Contraction Of Coronary Arteries Research Articles

Statins Decrease Serotonin-Induced Contractions in Coronary Arteries of Swine in vitro

Recent evidence suggests that statins improve the status of patients with coronary artery disease not only by reducing cholesterol levels, but also by acting at the level of the endothelium-smooth muscle unit. Previous results from our laboratory showed that these drugs interact with the vascular wall by partially inhibiting calcium-dependent, agonist-induced contractions in rat aortas. To evaluate whether this effect is also extended to the coronary vasculature, we assessed the effect of statins on serotonin (5-HT) induced contractions of left and right coronary arteries of swine. Concentration-response curves for the 5-HT-induced contractions (from 0.1 nmol/l to 100 µmol/l) were calculated on rings from both coronaries in the presence and absence of either (5 µmol/l) pravastatin, mevastatin, simvastatin, lovastatin, or atorvastatin. After a 45-min incubation period, all statins significantly reduced the E_max for the 5-HT-induced contractions, ranging from 51.9 ± 1.9% (simvastatin) to 15.9 ± 2.0% (pravastatin) in the left coronary artery and from 48.8 ± 2.0% (simvastatin) to 17.8 ± 2.5% (pravastatin) in the right coronary artery. The EC₅₀ values for the 5-HT-induced contractions were 0.150 ± 0.005 µmol/l for the left coronary artery and 0.171 ± 0.010 µmol/l for the right coronary artery. These values significantly changed after incubation with statins, ranging from 1.240 ± 0.101 µmol/l (for simvastatin) to 0.081± 0.008 µmol/l (for pravastatin) in the left coronary artery and from 1.410 ± 0.075 µmol/l (for simvastatin) to 0.084 ± 0.008 µmol/l (for pravastatin) in the right coronary artery. This evidence supports the possibility that, beyond their lipid-lowering properties, statins may provide a beneficial effect in atherosclerotic patients by reducing the tone in the coronary vasculature, facilitating blood flow to the myocardium.

Stereospecific Effects of Ginsenoside Rg3 Epimers on Swine Coronary Artery Contractions

Previous reports have shown that ginseng saponins, the active ingredients of Panax ginseng, induce relaxation of hormone- or high K(+)-induced blood vessel contraction. We recently demonstrated that 20(R)- and 20(S)-ginsenoside Rg(3) epimers regulate ion channel activities in a stereospecific manner. Here, we examined whether ginsenoside Rg(3) epimers also exhibit differential effects on swine coronary artery contractions induced by high K(+) or 5-HT. We found that treatment with 20(S)- but not 20(R)-ginsenoside Rg(3) caused a potent concentration-dependent, endothelium-independent relaxation of coronary artery contraction induced by 25 mM KCl. However, treatment with both 20(S)- and 20(R)-ginsenoside Rg(3) induced a significant, concentration-dependent relaxation of 3 microM 5-HT-induced coronary artery contractions in intact samples, while only 20(S)-ginsenoside Rg(3) inhibited coronary artery contraction in endothelium-denuded arteries. 20(S)- but not 20(R)-ginsenoside Rg(3) inhibited L-type Ca(2+) channel currents in a dose- and voltage-dependent manner. These results indicate that 20(S)- and 20(R)-ginsenoside Rg(3) epimers might exhibit stereospecific relaxation effects on swine coronary artery contractions caused by high K(+) and 5-HT receptor activation.

Estrogen-induced contraction of coronary arteries is mediated by superoxide generated in vascular smooth muscle

Although previous studies demonstrated beneficial effects of estrogen on cardiovascular function, the Women's Health Initiative has reported an increased incidence of coronary heart disease and stroke in postmenopausal women taking hormone replacement therapy. The objective of the present study was to identify a molecular mechanism whereby estrogen, a vasodilatory hormone, could possibly increase the risk of cardiovascular disease. Isometric contractile force recordings were performed on endothelium-denuded porcine coronary arteries, whereas molecular and fluorescence studies identified estrogen signaling molecules in coronary smooth muscle. Estrogen (1-1,000 nM) relaxed arteries in an endothelium-independent fashion; however, when arteries were pretreated with agents to uncouple nitric oxide (NO) production from NO synthase (NOS), estrogen contracted coronary arteries with an EC(50) of 7.3 +/- 4 nM. Estrogen-induced contraction was attenuated by reducing superoxide (O(2)(-)). Estrogen-stimulated O(2)(-) production was detected in NOS-uncoupled coronary myocytes. Interestingly, only the type 1 neuronal NOS isoform (nNOS) was detected in myocytes, making this protein a likely target mediating both estrogen-induced relaxation and contraction of endothelium-denuded coronary arteries. Estrogen-induced contraction was completely inhibited by 1 muM nifedipine or 10 muM indomethacin, indicating involvement of dihydropyridine-sensitive calcium channels and contractile prostaglandins. We propose that a single molecular mechanism can mediate the dual and opposite effect of estrogen on coronary arteries: by stimulating type 1 nNOS in coronary arteries, estrogen produces either vasodilation via NO or vasoconstriction via O(2)(-).

