Co-Existence of Hypertensive and Anti-Hypertensive Constituents, Synephrine, and Nobiletin in Citrus unshiu Peel.

A single herb can contain multiple constituents with diverse bioactivities. We found that the extract of Citrus unshiu peel (CUP), induced abnormal vasoconstriction responses on the freshly isolated rat aortic rings in vitro. CUP stimulated the vasoconstriction alone, and it suppressed the phenylephrine-stimulated vasoconstriction. We studied the reasons behind this abnormal vasoconstriction pattern. Major constituents of CUP were determined and evaluated for their vaso-activities. Notably, synephrine, a contractile agonist, and nobiletin, newly identified to have anti-contractile activity co-existed in CUP. Synephrine and nobiletin competitively blocked or activated the same contractile targets resulting in contradicting and abnormal vasoconstriction responses. Accordingly, the vasoconstriction pattern varies significantly depending on the relative contents of synephrine and nobiletin in CUP. Interestingly, this response pattern could be observed with another plant extract, Acorus gramineus Sol. Collectively, we demonstrated that active ingredients with contradicting bioactivities could co-exist in a single plant extract, interact and produce abnormal response patterns in bioassay, which would give an important insight into the interpretation of unusual activity patterns induced by plant extracts.

Pharmacological studies of tentacle extract from the jellyfish Cyanea capillata in isolated rat aorta.

Our previous studies demonstrated that tentacle extract (TE) from the jellyfish, Cyanea capillata, could cause a dose-dependent increase of systolic blood pressure, which seemed to be the result of direct constriction of vascular smooth muscle (VSM). The aim of this study is to investigate whether TE could induce vasoconstriction in vitro and to explore its potential mechanism. Using isolated aorta rings, a direct contractile response of TE was verified, which showed that TE could induce concentration-dependent contractile responses in both endothelium-intact and -denuded aortas. Interestingly, the amplitude of contraction in the endothelium-denuded aorta was much stronger than that in the endothelium-intact one, implying that TE might also bring a weak functional relaxation in addition to vasoconstriction. Further drug intervention experiments indicated that the functional vasodilation might be mediated by nitric oxide, and that TE-induced vasoconstriction could be attributed to calcium influx via voltage-operated calcium channels (VOCCs) from the extracellular space, as well as sarcoplasmic reticulum (SR) Ca²âº release via the inositol 1,4,5-trisphosphate receptor (IP3R), leading to an increase in [Ca²âº](c), instead of activation of the PLC/DAG/PKC pathway or the sympathetic nerve system.

Constriction of bovine vasculature caused by endophyte-infected tall fescue seed extract is similar to pure ergovaline.

Ergovaline has been extensively used to study vasoactive effects of endophyte- (Neotyphodium coenophialum) infected tall fescue (Lolium arundinaceum). However, initial results indicated that an extract of toxic tall fescue seed (E+EXT) is more potent than ergovaline alone in a right ruminal artery and vein bioassay. The E+EXT induced a greater contractile response than an equal concentration of ergovaline alone in the ruminal artery of heifers (P = 0.018). This led to a hypothesis that other compounds in the seed extract contribute to vasoconstriction. Thus, experiments were conducted to determine if vasoactivity of an E+EXT is different from a mixture of ergot alkaloids (ALK; ergovaline, ergotamine, ergocristine, ergocryptine, ergocornine, ergonovine, and lysergic acid) of similar concentrations and to determine if the vasoactivity of an E+EXT differs from an endophyte-free tall fescue seed extract (E-EXT). Segments of lateral saphenous vein and right ruminal artery and vein were collected from Holstein steers (n = 6) shortly after slaughter. Vessels were cleaned of excess connective tissue and fat and sliced into segments that were suspended in a multimyograph chamber with 5 mL of continually oxygenated Krebs-Henseleit buffer, equilibrated for 90 min, and exposed to a reference compound (120 mM KCl for ruminal vessels and 0.1 mM norepinephrine for saphenous vein). Increasing concentrations of each treatment (E+EXT, E-EXT, ALK, and ergovaline) were added to the respective chamber every 15 min after buffer replacement. Data were normalized as a percentage of maximal contractile response of the reference compound and fit to a sigmoidal concentration response curve. Ergovaline, ALK, and E+EXT induced similar responses in the saphenous vein, ruminal artery, and ruminal vein. The E+EXT displayed a smaller EC(50) (half maximal effective concentration) than ergovaline or ALK in the saphenous vein and ruminal vein (P < 0.008), but not the ruminal artery (P = 0.31). Extrapolated maximum response was greatest in the saphenous vein for ergovaline, least for E+EXT, and intermediate for ALK (P < 0.0001). The E-EXT did not induce a contractile response in any vessel tested (P > 0.1). Data from this study indicate that ergovaline is largely responsible for the locally induced vasoconstriction of bovine vasculature observed with endophyte-infected tall fescue.

