 반응성에 미치는 celecoxib와 aspirin, indomethacin의 영향을 비교 분석하였다. 또한 COX-1, COX-2 단백질 발현에 대한 indomethacin과 NO 공여제의 영향을 조사하였다. Phenylephrine 유발 수축반응에서 전처치 된celecoxib, indometacin, aspirin 순서로 혈관 반응성을 증가시켜, cyclooxygenase를 억제하면 혈관 수축성물질에 대한 반응성이 커질 수 있음을 나타낸다. 이중 cyclooxygenase에 대해 비가역적으로 강한 억제를 나타내는 aspirin이 제일 강한 효과를 나타내어 여기에 대한 연구는 더 필요할 것으로 생각된다. 혈관평활근 세포의 COX-2 단백질 발현은 indomethacin과 SNP, NOR-3 처치에 의해 증가되었으며, LPS를 이용하여 혈관염증을 유발 시키는 경우 혈관평활근 세포의 COX-2 단백질 발현이 증가되었고, 이 상태에서 SNP $100{\mu}M$ 전처치로 COX-2 단백질 발현을 감소되었으며, NOR-3 $100{\mu}M$은 COX-2 단백질 발현을 증가시켰다. LPS 유도 nitrite 생성에서 NOR-3는 SNP 보다 더 많은 nitrite를 생성시켰다. 이는 혈관의 수축반응에서 aspirin은 강한 상승작용을 유발하고, 혈관평활근 세포의 COX-2 발현은 NO 공여제, 혈관염증 유무에 따라 차이가 있는 것을 나타낸다.

• 대한약리학회지
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• 제26권1호
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• pp.25-33
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• 1990

가토의 적출동맥평활근 절편에 대한 peptide YY(PYY)의 수축작용을 관찰하고, PYY의 수축기전상 동원되는 칼슘의 기원을 조사하여 다음과 같은 결과를 얻었다. 각 동맥의 나선형 절편은 PYY의 실험조내 첨가에 의하여 농도의존적인 수축반응을 보였다. 그중 대퇴동맥이 가장 강력하고 예민한 수축경향을 보였으며, 그 다음은 대뇌의 기저동맥, 총장골동맥, 상장간막동맥, 신동맥, 총경동맥의 순으로 예민하였다. PYY에 대한 반응성을 Norepinephrine(NE)에 대한 반응성과 비교해볼때, 총경동맥과 신동맥은 PYY보다 NE에 대해서 유의하게 $(p{\leqslant}0.05)$예민하였고, 기저동맥은 NE보다 PYY에 더 예민하였다$(p{\leqslant}0.05)$. 대퇴동맥 절편에서 칼슘통로봉쇄제인 verapamil과 세포내 저장칼슘유리를 억제하는 3,4,5-Trimethoxybenzoic acid 8-(diethylamino)octyl ester ${\ulcorner}TMB-8{\lrcorner}$는 각각 PYY에 의한 수축을 억제하였는데 $(p{\leqslant}0.05)$, verapamil과 TMB-8이 동시에 존재할 때는 PYY에 의한 수축은 거의 완전히 억제되었고, ethyleneglycol-bis-(beta-aminoethyl ether), N,N,N‘,N’-tetraacetic acid${\ulcorner}EGTA{\lrcorner}$0.5mM를 첨가한 칼슘배제용액 내에서도 PYY에 의한 수축은 거의 완전히 억압되었다. 이상의 결과를 종합하면, 혈중 PYY가 증가했을 때는 교감신경계흥분시보다 강한 뇌혈관의 수축이 일어날 수 있으며, 뇌동맥압은 교감신경계 흥분시보다 더 높을 수가 있으리라 추정된다. 또 PYY에 의한 혈관 평활근 수축에는 세포외액의 칼슘과 세포내저장칼슘의 이용이 공히 필수적이라고 생각된다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.217-217
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• 1994

Calcium entry blockers, capable of inhibiting transmembrane influx of extracellular calcium through specific calcium channels, are useful drugs in the treatment of angina pectoris, hypertension, cardiac arrythmia, and various cardiovascular disorders. Compounds having isoquinoline structures have recently been reported to possess calcium antagonistic action. Therefore, in the present study, we have attempted to synthesize some isoquinoline and related compound.; in order to search for potentially effective chemicals acting on cardiovascular system, and evaluated their pharmacological properties focusing on calcium antagonistic actions. Almost all of the compounds so far synthesized, had inhibitory action against phenylephrine or high potassium-induced contraction in vascular smooth muscle with different degrees of potencies depending on their structures, However, some of tetrahydroisoquinoline analogs showed directly inhibit calcium current in isolated rabbit cardiac myocytes examined by patch clamp techniques. The pharmacological properties of these compounds need more intensive investigation as to whether these chemicals may have developed as a new cardiovascular active drugs. Therefore, we are now under investigation of the mechanism of action of these compounds.