Effects of Ginsenoside Rg3Epimers on Swine Coronary Artery Contractions

The previous reports demonstrated that ginseng saponins, active ingredient of Panax ginseng, inhibited blood vessel contraction induced by various hormones or high <TEX>$K^+$</TEX>. Recently, we demonstrated that 20(R)- and 20(S)-ginsenoside <TEX>$Rg_3$</TEX>. regulate ion channel activities with differential manners. The aim of this study was to examine whether ginsenoside <TEX>$Rg_3$</TEX> isomers also show differential effects on swine coronary artery contractionresponses induced by high <TEX>$K^+$</TEX>, serotonin (5-HT) or acetylcholine. Treatment of 20(S)- but not 20(R)-ginsenoside <TEX>$Rg_3$</TEX> caused a concentration-dependent relaxation of coronary artery contracted by 25mM KCI. 20(S)- and 20(R)-ginsenoside <TEX>$Rg_3$</TEX> induced significant relaxations of coronary artery contraction induced by 5-HT <TEX>$(3{\mu}M)$</TEX> in the presence of endothelium with concentration-dependent manner and, also in the absence of endothelium only 20(S)-ginsenoside <TEX>$Rg_3$</TEX> induced a strong Inhibition of coronary artery contraction induced by 5-HT in a concentration-dependent manner. 20(S)-ginsenoside <TEX>$Rg_3$</TEX> caused relaxation of coronary artery in the absence and presence of endothelium. In contrast, treatment of 20(S)- and 20(R)-ginsenoside <TEX>$Rg_3\;(100{\mu}M)$</TEX> did not show significant inhibition of coronary artery contraction induced by acetylcholine <TEX>$(0.01\;to\;30{\mu}M)$</TEX> in the presence of endothelium, whereas both isomers caused significant inhibition of coronary artery contraction induced by acetylcholine <TEX>$(0.01\;to\;30{\mu}M)$</TEX> in the absence of endothelium in a concentration-dependent manner. These findings indicate that 20(S)-or 20(R)-ginsenoside <TEX>$Rg_3$</TEX> exhibits differential relaxation eff3cts of swine coronary artery contractions caused by high <TEX>$K^+$</TEX>, acetylcholine, and 5-HT treatment and that this differential vasorelaxing effects of ginsenoside <TEX>$Rg_3$</TEX> isomers also might be dependent on endothelium.

INVOLVEMENT OF ENDOTHELIAL CYCLO‐OXYGENASE METABOLITES IN NORADRENALINE‐INDUCED CONTRACTION OF RAT CORONARY ARTERY

1. Noradrenaline (NA; 0.3 micromol/L) caused a contraction of the rat coronary artery that markedly increased in the presence of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 100 micromol/L) and arachidonic acid (1 micromol/L; P < 0.05). 2. The present experiments attempted to elucidate the endothelium dependency of the contraction and to pharmacologically characterize the factors involved in the contraction induced by NA (0.3 micromol/L) in the presence of L-NAME and arachidonic acid in ring preparations of the rat coronary artery. 3. The NA (0.3 micromol/L)-induced contraction was attenuated by a chemical remover of the endothelium (saponin at concentrations of 0.1 and 0.4 mg/mL) in a concentration-dependent manner (P < 0.05). 4. The cyclo-oxygenase (COX)-1 inhibitor flurbiprofen (0.01-1 micromol/L) and the COX-2 inhibitor nimesulide (0.01-1 micromol/L) attenuated the NA-induced contraction in a concentration-dependent manner and the inhibitory effect of flurbiprofen was significantly more potent than that of nimesulide (P < 0.05). The 5-lipoxigenase inhibitor ZM-230487 (1 micromol/L) did not affect the NA-induced contraction. 5. The thromboxane A2 (TXA2) synthetase inhibitor OKY-046 (30 micromol/L) and the TXA2 antagonist S-1452 (0.1-10 micromol/L) did not attenuate the NA-induced contraction. 6. These results indicate that the contraction induced by NA in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent and is due to endothelial COX metabolites of arachidonic acid.

