• The Korean Journal of Physiology and Pharmacology
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• v.5 no.1
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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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• v.50 no.12
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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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• v.23 no.2
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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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• v.23 no.1
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• pp.36-44
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• 2006

Background: There is controversy regarding whether COX-2 specific inhibitors are associated with elevation of blood pressure. We compared the effects of aspirin, indomethacin, and celecoxib for vascular reactivity induced by phenylephrine. We also tested the effects of indomethacin and NO donor on COX-1 and COX-2 protein expression, as well as nitrite production in culture medium of vascular smooth muscle cells. Materials and Methods: In this experiment, we used the isometric tension study for vascular reactivity. After 45 minutes of pretreatment with aspirin, indomethacin, celecoxib, and phenylephrine induced contractions were tested. COX-1 and COX-2 protein expressions were analyzed by Western blot and nitrite production by the Griess reaction. Results: Although celecoxib pretreatment caused enhanced arterial contraction, aspirin pretreatment induced more potent arterial contraction than celecoxib in the isometric tension study of rabbit femoral artery. COX-1 protein expression was unchanged by indomethacin, SNP and NOR-3; COX-2 protein expression was increased by the addition of indomethacin, SNP, and NOR-3. Especially, NOR-3, a NO donor, significantly increased COX-2 protein expression with unstimulated conditions as well as LPS stimulation. Induction of nitrite production was higher with NOR-3 treatment than SNP treatment with LPS stimulation. Conclusion: These results suggest that aspirin caused more potent vascular contraction than celecoxib and indomethacin. COX-2 expression in VSMC depended on the types of NO donor and LPS stimulation.

• The Korean Journal of Pharmacology
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• v.26 no.1
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• pp.25-33
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• 1990

The responsiveness of various arterial smooth muscles isolated from rabbit to peptide YY (PYY) and the calcium source responsible for the muscles to contract were studied in vitro. PYY contracted the muscle strips of femoral, basilar and common iliac arteries more sensitively than renal, superior mesenteric and common carotid arteries. Common carotid and renal arteries were less sensitive to PYY $(p{\leqslant}0.05)$ than to NE; and basilar artery was more sensitive to PYY$(p{\leqslant}0.01)$ than to NE. A calcium channel blocker, verapamil and an inhibitor of intracellular calcium release, 3, 4, 5-Trime-thoxybenzoic arid 8-(diethylamino)octyl ester [TMB-8] significantly $(p{\leqslant}0.001)$ suppressed the concentration-response of the strips from femoral artery to PYY. When both verapamil and TMB-8 existed in normal PSS, the concentration-response to PYY was inhibited almost completely; and a similar suppression was observed when the muscle was incubated in calcium-free, ethyleneglycol-bis-(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid [EGTA] containing PSS. The results of these experiments suggest that increased PYY activity in circulation may result in the more sensitive increase in the intracranial vascular resistance and the cerebral arterial pressure than the increased sympathetic activity and that both intra- and extracellular calcium are to be utilized for the PYY-induced contraction on arterial smooth muscle.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1994.04a
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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.

• YAKHAK HOEJI
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• v.41 no.5
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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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• v.21 no.2
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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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• v.17 no.1
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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.

• The Korean Journal of Pharmacology
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• v.30 no.1
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• pp.101-109
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• 1994

Pharmacological characterization of GS 283, a tetrahydroisoquinoline derivative has been elucidated using rat thoracic aorta, guinea pig tenea coli and rabbit mesentery artery in vitro. GS 283 showed calcium antagonistic action in vascular smooth muscle, since high $K^+-induced$ contraction was concentration dependently inhibited. GS 283 also inhibited the contraction induced by ${\alpha}_1$ receptor activation. Vasodilating action of GS 283 was not modified by the propranolol, indicating that GS 283 has no ${\beta}$ receptor stimulatory action. Simultaneous measurement of intracellular calcium change and muscle tension indicated that the inhibitory effect of GS 283 was accompanied by the increase in tissue fluorescence. This increment was not due to fura 2 fluorescence but to endogenous pyridine nucleotide, suggesting that GS 283 has an effect to inhibit mitochondrial function. GS 283 had an inhibitory action on cyclic AMP and GMP-dependent phosphodiesterases from rat brain with Ki values of 2.5 and 6.7 mM. From these findings we concluded that GS 283 has multiple action such as the inhibition of cyclic nucleotide-dependent phosphodiesterases, blocking of calcium channel as well as inhibition of mitochondrial function which are responsible for vasodilatation.