Contraction Of Rabbit Aorta Research Articles

Pharmacological basis for the folkloric uses of <i>Buxus wallichiana</i> in gastrointestinal, respiratory and vascular disorders

<p><em>In vitro</em> study was carried out to explore the pharmacological basis of crude extract of <em>Buxus wallichiana </em>for its folkloric uses in gastrointestinal, respiratory and vascular disorders. In jejunum preparations, crude extract (0.03 ± 1.0 mg/mL) caused a transient spasmogenic effect followed by the spasmolytic effect at higher doses (3.0–10 mg/mL). In atropinized jejunum preparation, crude extract inhibited the spontaneous and K<sup>+ </sup>(80 mM)-induced contraction, suggesting that spasmolytic effect is mediated through the Ca<sup>+2</sup>-channel blockade. The Ca<sup>+2</sup>-channel blockade effect was confirmed when pretreatment of tissue with extract produced a dose-dependent shift in Ca<sup>+2 </sup>concentration-response curves to the right, similarly as verapamil. Furthermore, crude extract exhibited non-specific relaxant effect on carbachol- (1 µM) and K<sup>+ </sup>(80 mM)-induced tracheal contractions, suggesting the coexistence of anticholi-nergic and Ca<sup>+2</sup>-antagonistic properties. Moreover, it relaxed the K<sup>+ </sup>(80 mM)- and phenylephrine (1 µM)-induced contraction in rabbit aorta, suggesting the Ca<sup>+2</sup>-channel blockade. These findings may validate the folkloric uses of <em>B. wallichiana</em> in constipation, bronchitis, asthma and hypertension.</p>

Synthesis and in vitro evaluation of ambrisentan analogues as potential endothelin receptor antagonists

A series of novel 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3,3-diphenyl butyric acid derivatives were synthesized and evaluated for their antagonistic activity for endothelin-1-induced contraction in rabbit aorta. Within this series of compounds, 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-cyano-3,3-diphenylpropionic acid (4) displays comparable potency with ambrisentan (1), and warrants further investigation.

Mechanism of superoxide anion-induced modulation of vascular tone

We investigated the effects of superoxide anions (O2−) generated by xanthine (X) plus xanthine oxidase (XO) on isolated rabbit aorta suspended in Krebs-Ringer solution. Xanthine plus xanthine oxidase produced concentration-dependent contractions of rabbit aorta. Superoxide dismutase completely reversed the contractile response observed. Superoxide anion-induced contraction of rabbit aorta was totally abolished in preparations denuded of endothelium. The contractile effect was reduced by 56% by the cyclooxygenase inhibitor, indomethacin. The contractile effect was not affected by the angiotensin converting enzyme inhibitor, captopril. These results indicate that O 1 − produces a contraction of the isolated rabbit aorta that is endothelium-dependent and is partly mediated by an arachidonic acid metabolite.

Coriander fruit exhibits gut modulatory, blood pressure lowering and diuretic activities

Aim of the study Coriander ( Coriandrum sativum) is traditionally used for various gastrointestinal and cardiovascular disorders and this study was designed to rationalize its use in dyspepsia, abdominal colic, diarrhea, hypertension and as diuretic. Materials and methods Coriander crude extract (Cs.Cr) was evaluated through in vitro and in vivo techniques. Results Cs.Cr caused atropine sensitive stimulatory effect in isolated guinea-pig ileum (0.1–10 mg/ml). In rabbit jejunum preparations, Cs.Cr evoked a similar contractile response but in the presence of atropine, it exhibited relaxation against both spontaneous and high K + (80 mM)-induced contractions as well as shifted the Ca 2+ concentration–response curves to right, similar to that caused by verapamil. Cs.Cr (1–30 mg/ml) caused fall in arterial blood pressure of anesthetized animals, partially blocked by atropine. Cs.Cr produced vasodilatation against phenylephrine and K + (80 mM)-induced contractions in rabbit aorta and cardio-depressant effect in guinea-pig atria. Cs.Cr produced diuresis in rats at 1–10 mg/kg. Bio-assay-directed fractionation revealed the separation of spasmogenic and spasmolytic components in the aqueous and organic fractions respectively. Conclusions These results indicate that coriander fruit exhibits gut stimulatory, inhibitory and hypotensive effects mediating possibly through cholinergic, Ca 2+ antagonist and the combination of these mechanisms respectively. Diuretic activity adds value to its use in hypertension.