Synthesis, antiproliferative, and vasorelaxing evaluations of coumarin α-methylene-γ-butyrolactones

Certain coumarin α-methylene-γ-butyrolactones were synthesized and evaluated for antiproliferative and vasorelaxing activities. These compounds were synthesized via alkylation of hydroxycoumarins 2a–f followed by oxidation and the Reformatsky-type condensation. The results of this study are as follows (1) for the vasorelaxing activity, coumarin-7-yl α-methylene-γ-butyrolactone 6d, with an IC 50 value of 9.4 μM against pig coronary arterial contraction induced by KCl, is a more active vasorelaxant than its coumarin-4-yl counterpart 6a and its γ-methyl congener 1. A methyl group substituted at C-4 of the coumarin-7-yl moiety reduced the vasorelaxing effect ( 6d vs 6e) while the 3,4,8-trimethyl derivative 6f was inactive. (2) For the antiproliferative activity, coumarin-4-yl α-methylene-γ-butyrolactone 6a, which exhibited the most potent antiproliferative activity on the growth of MCF7, NCI-H460, and SF-268 with IC 50 values of 6.97, 14.68, and 8.36 μM, respectively, is more cytotoxic than its coumarin-7-yl counterpart 6d and the 6,7-dimethyl derivative 6b. For the coumarin-7-yl derivatives, 6d is more active than its γ-methyl congener 1, indicating that substitution at the γ-position decreased cytotoxicity.

Theodrenalin produces transitory contraction of pig coronary artery pre-treated with propranolol

Usichenko, T. I.; Foellner, S.; Lehmann, Ch.; Wendt, M.; Pavlovic, D. Author Information

Changes in pH Increase Perfusion Pressure of Coronary Arteries in the Rat

Stricture of coronary arteries is closely related to ischemic heart disease. The purpose of this study was to examine whether changes in pH caused contraction of rat coronary arteries, as determined using Langendorff perfused hearts. Changing the pH of the perfusate increased perfusion pressure as an indication of the contractile state of coronary arteries. Alkaline pH-induced increase of perfusion pressure in Wistar Kyoto rats (WKY) was almost identical to that of spontaneously hypertensive rats (SHR), whereas acidic pH-induced increase in SHR was much greater than that in WKY. Acidic pH-induced increase in perfusion pressure was inhibited by verapamil, cromakalim, and adenosine. Feeding WKY with NG-nitro-L-arginine resulted in hypertension followed by enhanced acidic pH-induced increase in perfusion pressure. These results suggest that acidic-pH induced contraction of rat coronary arteries is caused by Ca2+ influx through voltage-dependent Ca2+ channels and the contraction is enhanced by hypertension.

An Autopsy Case of Postpartum Acute Myocardial Infarction Associated with Postpartum Ergot Alkaloids Administration in Old-Aged Pregnant Women

Cases of acute myocardial infarction (AMI) that occur during pregnancy or postpartum are rarely reported. Ergot derivatives are known to induce the spasmodic contraction of coronary arteries. Administration of ergot derivatives can cause AMI, even in normal healthy people. In several reported cases, ergot derivatives triggered severe AMI during the postpartum period. Here, we report the case of a forty-year-old woman who was successfully impregnated by artificial fertilization and died after treatment with ergot derivatives. The autopsy revealed AMI with severe coronary atherosclerosis. This is the first case that reports aggravation of pre-existent severe coronary atherosclerosis after postpartum infusion of ergot derivtives.

Novel diacylglycerol kinase inhibitor selectively suppressed an U46619-induced enhancement of mouse portal vein contraction under high glucose conditions.