• 약학회지
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• 제41권5호
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• pp.666-671
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• 1997

We studied effects of genistein and tyrphostin, inhibitors of tyrosine kinase, on contractions induced by high $K^+$ and norepinephrine in rat aorta. Genistein $(10^{-6}{\sim}10^{-4}M)$ and tyrphostin ($(10^{-5}{\sim}10^{-4}M)$) inhibited high $K^+$ and norepinephrine-induced sustained contractions, respectively in a concentration-dependent manner. High $K^+$ and norepinephrine caused an increase in $^{45}Ca^{2+}$ uptake while $10^{-4}M$ genistein and tyrphostin inhibited the $K^+$ and norepinephrine-increased $^{45}Ca^{2+}$ uptake, respectively. These results show that inhibitor of tyrosine kinase blocks the voltage-and receptor-operated $Ca^{2+}$ channels in rat aorta, respectively.

• Journal of Ginseng Research
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• 제21권2호
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• pp.125-132
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• 1997

Our previous study showed that in vivo treatment of spontaneously hypertensive rats (SHR) with protopanaxatriol ginsenosides (PPT) reduces the blood pressure and inhibits the con- tractions induced by endothelium-derived contracting factor (prostaglandin endoperoxide ($PGH_2$) and superoxide anion) in aorta isolated from SHR. The aim of the present study is to examine whether PPT improves endothelial functions in the isolated thoracic aorta of SHR in vitro. Treatments of aortic rings with PPT, purified ginsenoside $Rg_1$ ($Rg_1$) or indomethacin normalized endotheliuln-dependent relaxation to acetylcholine, but not with protopanaxadiol ginsenosides (PPD) and purified ginsenoside Rb1 (Rb1). The effects of PPT were dose-dependent. PGH,- and oxygen free radical-inducted contractions in rat aorta without endothelium were inhibited by PPT or $Rg_1$, but not by PPD or $Rb_1$. Contractions induced by PGF2$\alpha$, U-46619, a stable thromboxane A2 agonist or KCI (60 mM) were not inhibited by PPT, $Rg_1$ or $Rb_1$. These findings demonstrate that PPT but not PPD scavenges the oxygen-derived free radicals and/or antagonize the effects of $PGH_2$ in the vascular smooth muscle and may explain the hypotensive effect of ginseng in the SHR.

• Korean Journal of Acupuncture
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• 제17권1호
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• pp.75-80
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• 2000

Fructus Aristolochiae has been used in Korea for many centuries as a treatment for various disease.The purpose of the present study is to determine the effect of Fructus Aristolochiae on norepinephrine(NE) induced blood vessel contraction in rabbits. Rabbit(2 kg, male) were killed by $CO_2$ exposure and a segment (8-10mm) of each rabbit was cut into equal segments and mounted in a tissue bath. Contractile force was measured with force displacement transducers under 2-3 g loading tension. The dose of norepinephrine(NE) which evoked 50% of maximal response ($ED_{50}$) was obtained from cumulative dose response curves for NE ($10^{-6}{\sim}10^{-3}M$). Contractions evoked by NE ($ED_{50}$) were inhibited significantly by Fructus Aristolochiae in abdominal aorta and femoral artery. Fructus Aristolochiae inhibited the relaxation pretreated propranolol and L-NNA in femoral artery. But Fructus Aristolochiae did not effect the relaxation pretreated ODQ in femoral artery and abdominal aorta. These results indicate that Fructus Aristolochiae can relax NE induced contraction of rabbit blood vessel selectively, and that this relaxation relates to nitric oxide synthesis and sympathetic action.

• 대한약리학회지
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• 제30권1호
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• pp.101-109
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• 1994

Tetrahydroisoquinoline유도체인 GS 283의 약리학적 특성을 흰쥐 흉부대동맥, 기니픽 결장띠 및 토끼 장간막 동맥 및 흰쥐 뇌를 사용하여 조사하였다. 혈관 평활근에서 GS283은 고 $K^+$에 의한 수축을 농도 의존적으로 억제하여 $Ca^{2+}$ 길항작용을 보였다. 또한 ${alpha}_1$- 수용체 자극에 의한 수축도 억제하였다. GS 283의 혈관이완 작용은 propranolol영향을 받지 않으므로 ${\beta}$-수용체 자극작용에 의한 것이 아니었다. 세포내 칼슘이온과 근장력 변화를 동시에 측정하였을 때 GS 283의 억제효과는 조직내 형광의 증가를 수반했다. 이 증가는 fura 2형광에 의한것이 아니라 내인성 pyridine nucleotide에 의한 것이며 이는 GS 283이 미토콘드리아 기능을 억제하는 효과가 있음을 시사했다. 흰쥐 뇌의 cAMP와 cGMP 의존성 phosphodiesterase에 대한 GS 283의 $K_i$,값은 2.5와 6.7mM이었다. 이상의 결과에서 GS 283의 약리 작용은 $Ca^{2+}$ 길항작용, ${\alpha}_1$- 수용체억제 작용 및 cyclic nucleotide 의존성 phosphodiesterase 억제 등 다양한 작용이 있으며 평활근 수축 억제에 대한 GS283 작용에는 $Ca^{2+}$ 길항이 가장 중요한 요인이 될 것으로 생각된다.