Ascorbate enhancement of H1 histamine receptor sensitivity coincides with ascorbate oxidation inhibition by histamine receptors

Ascorbate has previously been shown to enhance both alpha(1)- and beta(2)-adrenergic activity. This activity is mediated by ascorbate binding to the extracellular domain of the adrenergic receptor, which also decreases the oxidation rate of ascorbate. H1 histamine receptors have extracellular agonist or ascorbate binding sites with strong similarities to alpha(1-) and beta(2)-adrenergic receptors. Physiological concentrations of ascorbate (50 microM) significantly enhanced histamine contractions of rabbit aorta on the lower half of the histamine dose-response curve, increasing contractions of 0.1, 0.2, and 0.3 microM histamine by two- to threefold. Increases in ascorbate concentration significantly enhanced 0.2 microM histamine (5-500 microM ascorbate) and 0.3 microM histamine (15-500 microM ascorbate) in a dose-dependent manner. Histamine does not measurably oxidize over 20 h in oxygenated PSS at 37 degrees C. Thus the ascorbate enhancement is independent of ascorbate's antioxidant effects. Ascorbate in solution oxidizes rapidly. Transfected histamine receptor membrane suspension with protein concentration at >3.1 microg/ml (56 nM maximum histamine receptor) decreases the oxidation rate of 392 microM ascorbate, and virtually no ascorbate oxidation occurs at >0.0004 mol histamine receptor/mol ascorbate. Histamine receptor membrane had an initial ascorbate oxidation inhibition rate of 0.094 min.microg protein(-1).ml(-1), compared with rates for transfected ANG II membrane (0.055 min.microg protein(-1).ml(-1)), untransfected membrane (0.052 min.microg protein(-1).ml(-1)), creatine kinase (0.0082 min.microg protein(-1).ml(-1)), keyhole limpet hemocyanin (0.00092 min.microg protein(-1).ml(-1)), and osmotically lysed aortic rings (0.00057 min.microg wet weight(-1).ml(-1)). Ascorbate enhancement of seven-transmembrane-spanning membrane receptor activity occurs in both adrenergic and histaminergic receptors. These receptors may play a significant role in maintaining extracellular ascorbate in a reduced state.

The combination of rat mast cell and rabbit aortic smooth muscle is the simple bioassay for the screening of anti-allergic ingredient from methanolic extract of Corydalis tuber.

We have assessed the release of histamine from mast cells by smooth muscle contraction. 0.3 microg/ml compound 48/80 showed no effect on concentration-response relationship of histamine in rabbit aorta. Compound 48/80 induced release of histamine from rat mast cells. When aorta was stimulated by compound 48/80 in the presence of mast cells, contraction was evoked in concentration-dependent manner. This mast cell-dependent contraction was completely blocked by H1 receptor antagonist, 1 microM diphenhydramine. When mast cells was treated with compound 48/80 inhibitor benzalkonium chloride, mast cell-dependent contraction was inhibited, although benzalkonium chloride itself showed no effect on concentration-response relationship of histamine in rabbit aorta. At high concentration of 10 microg/ml, benzalkonium chloride itself evoked histamine release from mast cells and indeed inhibitory effect of 10 microg/ml benzalkonium chloride on mast cell-dependent contraction was lower than that of 3 microg/ml. We have applied this bioassay to search anti-allergic ingredient from a total methanolic extract of Corydalis tuber (Corydalis turtschaninovii BESSER forma yanhusuo Y. H. CHOU et C. C. HSU). Successively, we have isolated five fractions. The fractions I-IV are identified to be corybulbine (1), tetrahydropalmatine (2), corydaline (3) and yuanhunine (4), respectively. Main component of fraction V is the mixture of 3 and canadine (5). Fractions II and V significantly inhibited mast cell-dependent contraction in rabbit aorta as well as inhibited histamine release from rat mast cells. Furthermore, fractions I, III and V inhibited histamine-induced contraction in rabbit aorta at non-competitive manner. From these results, combination of rat mast cells and rabbit aorta is good bioassay to search the anti-allergic ingredient, and we have obtained effective fractions from Corydalis tuber using this assay.