1. Diacylglycerol kinase (DG kinase) is a key enzyme in vascular contraction; however, alterations of the regulatory mechanisms in vascular dysfunction are poorly understood. In this study, the effect of a novel DG kinase inhibitor, stemphone, on vascular contraction was investigated. 2. The conventional DG kinase inhibitor, 6-[2-(4-[(4-fluorophenyl)phenyl-methylene]-1-piperidinyl)ethyl]-7-methyl-5H-thiazolo [3,2-alpha] pyrimidine-5-one (R59022) (0.1-30 microm), inhibited thromboxane A(2) analogue 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619)-induced sustained contractions in mouse aorta and porcine coronary artery in a dose-dependent manner. Treatment with stemphone did not affect contractions in these tissues. However, stemphone significantly inhibited (>0.3 microm) U46619-induced spontaneous phasic contraction in mouse portal vein. This inhibitory effect was not detected following R59022 treatment in portal vein. Therefore, stemphone demonstrated selectivity in terms of portal vein contraction. 3. Under high glucose (22.2 mm) conditions, U46619-induced contraction was enhanced in these three types of vascular tissue. Inhibitory effects of R59022 were attenuated under these conditions; however, effects of stemphone were observed. These results indicated that stemphone could inhibit portal vein contraction under high glucose conditions, for example, diabetes. These data suggested the possibility that DG kinase may be a target of hyperportal pressure. 4. Total mass of DG was enhanced under high glucose conditions. DG was derived from incorporated glucose via de novo synthesis in the absence of phospholipase C pathway mediation. This enhanced DG under high glucose conditions activated a calcium-independent protein kinase C (PKC). This PKC was associated with calcium-independent DG kinase activation. Treatment with stemphone also inhibited calcium-independent DG kinase. These signal transduction pathways were distinguishable from a DG-PKC pathway under normal glucose conditions. 5. The present investigation suggested that stemphone selectively inhibited overcontraction of portal vein induced by high glucose levels. This phenomenon was attributable to inhibition of calcium-independent DG kinase activation that occurred under high glucose conditions mediated by both DG synthesized from glucose and calcium-independent PKC activation.

Influence of several Styrian wines on bovine coronary artery contractions induced by endogenous agents

In the current study, seven Styrian white wine varieties, as well as their corresponding grape skin extracts (GSE), were tested for possible antagonistic effects on several endogenous vasoconstrictors known to be involved in the pathogenesis of cardiovascular diseases via tissue contraction experiments. Results were compared to those of Zweigelt, the most cultivated Styrian red wine. Bovine coronary artery strips were attached to a force transducer connected to a bridge amplifier, and isometric force was recorded on a multipen recorder. Preincubation of the vessels with the dealcoholized wines (DAW; 330 μl/ml) inhibited the constrictions to histamine and serotonin (5-HT) NO-dependently in the range of 5–80% and 30–90%, respectively (Zweigelt 47% and 90%, respectively). The corresponding GSE (20 mg/ml) inhibited the coronary constrictions to histamine in the range of 40% to 80% (Zweigelt 80%). Additionally, all DAW antagonized the contractile responses to the thromboxane-mimetic U46619 and the isoprostane 8- iso-PGF 2α, indicating a nonspecific inhibition. To characterize the vasoactive component(s), the Traminer GSE was separated representatively using ultrafiltration, solid phase extraction (SPE) on Isolute C18(EC), and Isolute SCX-2, as well as column chromatography (CC) on polyamide. The resulting fractions were subsequently bioassayed for vasorelaxing activity. Preliminary results refer to a very hydrophilic, nonpolyphenolic basic compound with a MW<1000 Da. Our findings demonstrate that certain Styrian wines have remarkable antagonistic effects on several endogenous agonists in vitro, and that also nonpolyphenolic components in grapes may contribute to cardiovascular protection. Further separation steps as well as phytochemical and pharmacological investigations are in progress.

Extracellular Mg(2+) blocks endothelin-1-induced contraction through the inhibition of non-selective cation channels in coronary smooth muscle.

