Hyperthermia-induced vasoconstriction of the carotid artery, a possible causative factor of heatstroke.

Clinical and experimental studies indicate that hyperthermia can cause heatstroke with cerebral ischemia and brain damage. However, no study has examined the direct effects of heating carotid artery smooth muscle and tested the hypothesis that hyperthermia induces arterial vasoconstriction and, thereby, decreases cerebral blood flow. We recorded isometric tension of rabbit carotid artery strips in organ baths during stepwise temperature elevation. The heating responses were tested at basal tone, in norepinephrine- and KCl-precontracted vessels, and after electrical field stimulation. Stepwise heating from 37 degrees C to 47 degrees C induced reproducible graded contraction proportional to temperature. The responses could be elicited at basal tone and in precontracted vessels. Heating decreased the contractile responses to norepinephrine and electrical field stimulation but increased contraction to KCl. These responses were not eliminated by pretreatment with the neuronal blocker tetrodotoxin. Our results demonstrate that heating carotid artery preparations above 37 degrees C (normothermia) induced a reversible graded vasoconstriction proportional to temperature. In vivo this reaction may lead to a decrease in cerebral blood flow and cerebral ischemia with brain damage as in heatstroke. The heating-induced contraction is not mediated by a neurogenic process but is due to altered transcellular Ca2+ transport. Cooling, in particular of the neck area, therefore, should be used in the treatment of heatstroke.     

Effect of heating on vascular reactivity in rat mesenteric arteries

Vasoconstrictionin the viscera is one of the primary cardiovascular adjustments toheating. Local temperature can influence vascular responsiveness tocatecholamines and sympathetic nerve activity. Therefore, wehypothesized that heating would alter vascular reactivity in ratmesenteric arteries. Concentration-response curves to norepinephrine,phenylephrine, potassium chloride (KCl), calcium, acetylcholine, andsodium nitroprusside were obtained in vascular ring segments from ratmesenteric arteries at 37 and 41°C. In some rings, basal tensionincreased slightly during heating. Heating to 41°C did not alterthe contractile responses to norepinephrine in endothelium-intact or-denuded rings but augmented the responses to KCl and calcium inendothelium-intact rings. The potentiating effect of heating on theresponses to KCl and calcium was eliminated after endothelium removal.In contrast, the relaxant responses to acetylcholine and sodiumnitroprusside were significantly attenuated at 41°C. Collectively,these results demonstrate that heating alters vascular reactivity inrat mesenteric arteries. Furthermore, these data imply that heatingreduces the ability of vascular smooth muscle to relax, possibly due toa decrease in sensitivity to nitric oxide.

     

Inhibition of iloprost of the contractile effect of noradrenaline in mesenteric artery rings: evidence for a possible calcium-dependent mechanism.

Iloprost caused a concentration-dependent decrease in the response to noradrenaline in the rabbit isolated endothelium denuded rings from superior mesenteric artery but not thoracic aorta. Similar inhibition was obtained by verapamil using identical concentrations. In Ca(2+)-free EGTA containing medium noradrenaline both at lower and higher concentrations elicited a reduced contractile response and further addition of Ca2+ (2.5 mM) to the medium produced a second contraction in both mesenteric artery and aortic rings which was significantly and equally inhibited by iloprost and verapamil using identical concentrations in mesenteric artery but not in aortic rings. Prior addition of iloprost to the medium did not protect the inhibitory effect of phenoxybenzamine against noradrenaline-induced contraction. These results were taken as an evidence for the possible Ca2+ entry reducing effect of iloprost in mesenteric artery but not thoracic aorta. These results were also taken as an indirect evidence supporting the hypothesis that increased synthesis of prostacyclin by noradrenaline in the vascular wall may inhibit the contractile effect of the agonist by a (-) feedback mechanism mediated by Ca2+ entry into the vascular smooth muscle.     