Mechanism of superoxide anion-induced modulation of vascular tone

We investigated the effects of superoxide anions (O2−) generated by xanthine (X) plus xanthine oxidase (XO) on isolated rabbit aorta suspended in Krebs-Ringer solution. Xanthine plus xanthine oxidase produced concentration-dependent contractions of rabbit aorta. Superoxide dismutase completely reversed the contractile response observed. Superoxide anion-induced contraction of rabbit aorta was totally abolished in preparations denuded of endothelium. The contractile effect was reduced by 56% by the cyclooxygenase inhibitor, indomethacin. The contractile effect was not affected by the angiotensin converting enzyme inhibitor, captopril. These results indicate that O2 − produces a contraction of the isolated rabbit aorta that is endothelium-dependent and is partly mediated by an arachidonic acid metabolite.

In vitro effects of dantrolene sodium and verapamil on noradrenaline-induced contractions of rabbit aorta and their interactions.

The effects of dantrolene sodium (0.1 to 10 microM) and verapamil (0.01 to 1 microM) administered alone or together (1 microM verapamil, 0.1 to 10 microM dantrolene sodium) were investigated in isolated rabbit thoracic aorta precontracted with 0.1 microM noradrenaline (NA). Verapamil plus dantrolene sodium produced a dose-dependent inhibition of aortic strips contractions evoked by NA, and all concentrations of dantrolene sodium significantly decreased the inhibitory effect of 1 microM verapamil (p < 0.001, ANOVA). In conclusion, dantrolene sodium and verapamil inhibited 0.1 microM noradrenaline-evoked aorta contractions, and all doses of dantrolene sodium decreased the inhibitory effect of 1 microM verapamil in a dose-dependent manner.

Prevention of LDL α-tocopherol consumption, cholesterol oxidation, and vascular endothelium dysfunction by polyphenolic compounds from red wine

Red wine polyphenolic compounds (RWPCs) have been demonstrated to possess antioxidant properties, and several studies have suggested that they might constitute a relevant dietary factor in the protection from coronary heart disease. The aim of the present study was to determine further the mechanism by which RWPCs can prevent the formation of vasoactive compounds in oxidized LDL. RWPCs were obtained from the Cabernet-Sauvignon grape variety. Human LDL was oxidized in the presence of CuSO 4 (ox-LDL). Vascular reactivity studies were conducted on rabbit aortic rings. RWPCs significantly reduced the formation of 7β-hydroxycholesterol and 7-ketocholesterol and in a lower extent the emergence of lysophosphatidylcholine in ox-LDL. The ability of RWPCs to prevent cholesterol oxide formation was directly dependent on the LDL α-tocopherol content. Once the LDL α-tocopherol has been consumed, RWPCs were no longer effective, indicating that RWPCs act by sparing endogenous α-tocopherol. As a consequence of the preservation of the endogenous α-tocopherol content of LDL, RWPCs could prevent the inhibition of the acetylcholine-mediated endothelium-dependent relaxation of rabbit aorta which was linked to a direct effect on NO release. Independently of a treatment with ox-LDL, RWPC exerted a concentration-dependent and persistent inhibitory effect on the norepinephrine-induced contraction of rabbit aorta. In conclusion, RWPCs can preserve a normal vascular reactivity by acting at different stages of the cascade that leads to lipid oxidation, endothelium dysfunction and vasospasm.