This study investigated the effects of changing the extracellular [Mg(2+)] ([Mg(2+)](o)) on endothelin-1 (ET-1)-induced contraction of rabbit coronary artery smooth muscle and the involvement of non-selective cation (NSC) channels in this response. Increased [Mg(2+)](o) shifted the concentration/contraction relationship curve of ET-1 to the right. In whole-cell patch clamp recordings, ET-1 (10(-7) M) induced a long-lasting inwards current (94.7+/-7.2 pA) that was inhibited by 8 mM [Mg(2+)](o) (45.3+/-4.4%) and NSC channel blockers (10(-3) M streptomycin and 10(-3) M La(3+)), but not by the voltage-dependent Ca(2+) channel blocker nicardipine. The current/voltage (I/V) curve was linear. Furthermore, in pressurized arteries, the ET-1-induced contraction was also inhibited by La(3+) and streptomycin, but not by nicardipine. U-73122, a selective phospholipase C (PLC) inhibitor and staurosporine and GF 109203X, which block protein kinase C (PKC), reduced ET-1-activated NSC currents by 54.2+/-5.1%, 60.3+/-5.5% and 48.5+/-2.9%, respectively. The inwards current was increased by 1-oleoyl-2-acetyl-sn-glycerol (OAG) and phorbol 12,13-dibutyrate (PDBu), which activate PKC selectively. Like transient receptor potential channel (TRPC3) currents, ET-1-activated NSC currents had a linear I/V relationship, were blocked by flufenamate and activated by a diacylglycerol analogue. These results suggest that [Mg(2+)](o) blocks ET-1-induced contraction of coronary arteries by inhibiting NSC channels. Activation of PLC and PKC might be involved in activation of NSC channels.

Hirudin (desulfated, 54–65) contracts canine coronary arteries: Extracellular calcium influx mediates hirudin-induced contractions

Objective Although the anticoagulatory properties of hirudin are well known, its direct vasoactive effects have not been investigated extensively. Hirudin stimulates nitric oxide and prostacyclin production in noncoronary vascular beds, but its actions on coronary arteries are unknown. Materials and methods Five-millimeter segments of canine left circumflex coronary arteries were obtained for organ chamber experiments. Some segments were denuded of endothelium before study. Segments were exposed to hirudin (10 −10–10 −6 mol/L) following precontraction with prostaglandin F 2α with or without pretreatment with indomethacin or calcium channel blockers (verapamil and nifedipine). Results Hirudin stimulated endothelium-independent contraction in coronary arterial segments. Maximum tension (hirudin 10 −6 mol/L) above precontraction baseline was 33.6 ± 9.0% ( n = 10, P < 0.05) for endothelium-intact and 31.8 ± 11.5% ( n = 8, P < 0.05) for endothelium-denuded arterial segments. Differences between endothelium-intact and endothelium-denuded segments were not significant. Contractile responses to hirudin were unaffected by the presence of indomethacin. Pretreatment with either verapamil or nifedipine (10 −4 mol/L) for 1 h attenuated these contractions. The maximal increase in tension above baseline (hirudin 10 −6 mol/L) for verapamil and nifedipine was only 6.2 ± 12.4 and 3.8 ± 7.0% ( n = 6, P < 0.05 versus endothelium-intact control), respectively. Conclusions Hirudin stimulates endothelium-independent contractions of canine coronary arteries in vitro. Pretreatment with calcium channel blockers attenuates this response, suggesting that extracellular influx of calcium has an important mechanistic role in hirudin-mediated coronary artery constriction.

Age- and endothelium-dependent changes in coronary artery reactivity to serotonin and calcium

The influence of ageing and endothelium removal on the sensitivity and contractile response of rat coronary arteries to intracellular Ca 2+ ([Ca 2+] i) during activation with serotonin (5-HT) and membrane depolarisation with 125 mM K + was investigated. The sensitivity and contractile response of coronary arteries to 5-HT were significantly higher in 2-year-old than in 3-month-old rats. The receptor responsible for the 5-HT-induced contractions in coronary arteries belongs to a population of 5-HT 2 receptors in both young and old rats based on the Schild plot. The resting levels of [Ca 2+] i and active tension were both increased by age and endothelium removal. During depolarisation with 125 mM K +, the sensitivity to [Ca 2+] i and maximal tension induced by [Ca 2+] i were not affected by age or endothelium. During activation with 10 μM 5-HT, the maximal tension induced by [Ca 2+] i was increased by age but not affected by endothelium, whereas the sensitivity to [Ca 2+] i was increased by endothelium removal. In conclusion, ageing is associated with an increased sensitivity to 5-HT in rat coronary small arteries. The increased sensitivity to 5-HT seems to involve an augmented contractile response to [Ca 2+] i in 5-HT-activated coronary arteries and a diminished endothelial basal vasodilator function.

Alterations in PKC signaling underlie enhanced myogenic tone in exercise-trained porcine coronary resistance arteries.