Pharmacological characterization of FE 202158, a novel, potent, selective, and short-acting peptidic vasopressin V1a receptor full agonist for the treatment of vasodilatory hypotension.

FE 202158, ([Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]vasopressin, where Hgn is homoglutamine and iPr is isopropyl), a peptidic analog of the vasoconstrictor hormone [Arg(8)]vasopressin (AVP), was designed to be a potent, selective, and short-acting vasopressin type 1a receptor (V(1a)R) agonist. In functional reporter gene assays, FE 202158 was a potent and selective human V(1a)R agonist [EC(50) = 2.4 nM; selectivity ratio of 1:142:1107:440 versus human vasopressin type 1b receptor, vasopressin type 2 receptor (V(2)R), and oxytocin receptor, respectively] contrasting with AVP's lack of selectivity, especially versus the V(2)R (selectivity ratio of 1:18:0.2:92; human V(1a)R EC(50) = 0.24 nM). This activity and selectivity profile was confirmed in radioligand binding assays. FE 202158 was a potent vasoconstrictor in the isolated rat common iliac artery ex vivo (EC(50) = 3.6 nM versus 0.8 nM for AVP) and reduced rat ear skin blood flow after intravenous infusion in vivo (ED(50) = 4.0 versus 3.4 pmol/kg/min for AVP). The duration of its vasopressor effect by intravenous bolus in rats was as short as AVP at submaximally effective doses. FE 202158 had no V(2)R-mediated antidiuretic activity in rats by intravenous infusion at its ED(50) for reduction of ear skin blood flow, in contrast with the pronounced antidiuretic effect of AVP. Thus, FE 202158 seems suitable for treatment of conditions where V(1a)R activity is desirable but V(2)R activity is potentially deleterious, such as vasodilatory hypotension in septic shock. In addition to the desirable selectivity profile, its short-acting nature should allow dose titration with rapid onset and offset of action to optimize vasoconstriction efficacy and safety.

Vasoconstrictor and inotropic effects induced by the root bark extracts of Anthocleista schweinfurthii.

The present study was undertaken to investigate the cardiovascular effect of three extracts from the root bark of Anthocleista schweinfurthii Gilg.: an aqueous extract (AE), a dichloromethane extract (DCMR) and a fraction enriched in cardiac glycoside type compounds (CARDAN). In isolated perfused frog heart, bolus injection of the extracts produced a positive inotropic effect. The responses to AE and DCMR, but not to CARDAN, were depressed by propranolol. In isolated rat aorta, DCMR produced a transient increase in contractile tension while AE and CARDAN induced a sustained constriction. AE vasoconstrictor effect was abolished by phentolamine, while contraction evoked by CARDAN was antagonized by verapamil. In aortic rings contracted in low K+ media, the addition of K+ evoked a relaxation, which was abolished by ouabain, depressed by DCMR but not affected by either A(E) or CARDAN. These observations indicate that Anthocleista schweinfurthii contains substances that promote vasoconstriction and increase cardiac contraction. The effect of DCMR was only partially mediated by inhibition of the Na+ pump while the mechanism of action of A(E) and CARDAN was distinct from the inhibition of the Na+, K+ - ATPase pump, but could involve adrenergic receptors, or either direct or indirect activation of L-type calcium channels.

Two new benzylbenzoate glucosides from Curculigo orchioides.

An extract from in vitro cultures of Curculigo orchioides grown as bulbils in shake flasks, afforded two new glucosides of substituted benzylbenzoate - curculigoside C (3) and curculigoside D (4) - together with two known compounds - curculigoside A (1) and curculigoside B (2). Their structures were elucidated on the basis of spectral evidence, in particular by using 2D NMR methods. Their vasoactive properties were assessed in isolated rat aortic rings.

Effect on capillary permeability in rabbits of iridoids from Buddleia scordioides.