Mechanisms of blockade by the novel migraine prophylactic agent, dotarizine, of various brain and peripheral vessel contractility

The novel antimigraineur, dotarizine, inhibited 5-HT (5 hydroxytryptamine)-evoked contractions of rabbit vertebral, aorta, femoral and mesenteric arteries, with IC 50s of 1.35, 1.40, 0.52 and 1.09 μM, respectively. Flunarizine had little effect on these contractions, while ketanserin was more potent (IC 50s of 0.17 μM for vertebral, 0.22 μM for aorta, 0.05 μM for femoral and 0.03 μM for mesenteric arteries). At 10 μM, dotarizine caused 40% blockade of K +-evoked contractions of rabbit aorta, and 70% inhibition of 5-HT-evoked responses; these values were 30% and 20% for 10 μM flunarizine. Contractions of rabbit aorta elicited by noradrenaline, angiotensin II or prostaglandin F 2α were not affected by 10 μM dotarizine or flunarizine. Ketanserin shifted to the right, in parallel, the concentration–response curves for 5-HT in rabbit aorta; however, dotarizine caused a non-competitive type of blockade, increasing the maximum 5-HT contraction at 30 nM and decreasing it at 3 and 30 μM. K +-evoked contractions of rabbit aorta were halved by 3 μM dotarizine in a voltage-independent manner; flunarizine caused a delayed-type, non-reversible post-drug blockade, and exhibited some voltage-dependence. Blockade by nifedipine was voltage-dependent and fully reversible. Ca 2+-evoked contractions of depolarised bovine middle cerebral arteries were blocked by 1–3 μM dotarizine in a non-surmountable manner. Contraction of these vessels evoked by electrical stimulation was blocked 50% and 70% by 1 and 3 μM dotarizine, respectively. Dotarizine (1–3 μM) also inhibited to a similar extent the K +-evoked [ 3H]noradrenaline release from cultured rat sympathetic neurones. These data suggest that the mechanism of blockade by dotarizine of cerebral vessels contractility has three components: (i) presynaptic inhibition of noradrenaline release; (ii) blockade of postsynaptic vascular 5-HT receptors; (iii) blockade of Ca 2+entry into the vascular smooth muscle cell cytosol. The compound does not affect the vascular receptors for noradrenaline, angiotensin II or prostaglandin F 2α.

Benzylbenzoate and norlignan glucosides from Curculigo pilosa: structural analysis and in vitro vascular activity

From the rhizomes of Curculigo pilosa, two benzylbenzoate diglucosides, piloside A and piloside B, and a glucosyl-fused norlignan, pilosidine, previously obtained only as the tetra- O-methyl derivative, were isolated. Pilosidine showed facilitating effect on adrenaline evoked contractions in rabbit aorta isolated preparations.

Hypotensive action of coumarin glycosides from Daucus carota.

Daucus carota (carrot) has been used in traditional medicine to treat hypertension. Activity-directed fractionation of aerial parts of D. carota resulted in the isolation of two cumarin glycosides coded as DC-2 and DC-3. Intravenous administration of these compounds caused a dose-dependent (1-10 mg/kg) fall in arterial blood pressure in normotensive anaesthetised rats. In the in vitro studies, both compounds caused a dose-dependent (10-200 microg/ml) inhibitory effect on spontaneously beating guinea pig atria as well as on the K+ -induced contractions of rabbit aorta at similar concentrations. These results indicate that DC-2 and DC-3 may be acting through blockade of calcium channels and this effect may be responsible for the blood pressure lowering effect of the compounds observed in the in vivo studies.

Effects of three different Ca 2+ pump ATPase inhibitors on evoked contractions in rabbit aorta and activities of Ca 2+ pump ATPases in porcine aorta