The intracellular mechanisms underlying enhanced myogenic contraction (MC) in coronary resistance arteries (CRAs) from exercise-trained (EX) pigs have not been established. The purpose of this study was to test the hypothesis that exercise-induced alterations in protein kinase C (PKC) signaling underlie enhanced MC. Furthermore, we sought to determine whether modulation of intracellular Ca(2+) signaling by PKC underlies enhanced MC in EX animals. Male Yucatan miniature swine were treadmill trained (n = 7) at approximately 75% of maximal O(2) uptake for 16 wk (6 miles/h, 60 min) or remained sedentary (SED, n = 6). Diameter measurements in response to intraluminal pressure (60, 75, and 90 cmH(2)O) or 60 mM KCl were determined in single, cannulated CRAs ( approximately 100 microm ID) with and without the PKC inhibitor chelerythrine (CE, 1 microM). Confocal imaging of Ca(2+) signaling [myogenic Ca(2+) (Ca(m))] was also performed in CRAs of similar internal diameter after abluminal loading of the Ca(2+) indicator dye fluo 4 (1 microM, 37 degrees C, 30 min). We observed significantly greater MC in CRAs isolated from EX than from SED animals at 90 cmH(2)O, as well as greater reductions in MC after CE at all pressures studied. At intraluminal pressures of 75 and 90 cmH(2)O, CE produced greater decreases in Ca(m) in CRAs from EX than from SED animals (64% vs. 25%, P < 0.05). Inhibition of KCl constriction and Ca(m) by CE was also greater in EX animals (P < 0.05). Western blotting revealed significant increases in Ca(2+)-dependent PKC-alpha ( approximately 50%) but not Ca(2+)-independent PKC-epsilon levels in CRAs isolated from EX animals (P < 0.05). We also observed significant group differences in phosphorylated PKC-alpha levels. Finally, voltage-gated Ca(2+) current (VGCC) was effectively blocked by CE, bisindolylmaleimide, and staurosporine in isolated smooth muscle cells from CRAs, providing evidence for a mechanistic link between VGCCs and PKC in our experimental paradigm. These results suggest that enhanced MC in CRAs from EX animals involves PKC-dependent modulation of intracellular Ca(2+), including regulation of VGCCs.

Noradrenaline-induced contraction mediated by endothelial COX-1 metabolites in the rat coronary artery.

Noradrenaline-induced contraction of the rat coronary arteries was significantly augmented by the presence of NG-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid. The experiments in the study presented here were undertaken to characterize pharmacologically the augmented noradrenaline-induced contraction in ring preparations of rat coronary arteries. The contraction was stopped by a chemical remover of endothelium (saponin). Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 inhibitors (flurbiprofen, 10(-7) M) attenuated the noradrenaline-induced contraction and cyclooxygenase-2 (nimesulide, 10(-7) M) slightly attenuated the contraction. A thromboxane A2 (TXA2) synthetase inhibitor (OKY-046) and a TXA2 receptor antagonist (S-1452) did not affect the contraction. Based on these results, it was suggested that the contraction induced by noradrenaline in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium-dependent, and that it involves reactive oxygen species and endothelial cyclooxygenase-1 metabolites of arachidonic acid.