Ionizing radiation alters myofilament calcium sensitivity in vascular smooth muscle: potential role of protein kinase C

Radiation exposure increases vascular responsiveness, and this change involves endothelial damage, as well as direct effects on vascular smooth muscle. In this study, we tested the hypothesis that myofilament Ca(2+) sensitivity in vascular smooth muscle is increased from single whole body gamma irradiation (6 Gy). We measured contractile responses from intact and permeabilized rat thoracic aortic rings combined with cytosolic Ca(2+) ([Ca(2+)](i)) measurements. The sensitivity to KCl and phenylephrine increased significantly in tissues from animals on the 9th and 30th days postirradiation compared with control. Irradiation also significantly increased Ca(2+) sensitivity in beta-escin permeabilized smooth muscle on the 9th and 30th days postirradiation. Inhibitors of protein kinase C, chelerythrine, and staurosporine, had no effect on the pCa-tension curves in control permeabilized tissues but significantly decreased Ca(2+) sensitivity in permeabilized tissues on the 9th and 30th days postirradiation. Phorbol dibutyrate (PDBu, 10(-7) M) increased Ca(2+) sensitivity in control skinned smooth muscle but was without effect in irradiated vascular rings. Simultaneous measurement of contractile force and [Ca(2+)](i) showed that myofilament Ca(2+) sensitivity defined as the ratio of force change to [Ca(2+)](i) significantly increased following gamma-irradiation. PDBu (10(-6) M) stimulation of intact aorta produced a sustained contraction, while the increase in [Ca(2+)](i) was transient. In irradiated tissues, PDBu-induced contractions were greater than those seen in control tissues but there was no elevation in [Ca(2+)](i). Taken together, these data strongly support the hypothesis that irradiation increases the sensitivity of vascular smooth muscle myofilaments to Ca(2+) and this effect is dependent on activation of protein kinase C.     

铁对血管收缩活动的影响及其机制

动脉粥样硬化的发生和铁引起的氧化应激密切相关。铁对血管的直接效应及其对血管收缩功能的影响尚不明确。本文采用血管环灌流装置 ,观察铁对离体SD大鼠去内皮胸主动脉环的直接效应 ,及对去内皮主动脉环KCl和苯肾上腺素 (PE)引发的收缩效应的影响。结果显示 :( 1) 10 0 μmol/L枸橼酸铁 (FAC)引起大鼠血管环发生相位性收缩 ,最大收缩幅度可达KCl诱发的最大收缩的 2 4 0 2± 2 3 7%。当 [Ca2 +]o 增加 1倍时 ,铁所致的血管环收缩幅度明显增加 (P <0 0 1)。阻断L 型钙通道后 ,铁所致的血管环收缩幅度明显降低 (P <0 0 1)。在无钙液中 ,用佛波酯收缩血管环 ,待收缩稳定后给予FAC ,此时收缩幅度增加 49 18± 3 75 %。 ( 2 )铁孵育 3 0min后 ,KCl引起血管环收缩的幅度显著降低 (P <0 0 1)。铁孵育可使PE引起的收缩量 -效曲线右移 (P <0 0 5 )。 ( 3 )二甲基亚砜、过氧化氢酶和谷胱甘肽可明显降低铁对PE血管收缩反应的抑制作用 (P <0 0 5 )。从这些结果可得到以下结论 :铁可引起胸主动脉发生相位性收缩 ,其机制可能与L 型钙通道短暂开放导致钙离子内流 ,及平滑肌对钙的敏感性增加有关 ;较长时间与铁孵育后 ,可对血管收缩功能产生损伤 ,氧自由基的生成增加和细胞内GSH的水平降低可能参与铁对收缩功能的     

Circulatory responses to vasoconstrictor agents during passive heating in the rat

The purpose of this study was to determine the actions of several pharmacological agents on the circulatory system, and more specifically on the superior mesenteric vascular bed, in response to environmental heat stress in chloralose-anesthetized rats. Animals were instrumented with Doppler flow probes on the mesenteric and renal arteries and exposed to an ambient temperature of 40 degrees C. Heart rate, mean arterial blood pressure (MAP), and core (Tc) and tail skin temperatures were also monitored. As Tc progressively increased from 37 degrees C during heat exposure, MAP rose to a plateau and then fell precipitously as Tc exceeded 41.5 degrees C. Mesenteric resistance increased throughout the early stages of heating before sharply declining prior to the reduction in MAP. The pressor and mesenteric resistance responses to constant infusions of several adrenergic agonists after MAP began falling (Tc = 41.3 degrees C) were significantly (P less than 0.05) attenuated compared with infusions into normothermic animals. In a second set of experiments, injections of both norepinephrine and angiotensin II were made 30 min before and approximately 10, 30, 50, 70, and 90 min after initiation of heating. These injections increased both MAP and mesenteric resistance; however, at TcS greater than 40 degrees C, the responses to both agonists were progressively and significantly attenuated. In a final group of animals, barium chloride infusions produced similar pressor and regional resistance changes during both normothermia and severe hyperthermia (Tc greater than 42 degrees C). These results indicate that, in the chloralose-anesthetized rat, hyperthermia disrupts adrenoceptor function but does not alter the intrinsic ability of vascular smooth muscle to contract.     