Using vascular smooth muscle, we describe the actions of three pharmacological tools, cyclopiazonic acid (CPA), thapsigargin (TG) and 2,5-di-( tert-butyl)-1,4-benzohydroquinone (tBHQ), which are presumed to act as selective inhibitors of the sarco-endoplasmic reticulum Ca 2+-ATPases (SERCAs). In porcine aortic smooth muscle microsomes two Ca 2+-ATPase activities have been described, one vanadate-sensitive and one vanadate-resistant, representing the Ca 2+-ATPase activities of the plasma membrane and SERCAs, respectively. In agreement, CPA, TG and tBHQ, in the concentration range 0.1 μM to 0.1 mM, dose-dependently inhibit the Ca 2+-ATPase activity only in the vanadate-resistant microsomes. However, 0.1 mM tBHQ also significantly inhibited the Ca 2+-ATPase activity of vanadate-sensitive microsomes. In rabbit aortic rings, all three SERCA inhibitors produced a dose-dependant inhibition of contractions evoked by 20 mM caffeine or 1 μM phenylephrine (PE) in a Ca 2+-free physiological solution. However, in PE-contracted rings, tBHQ (≥30 μM) also significantly inhibited the ability of cromakalim to induce relaxation. In conclusion, the data suggest that CPA, TG and tBHQ can all act as selective SERCA inhibitors in both porcine and rabbit aortic smooth muscle. However, in contrast to CPA and TG, high concentrations of tBHQ can exhibit some nonspecific effects, which include inhibition of the plasma membrane Ca 2+-ATPase and possibly K + channels regulated by cromakalim.

Isometric contraction induces the Ca2+-independent activation of the endothelial nitric oxide synthase.

Shear stress and tyrosine phosphatase inhibitors have been shown to activate the endothelial NO synthase (eNOS) in a Ca2+/calmodulin-independent manner. We report here that isometric contraction of rabbit aorta activates eNOS by a pharmacologically identical pathway. Endothelium-intact aortic rings were precontracted under isometric conditions up to 60% of the maximal phenylephrine-induced tone. The NO synthase inhibitor NGnitro-L-arginine (L-NA) and the soluble guanylyl cyclase inhibitor NS 2028 induced an additional contraction, the amplitude of which depended on the level of precontraction. The maximal production of NO by isometrically contracted aortic rings (as estimated by the increase in cGMP in detector smooth muscle cells in a superfusion bioassay) was observed during the initial phase of isometric contraction and was greater than that detected following the application of acetylcholine. The supplementary L-NA-induced increase in vascular tone was inhibited by the nonselective kinase inhibitor staurosporine and the tyrosine kinase inhibitors erbstatin A and herbimycin A. Another tyrosine kinase inhibitor, genistein, the calmodulin antagonist calmidazolium, and the selective protein kinase C inhibitor, Ro 31-8220, had no effect. Coincident with the enhanced NO formation during isometric contraction was an increase in the tyrosine phosphorylation of endothelial proteins, which also correlated with the level of precontraction. Thus, isometric contraction activates eNOS via a Ca2+-independent, tyrosine kinase inhibitor-sensitive pathway and, like shear stress, seems to be an independent determinant of mechanically induced NO formation.

Characteristics of Ca 2+ channel blockade by oxodipine and elgodipine in rat cardiomyocytes

The two novel dihydropyridines, oxodipine and elgodipine greatly depressed the KCl-induced contraction of rabbit aorta and decreased the cardiac force of contraction of rat ventricular strips with lower potency. Both compounds markedly shortened cardiac action potentials. In rat cultured neonatal ventricular myocytes, oxodipine and elgodipine decreased the L-type Ca 2+ current ( I CaL) with IC 50 of 0.24 and 0.33 μM respectively while oxodipine was slightly more potent on the T-type Ca 2+ current ( I CaT) than elgodipine (IC 50=0.41 vs. 2.18 μM). Both compounds were less potent in inhibiting I CaL of adult cardiomyocytes. Oxodipine exhibited mostly a tonic block of both currents while elgodipine induced mainly a use-dependent block. Oxodipine and elgodipine increased by at least one order of magnitude their inhibitory potency on I CaT and I CaL when the cells were partially depolarized. We conclude that the mechanisms of inhibition of Ca 2+ channels by these two dihydropyridines are different and suggest that the underlying mechanism of vascular selectivity is the voltage-dependent block of I CaL, with the use-dependent inhibition of Ca 2+ currents by elgodipine further contributing to this selectivity.

Solution-structure of a peptide designed to mimic the C-terminal hexapeptide of endothelin.