The methanol soluble fraction of the leaves of Buddleia scordioides after column chromatography resulted in the isolation of two known iridoid glucosides, catalpol and methylcatalpol. The structures were elucidated by extensive 1D-2D-NMR spectroscopy. The structure of methylcatalpol was confirmed by single-crystal x-ray diffraction. These compounds showed protective activity against increased (both chloroform and histamine) skin vascular permeability in rabbits. The protective effect was measured as the reduction in leakage of Evans blue. The results showed that the iridoids produced a significant inhibition of microvascular permeability. A comparison was made between the action of the iridoids and a known inhibitor of vascular permeability, troxerutin (50 mg/kg). Methylcatalpol and catalpol were found to be less effective than troxerutin.

Adverse drug reactions to local anesthesia.

A dentist's ability to safely administer regional anesthesia is essential for dental practice. Local anesthetic solutions used in the United States for dental anesthesia are formulated with several components. The contents of a standard local anesthetic cartridge may include an amide or ester local anesthetic drug, an adrenergic vasoconstrictor, and an antioxidant. In susceptible patients, any of these components may induce systemic, dose-dependent adverse reactions. Although extremely rare, allergic reactions may also occur. Signs and symptoms of the various adverse reactions associated with local anesthetics are quite distinctive, permitting rapid diagnosis and treatment. Serious reactions are extremely infrequent and, when treated properly, unlikely to result in significant morbidity or mortality.

Cardioactive diterpenoids from the roots of Salvia amplexicaulis.

Five diterpenoids, three steroids, four triterpenoids and one flavonoid were isolated from the roots of Salvia amplexicaulis Lam. (Lamiaceae). Structures of these compounds were elucidated by spectroscopic analysis. The crude extract and the pure compounds were tested for cardiovascular parameters using Wistar Albino rats. The crude extract, and 7-oxo-abieta-9,12,14-triene, ferruginol, stigmast-4-en-3-one showed a vasodepressor effect.

Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults.

The Seville orange extract Citrus aurantium contains m-synephrine (phenylephrine) and octopamine; it causes cardiac disturbances in animals and is used by humans for weight loss. Juice from the orange (Seville orange juice [SOJ]) is used to "knock out" intestinal cytochrome P450 (CYP) 3A4 in bioavailability studies. The purpose of this study was to determine synephrine and octopamine concentrations in SOJ and SOJ's cardiovascular effects in normotensive humans. Subjects consumed 8 ounces of SOJ and water in crossover fashion followed by a repeat ingestion 8 hours later. Hemodynamic (heart rate; systolic, diastolic, and mean arterial pressure) measurements followed. Synephrine and octopamine were determined by high-performance liquid chromatography. Hemodynamics did not differ significantly between water and SOJ groups. Mean synephrine concentration of SOJ samples was 56.9 +/- 0.52 microg/ml; octopamine was not detected. SOJ ingestion by normotensive subjects is expected to be safe. Individuals with severe hypertension, tachyarrhythmias, and narrow-angle glaucoma and monoamine oxidase inhibitor recipients should avoid SOJ consumption. Persons taking decongestant-containing cold preparations should also refrain from SOJ intake.

Primary structure and biological activity of hemoglobin-related hypothalamic peptides.

Five individual fractions from bovine hypothalamic extract, displaying coronary constrictory activity, were isolated and sequenced. All of them belong to the hemorphin group of hemoglobin-derived peptides. These peptides bind calmodulin and activate calmodulin-dependent enzymes. The relationship of isolated peptides with other members of the hemorphin group is discussed. Several new fragments of hemoglobin alpha- and beta-chains with yet unidentified activity were obtained from the same source. Their amino acid sequences have considerable overlap with the known sequences of hemoglobin fragments isolated from other tissues.

Carbazole alkaloids from Clausena excavata and their biological activity.

Five new carbazole alkaloids, clausines B, E, H, I and K, as well as 22 known compounds, were isolated from the stem bark of Clausena excavata. The structures were established from spectral data and chemical transformation. These compounds showed significant inhibition of rabbit platelet aggregation and caused vasocontraction. The crude methanol extract, partitioned layers and chromatographic fractions revealed the presence of promotive and inhibitive constituents, simultaneously. These results might explain the philosophy of use in Chinese medicine, in that the dose and content variation in a prescription produced different, promotive or inhibitive, effects on therapy.

Vasoconstrictor activity of 8-O-acetylharpagide from Ajuga reptans.

The traditional therapeutic indications for the use of Ajuga reptans (Labiatae) have been investigated. The H2O-soluble part of a crude and partially purified MeOH extract and two isolated iridoids (8-O-acetylharpagide and harpagide), were tested for a biological activity on isolated smooth muscle preparations from guinea pig.