Hsp70 does not mediate the hyperthermia-associated hyporesponsiveness to angiotensin in isolated rat portal veins

In rat portal veins (RPV) isolated from septic rats, we previously showed that the contractile response to angiotensin II (AT(II)) was significantly decreased and that the vascular failure was correlated with the severity of the disease. We hypothesized that hyperthermia might be one of the factors responsible for the vascular failure. Moreover, hyperthermia should concomitantly increase heat shock proteins (Hsps) expression. We then compared the vascular contractility and the heat shock protein 70 (Hsp70) expression in RPV incubated at 37 degrees C and 39.5 degrees C and sought for a relationship between both events. In our experimental model, hyperthermia increased the Hsp70 expression and decreased the contractile response to AT(II). Incorporation of the Hsp70 antisense oligonucleotide in RPV blocked the increase in Hsp70 expression but had no consequence on the contractile response to AT(II). In conclusion, hyperthermia increases Hsp70 expression but does not mediate the decreased response to AT(II). Hsp70 overexpression has no effect on the actin-myosin interaction in vascular smooth muscle.     

Nitric oxide relaxes rat tail artery smooth muscle by cyclic GMP-independent decrease in calcium sensitivity of myofilaments

The effects of authentic nitric oxide (NO, 10(-6) M) and NO-donors such as sodium nitroprusside (SNP, 10(-5) M) and glyceryl trinitrate (GTN, 10(-4) M) on contractile force and free intracellular calcium level ([Ca2+]i) were studied on precontracted with high potassium chloride (KCl, 70 mM) isolated rings of rat tail artery. The sensitivity of contractile myofilaments to Ca2+ was measured using chemically permeabilized (alpha-toxin, beta-escin, Triton X-100) vascular rings. [Ca2+]i and contractile activity were measured simultaneously. The relationship of [Ca2+]i and tension developed was studied in endothelium-denuded rings and controlled calcium response was evaluated in both endothelium-denuded and permeabilized vascular rings. Both authentic NO and NO-donors decreased [Ca2+]i and high potassium-induced tension with a different time course. Inhibitor of soluble guanylyl cyclase (sGC) LY83583 (10(-5) M) did not affect SNP-induced relaxation whereas the other sGC inhibitor ODQ (10(-6) M) attenuated SNP-induced relaxation. Both inhibitors had no effect on NO- and SNP-induced reduction in [Ca2+]i. On the contrary, GTN induced neither relaxation nor decrease in [Ca2+]i on application of both LY83583 and ODQ. Tail artery rings permeabilized with alpha-toxin, beta-escin, but not with Triton X-100 were relaxed by authentic NO and NO-donors, but to a less extent than non-permeabilized rings. Dithioerythritol (DTE, 5 x 10(-3) M) that maintains sulfhydryl (SH) groups in reduced state preventing their nitrosylation attenuated NO-induced relaxation in both non-permeabilized and permeabilized tail artery rings. The cyclic heptapeptide mycrocystin-LR (MC-LR) (10(-5) M), an inhibitor of type 1 and 2A phosphatases, induced sustained increase in tension of beta-escin permeabilized rings in low Ca2+ (10(-8) M) solution. The tension was not affected by authentic NO and SNP. We conclude that authentic NO and SNP relax rat tail artery smooth muscle (SM) in the presence of inhibitors of sGC via cyclic guanosine monophosphate (cGMP)-independent pathway, whereas relaxation induced by GTN is inhibited. The data demonstrate that cGMP-dependent pathway in vascular smooth muscle is ubiquitous, but not the only way of relaxation induced by NO. NO can modulate vascular tone directly by reducing sensitivity of contractile myofilaments to [Ca2+]i and may involve activation of protein phosphatase(s).     