Preface

Oliver and Schaefer (1895) first demonstrated the pressor effect of adrenal extract. Von Euler (1946) demonstrated that mammalian peripheral sympathetic adrenergic nerves use norepinephrine as a transmitter. Ahlquist (1948) proposed the existence of αand βadrenergic receptors. Black and his colleagues initiated a program in the late 1950s to develop βadrenergic receptor antagonists and synthesized propranolol (1962). Over a long period of time, catecholamines have occupied the keen interest of a huge number of basic and clinical scientists. The symposium on Catecholamines and Cardiovascular System in Japan was first held in 1978, and then opened annually. The scientific standard of this meeting has been evaluated significantly high enough that most of the results presented in this meeting have been published later in leading international journals. Recently, the meeting also covered the research field on the physiological and pathophysiological cardiovascular effect of endogenous substances. The 24th symposium was held in Tokyo on November 30, 2002. The research field also covered the physiological and pathophysiological cardiovascular effects of endogenous substances. As a result, we received 23 papers including one from each of three invited lectures, and these were accepted after careful review. In the invited lectures, the role of the renin- angiotensin system in the heart, kidney and brain has been extensively reviewed by three distinct clinical scientists. Professor I. Komuro (Chiba, Japan) summarized the importance of the renin-angiotensin system in the pathogenesis of heart failure, and presented the difference of gene expression profiles treated with angiotensin II receptor blocker from those treated with angiotensin-converting enzyme inhibitor in heart failure. The papers submitted from basic and clinical studies have been divided into five categories in relation to: (1) sympathetic nervous system; (2) blood vessels; (3) angiotensin II receptor; (4) hypertension; and (5) heart failure. The first section of this issue focuses on the role of the sympathetic nervous system for cardiovascular functions. Individual papers discuss: the evaluation of norepinephrine release from hindlimb muscle sympathetic nerve endings during acute ischemia; the dynamic nature of heart rate baroreflex under closed-loop conditions; the mode of action of the catecholamine-release inhibitor derived from marine sponge; the optimal increase in heart rate to provoke vasovagal response during tilt testing; the role of the autonomic nervous system in postprandial hypotension in the elderly; and polymorphism of type 6 adenylyl cyclase gene related to left ventricular hypertrophy. The second section deals with the mechanism of action of catecholamines on vascular smooth muscles. Discussions include: the examination of receptor subtype of neuropeptide-Y in potentiation of α1 receptor-mediated vasoconstriction; noradrenaline-induced contraction of coronary artery in relation to reactive oxygen species and cyclooxygenase-1 metabolites; and the role of Rhokinase in neointima formation after vascular injury. The third section concentrates on topics dealing with the regulatory mechanism of angiotensin II receptor in the heart. These papers cover: distributions of tissue kallikrein-kinin system in the mouse heart; modification of endothelial cell proliferation by angiotensin-converting enzyme inhibitor; inhibition of perivascular fibrosis in the heart with angiotensin II type-1 receptor blocker; and increase in hydroxyl radicals in cardiac hypertrophy mediated through angiotensin II type-1a receptor. The fourth and final section is devoted to receptor mechanisms of hypertension and heart failure. In section four, topics deal with: comparison of the effects of amlodipine and valsartan on neurohumoral factors in hypertensive patients; renal dopamine production and dopamine-induced sodium excretion in D2 receptor knockout mice; role of the presynaptic β2 receptors and cAMP-dependent protein kinase in regulation of norepinephrine release in the central nervous system in spontaneously hypertensive rats; the clinical implication of the morning blood pressure surge in hypertensive elderly patients; blood pressure response to carvedilol in dilated cardiomyopathy rats; possible autoimmune mechanism in the pathogenesis of dilated cardiomyopathy in mice; the cardioprotective properties of perindopril in dilated cardiomyopathy rats; the reduction of neural nitric oxide synthase expression in the brainstem in heart failure rats; and the role of estrogen in emotional stress induced cardiomyopathy. As guest editors, we are proud of the quality of the research presented at this symposium, and would like to thank the authors for sending their manuscripts in good time. Finally, we would like to inform you that this symposium on Catecholamines and Cardiovascular System in Japan has achieved our intended objectives and has come to an end. We are proud that the achievements of this symposium have made significant contributions to basic and clinical studies of catecholamines in the cardiovascular system.

Brain in the Brawn

Nitric oxide (NO) plays a central role in the regulation of cardiovascular homeostasis and is involved in the regulation of vascular tone and cardiac contractility as well as gene expression and cell proliferation. Furthermore, NO modulates renin secretion and salt and fluid reabsorption in the kidney.1 Three isoforms of NO synthase (NOS) have been identified, the neuronal NOS (nNOS or NOS I), the inducible NOS (iNOS or NOS II), and the endothelial NOS (eNOS or NOS III). While all of these enzymes potentially affect blood pressure, only eNOS-deficient mice are hypertensive.2,3 Although nNOS is expressed in cardiac myocytes,4,5 as well as in vascular smooth muscle cells,6–8 relatively little is known about the role played by nNOS-derived NO in cardiovascular homeostasis. Both pro- and antihypertensive actions have been attributed to nNOS, and selective inhibitors of this isoform have been reported to normalize blood pressure,9 as well as to attenuate flow-induced vasodilatation in eNOS−/− mice.8 The regulation of nNOS activity, like that of eNOS, is determined by phosphorylation of the enzyme as well as by its association with a number of regulatory proteins.10 One protein that associates with nNOS in human embryonic kidney (HEK293) cells and is reported to play a major role in regulating the activity of the Ca2+-dependent enzyme, is the plasma membrane Ca2+/calmodulin-dependent Ca2+-ATPase (PMCA).11 The ATPase binds to nNOS via an interaction between its carboxyl terminus and the PDZ domain of nNOS. Increasing expression of the PMCA4b isoform markedly attenuates NO synthesis by nNOS, an effect not observed in cells overexpressing a mutant PMCA that was devoid of Ca2+-transporting activity.11 Thus, …

Late-gestation betamethasone enhances coronary artery responsiveness to angiotensin II in fetal sheep.