Role of myosin light chain kinase in regulation of basal blood pressure and maintenance of salt-induced hypertension

Vascular tone, an important determinant of systemic vascular resistance and thus blood pressure, is affected by vascular smooth muscle (VSM) contraction. Key signaling pathways for VSM contraction converge on phosphorylation of the regulatory light chain (RLC) of smooth muscle myosin. This phosphorylation is mediated by Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) but Ca(2+)-independent kinases may also contribute, particularly in sustained contractions. Signaling through MLCK has been indirectly implicated in maintenance of basal blood pressure, whereas signaling through RhoA has been implicated in salt-induced hypertension. In this report, we analyzed mice with smooth muscle-specific knockout of MLCK. Mesenteric artery segments isolated from smooth muscle-specific MLCK knockout mice (MLCK(SMKO)) had a significantly reduced contractile response to KCl and vasoconstrictors. The kinase knockout also markedly reduced RLC phosphorylation and developed force. We suggest that MLCK and its phosphorylation of RLC are required for tonic VSM contraction. MLCK(SMKO) mice exhibit significantly lower basal blood pressure and weaker responses to vasopressors. The elevated blood pressure in salt-induced hypertension is reduced below normotensive levels after MLCK attenuation. These results suggest that MLCK is necessary for both physiological and pathological blood pressure. MLCK(SMKO) mice may be a useful model of vascular failure and hypotension.     

Sexual dimorphism of vascular smooth muscle responsiveness is dependent on anions and estrogen.

Alteration of the extracellular anion environment by replacement of chloride ions (Cl-) with thiocyanate ions (SCN-) in normal Krebs-Ringer bicarbonate solution (NKRB) induced sustained development of basal tension in isolated aortas from male adult Sprague-Dawley and Long-Evans rats, but not from females of these strains. However, aortic smooth muscle isolated from sexually immature male and female Wistar rats underwent more marked tension development under such treatment, exhibiting no gender differences. Such SCN(-)-induced contractile responses are not tachyphylactic, completely dependent on extracellular calcium ([Ca2+]0), and could be aborted (relaxed to basal tone) by readmission of Cl-. Castration and replacement of male sex hormones with estradiol inhibited SCN(-)-induced contractions in isolated aortas from adult Wistar male rats, while castration and testosterone supplementation failed to induce contraction in aortic muscle of adult female Wistar rats exposed to SCN-. We believe these data are compatible with the notion that gender differences in vascular activity may be modulated by actions of estradiol on the metabolism of Cl- and other anions in vascular smooth muscle, which may be linked to transport of Ca2+ across the vascular muscle cell membrane.     

Leukemia inhibitory factor relaxes arteries through endothelium-dependent mechanism

Leukemia inhibitory factor (LIF) is a cytokine, which inhibits angiogenesis and decreases endothelial cell proliferation and migration, suggesting that LIF may modulate vascular tone. In this study, we examined the effects of LIF on the tone of rat arteries. The isometric tension of ring preparations from rat superior mesenteric arteries was continuously measured. LIF relaxed the mesenteric arteries in a dose-dependent manner, when the arterial rings were precontracted with phenylephrine. The relaxation was totally inhibited by mechanical removal of endothelium. N(G)-nitro-L-arginine methyl ester did not affect the relaxation by LIF. Ca(2+)-dependent K channel (KCa) blockers, apamin with charybdotoxin, inhibited the relaxation by LIF. Catalase, an enzyme which scavenges hydrogen peroxide, also inhibited the relaxation by LIF. Endothelium-derived hyperpolarizing factor relaxes smooth muscle cells and the effect is blocked by KCa and catalase. Our results suggest that LIF regulates vascular tone through the effect of this factor.     

Effect of small changes in extracellular magnesium concentration on the tone of feline mesenteric arteries: involvement of endothelium.

The aim of this study was to investigate the effect of small alterations in extracellular magnesium concentration on the tone of feline mesenteric arteries and to examine the role of endothelium in these responses. We measured isometrical tension of isolated arterial rings, placed between two stainless steel wires in a tissue chamber containing Krebs-Henseleit solution, aerated with a gas mixture containing 95% O2 and 5% CO2 at 37 degrees C. After precontraction with noradrenaline, a decrease of extracellular magnesium concentration from 1.2 mM to 1.0 and 0.8 mM resulted in sustained relaxations, whereas the elevation of extracellular magnesium from 0.8 mM to 1.2 mM caused an increase in vascular tone when endothelium was intact. The magnesium-withdrawal related dilations were absent in endothelium-denuded vessels and were inhibited by oxyhemoglobin (5 x 10(-6) M) and methylene blue (10(-5) M), suggesting the involvement of endothelium-derived relaxing factor in this vascular response. Nifedipine (5 x 10(-7) M) or dichlorobenzamil (3 x 10(-5) M), however, did not affect the magnesium-deficiency related relaxations. Therefore, in this vascular action of magnesium, nifedipine-sensitive calcium channels or the sodium- calcium antiport system are not involved. We conclude that small alterations in extracellular magnesium concentration, possibly within the physiological range, are able to modify the basal formation and release of EDRF, and thus alter arterial smooth muscle tone in this vascular bed. This endothelium- and magnesium-dependent system appears to be more sensitive than the direct smooth muscle actions of magnesium. The possible physiological and pathophysiological consequences of these observations are discussed.     

Sphingomyelinase and ceramide analogs induce contraction and rises in [Ca(2+)](i) in canine cerebral vascular muscle

Studies were designed to investigate effects of neutral sphingomyelinase (N-SMase) and ceramide analogs as well as phosphorylcholine on vascular tone and Ca(2+) mobilization in isolated canine cerebral arterial smooth muscle. N-SMase (0.001-0.1 U/ml) provoked a gradual but sustained vasoconstriction of arterial rings in a concentration-related manner that was endothelium independent. Incubation of denuded arterial rings in Ca(2+)-free medium or pretreatment with verapamil in extracellular Ca(2+) resulted in a reduction of the N-SMase-evoked constriction. Exposure of arterial rings to 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid (BAPTA)-AM did not, however, result in a reduction of N-SMase-induced constriction. Both staurosporine and bisindolymaleimide I attenuated N-SMase-induced contractions to 66% and 72% of control, respectively. N-SMase caused gradual and sustained rises in intracellular Ca(2+) concentration ([Ca(2+)](i)) in primary cultured cerebral vascular smooth muscle cells. Pretreatment of these cultured cells with nimodipine and verapamil caused a steady decline in N-SMase-induced rises in [Ca(2+)](i). Exposure of the cells to Ca(2+)-free solution reversed the [Ca(2+)](i)-induced rise triggered by N-SMase to the resting baseline. Both C(8) and C(16) ceramide (10(-9)-10(-6) M), but not phosphorylcholine, constricted denuded canine arterial rings in a concentration-related manner and elevated [Ca(2+)](i). Our results suggest that the sphingomyelin-signaling pathway, via a probable release of ceramide molecules, may play an important role in regulation of cerebral arterial wall tone.     

Inhibitory effect of manganese on contraction of isolated rat aorta

The effects of MnCl2 on vascular smooth muscle contraction induced by noradrenaline (NA) and KCl were investigated. Rings segments from rat aorta were isolated and changes in isometric tension recorded. MnCl2 (10 microM and 1 mM) significantly attenuated the contractile responses to NA and KCI. There were also reductions in the contractile responses to CaCl2 in NA- and KCl-stimulated rings, after pretreatment with MnCl2. The magnitude of the phasic contraction to NA was significantly reduced in presence of MnCl2. The results suggest that MnCl2 inhibits vascular smooth muscle contraction by influencing a Ca2+-mediated mechanism.     

Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle

Reactive oxygen species alter pulmonary arterial vascular tone and cause changes in pulmonary vascular resistance. The objective of this investigation was to determine direct effects of oxygen radicals on the contractile properties of pulmonary arterial smooth muscle. Isolated pulmonary arterial rings from Sprague-Dawley rats were placed in tissue baths containing Earle's balanced salt solution (gassed with 95% O2 - 5% CO2, 37 degrees C, pH 7.4). Vessels were contracted with 80 mM KCl to establish maximum active force production (Po). All other responses were normalized as percentages of Po for comparative purposes. Reactive oxygen metabolites were generated enzymatically with either the xanthine oxidase (XO) reaction or the glucose oxidase (GO) reaction, or hydrogen peroxide (H2O2) was added directly to the muscle bath. Exposure to XO, GO, or to H2O2 resulted in a contractile response that was sustained during the 30-min exposure period. The muscle fully relaxed following removal of the reactive oxygen species. Resting tension remained unchanged throughout the experimental period, suggesting no functional change in membrane potential. The contractile response was dose dependent and was not prevented by either cyclooxygenase or lipoxygenase inhibition, or by removal of the endothelium. Pretreatment of vessels with superoxide dismutase (SOD) partially blocked the XO-induced contraction, while mannitol or deferoxamine had no effect on the response to XO. However, pretreatment with catalase (CAT) completely blocked the XO-induced contraction. These data suggest that superoxide ions and hydrogen peroxide are the major causative agents. Following O2-radical exposure, vessels showed a decrease in contractile responsiveness to 80 mM KCl (recovery response), suggesting damage to the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro reactivity of ventral aorta to acetylcholine and noradrenaline in yellow freshwater eel (Anguilla anguilla L.) acclimatized to 10.1 MPa hydrostatic pressure