Antenatal glucocorticoids are used to promote the maturation of fetuses at risk for preterm delivery. While perinatal glucocorticoid exposure has clear immediate benefits to cardiorespiratory function, there is emerging evidence of adverse long-term effects. To determine if antenatal betamethasone alters vascular reactivity, we examined isometric contraction of endothelium-intact coronary and mesenteric arteries isolated from twin fetal sheep at 121-124 days gestation (term being 145 days). One twin received betamethasone (10 microg/h iv) while the second twin received vehicle (0.9% NaCl) for 48 h immediately before the final physiological measurements and tissue harvesting. Fetuses that received betamethasone had higher mean arterial blood pressures than the saline-treated twin controls (53 +/- 1 vs. 48 +/- 1 mmHg, P < 0.05). Coronary vessels from betamethasone-treated fetuses exhibited enhanced peak responses to ANG II (72 +/- 17 vs. 23 +/- 6% of the maximal response to 120 mM KCl, P < 0.05). There was no significant difference in response of the coronary arteries to other vasoactive compounds [KCl, U-46619, sodium nitroprusside, 8-bromo-cGMP (8-BrcGMP), isoproterenol, and forskolin]. Contractile responses to ANG II were similar in betamethasone and control mesenteric arteries (48 +/- 17 vs. 36 +/- 12% of the maximal response to 10-6 M U-46619). Western blot analysis revealed AT1 receptor protein expression was increased by betamethasone in coronary but not in mesenteric arteries. These findings demonstrate that antenatal betamethasone exposure enhances coronary but not mesenteric artery vasoconstriction to ANG II by selectively upregulating coronary artery AT1 receptor protein expression.

Role of 5-HT2A Receptor Gene T102C Polymorphism in Coronary Artery Disease and Serum Lipid Level

Background and Objectives:The 5-HT2A receptor is one of the main mediators of a serotonin-evoked coronary artery contraction. This is because vasoconstriction is selectively blocked by the 5-HT2 receptor antagonist, with the 5-HT2A receptor gene mRNA being detected in spastic coronary arteries. The relationship between the T102C polymorphism of the 5-HT2A receptor gene and the response to the 5-HT2A antagonist (clozapine) has recently been established, suggestive of a functional implication. Previous studies have observed an association between low cholesterol levels and mental disorders, but the underlying cause has not been determined. It has been established that the T102C polymorphism of the 5-HT2A serotonin receptor gene and a variety of psychological problems are related, but the relationship between the serum lipid level and this genetic polymorphism has not been reported. We investigated the influence of this polymorphism on coronary artery disease, including vasospastic angina and the clinical parameters, such as the lipid profile. Subjects and Methods:After a diagnostic angiography was performed, the genotype was identified from the genomic DNA extracted from the peripheral blood of 646 patients without specific psychiatric diseases. Results:There were no differences in the genotype frequencies between coronary artery disease, coronary artery disease with vasospasm, and the normal control groups, even from a subgroup analysis of the clinical parameters. Contrary to previous reports, the genotype distribution was not related to a myocardial infarction or hypertension. The lipid profile analysis showed significantly lower total cholesterol (193.5 vs. 202.1 mg/dL, p=0.016) and HDL-cholesterol (42.7 vs. 46.2 mg/dL, p=0.003) levels in the CC genotype than the other genotypes, and the frequencies of CC genotype showed a significantly decreasing trend between the HDLcholesterol (p=0.003) and total cholesterol (p=0.003) quartiles. From a multivariate analysis, only the HDL-cholesterol level was significantly associated with a lower frequency of the CC genotype (p=0.006). Conclusion:The T102C polymorphism is not related to coronary artery disease, including vasospasm of the coronary artery, but the CC genotype of this polymorphism is related to low HDL-cholesterol. We identified a novel genetic polymorphism of the serotonin receptor, which affects the HDL-cholesterol level. Because previous observational studies have shown an association between low cholesterol levels and mental disorders, our data should be considered when analyzing the serum lipid levels and serotonin receptor function in humans. (Korean Circulation J 2003;33 (4):269-276)