We examined in vitro vascular reactivity of eels previously acclimatized to 10.1 MPa hydrostatic pressure (HP) for 21 days. The isometric tension developed by ventral aortic rings was measured at atmospheric pressure. Dose-response curves for either acetylcholine (ACh) or noradrenaline (NA), as well as contractions evoked by 80 mM K+, were compared with time-matched experiments conducted on rings obtained from control eels. Results showed that neither the optimal tension nor the maximal force of the K+-evoked contraction were significantly modified, suggesting that acclimatization to high HP did not change the vascular smooth muscle contractile machinery. The dose-response curve to ACh was not significantly changed. Conversely, although NA always relaxed aortic rings, the response of acclimatized eels was significantly reduced over the entire range of the agonist concentration tested (10(-8) to 10(-3) M), except for the lowest one (10(-9) M). The maximal amplitude of the NA-induced relaxation was significantly reduced in aortic rings from acclimatized eels as compared with non-acclimatized samples (339.3 +/- 86.5 vs. 744.3 +/- 72.1 mg x mg(-1) dry weight, P < 0.005). Our results suggest that acclimatization to high HP could selectively alter the control of vascular tone by catecholamines.     

Vascular smooth muscle-derived relaxing factor (MDRF) and its close similarity to nitric oxide

The principal finding in this study is that vascular smooth muscle generates a labile relaxing factor that possesses pharmacological and chemical properties that are similar to those of authentic nitric oxide. MDRF was generated by perfusion of endothelium-denuded bovine pulmonary artery as assessed by bioassay. In addition, endothelium-denuded arterial rings that were incubated at 37 degrees C for 24 hr to lower endogenous L-arginine levels relaxed in response to L-arginine but not D-arginine. Freshly mounted, endothelium-denuded arterial rings were not relaxed by L-arginine but did relax in response to the dipeptide L-arginyl-L-alanine. Relaxant responses were accompanied by increases in smooth muscle levels of cyclic GMP and nitrite, and were inhibited by oxyhemoglobin, methylene blue, and NG-nitro-L-arginine. NG-Nitro-L-arginine also caused endothelium-independent contractile responses. Thus, a relaxing factor with the properties of nitric oxide can be generated from vascular smooth muscle.     

Endothelium-independent vasorelaxation by leonurine, a plant alkaloid purified from Chinese motherwort

Leonurine, a plant alkaloid present in Chinese motherwort, induced concentration- dependent and endothelium-independent relaxation of phenylephrine (PE)- pretreated rat aortic arterial rings. The IC50 values for leonurine were 86.4+/-10.4 and 85.9+/-17.2 microM in the presence and absence of endothelium respectively. It inhibited the responses of aortic smooth muscle to PE in Ca2+ free medium containing 100 microM EGTA, suggesting a possible action on the release of intracellular Ca2+. Leonurine is not a specific alpha-adrenoceptor blocker, since it also caused a concentration-dependent inhibition of vascular contractile responses to KCl with an IC50 value of 96.4+/-13.4 microM, suggesting that leonurine also blocks the L-type Ca2+-channel. In addition, leonurine relaxed the aortic contraction induced by prostaglandin F2alpha (PGF2alpha). These inhibitory effects of leonurine were reversible and did not affect the resting tension. In conclusion, these findings suggest that leonurine is an effective inhibitor of vascular smooth tone, probably acting by inhibiting the Ca2+ influx and the release of intracellular Ca2+.