Ac-cyclo(Cys-His-Leu-Asp-Cys)-Ile-Trp-OH, has been designed by computer-aided molecular-modelling techniques to mimic the proposed alpha-helical conformation of the C-terminal hexapeptide of endothelin. Two-dimensional proton nuclear magnetic resonance spectra were acquired for the peptide dissolved in d6-DMSO or D2O-H2O and the distance and angle constraints incorporated into simulated annealing experiments. Conformers generated from the D2O-H2O data superposed on the corresponding main-chain atoms in the crystal structure of endothelin 1 and the solution structure of BQ-123 with root mean square co-ordinate differences of 0.9A and 0.77A, respectively. The peptide did not elicit antagonism of endothelin-induced in-vitro contractions of rabbit aorta (endothelin A receptor) or rabbit bronchus (endothelin B receptor) preparations. Because the peptide can adopt a conformer which closely matches the equivalent residues in the endothelin 1 crystal structure and in BQ-123, we suggest BQ-123 does not necessarily mimic the endothelin C-terminal region to achieve its antagonism, and that a helical conformation of the endothelin C-terminal hexapeptide does not favour its interaction at the endothelin B receptor.

Physiological Role of Ca2+-Permeable Nonselective Cation Channel in Endothelin-1-Induced Contraction of Rabbit Aorta

We previously showed a role for a nonselective cation channel (NSCC) in the ETA-dependent action of endothelin-1 in mouse fibroblast and rabbit aortic smooth-muscle cell. To clarify the physiological significance of NSCCs in endothelin-1 (ET-1)-induced vasocontraction, we examined the effects of NSCC blockers such as mefenamic acid and SK&F 96365 on the contractions of deendothelialized rabbit aortic rings induced by a low (10[-10] M) or high (10[-8] M) concentration of ET-1. Mefenamic acid (< or =10[-3] M) had little effect on the contraction induced by 45 x 10(-3) M K+ or 1 x 10(-6) M Bay K-8644 in combination with 15 x 10(-3) M K+, indicating that it does not affect voltage-operated calcium channels (VOCs) and contractile mechanisms. The contraction by a low concentration of ET-1 was abolished after removal of extracellular Ca2+, but it was reduced only to 50% by a maximally effective concentration (10[-5] M) of nifedipine, an inhibitor of L-type VOCs (L-VOC). Mefenamic acid and SK&F 96365 inhibited the ET-1-induced contraction with 50% inhibitory concentration (IC50) values of 10(-4) M and 2 x 10(-5) M, respectively, and abolished it at 10(-3) M and 10(-4) M. By contrast, nifedipine, mefenamic acid, or SK&F 96365 had little effect on the contraction by a high concentration of ET-1. The contraction induced by a low or high concentration of ET-1 was abolished by an ETA antagonist, BQ-123, but not by an ETB antagonist, BQ-788. These results demonstrate that the contraction induced by ET-1 is totally mediated exclusively by ETA, but that Ca2+ entry through NSCCs in addition to L-VOCs plays an important role in contractions induced by low concentrations of ET-1, whereas it plays only a minor role in contractions induced by high concentrations of ET-1.

The role of myosin light chain kinase-dependent phosphorylation of myosin light chain in phorbol ester-induced contraction of rabbit aorta

We investigated the role of 20 kDa myosin light chain (MLC20) phosphorylation in contractions following protein kinase C (PKC) activation by 12-deoxyphorbol-13-isobutyrate (DPB) in rabbit aortae. DPB induced a sustained contraction and phosphorylation of MLC20 independent of a change in cytosolic Ca2+ ([Ca2+]i). Phosphorylation on Ser19 of MLC20, which is a target site of MLC kinase (MLCK), was 9.2 +/- 5.1% and 22.3 +/- 4.9% of the phosphorylation caused by KCl, at 5 and 30 min of application of DPB, respectively. When KCl-precontracted muscles were rinsed with Ca2+-free, EGTA solution, [Ca2+]i rapidly declined, MLC20 was dephosphorylated and the tension decreased. If DPB was present in the Ca2+-free solution, the relaxation and the dephosphorylation of either total MLC20 or Ser19 were inhibited. The phospholipase A2 inhibitor ONO-RS-082 partially antagonized the effects of DPB on the tension and the MLC20 dephosphorylation. In Ca2+-free solution, DPB induced a contraction smaller than that in normal solution without an increase in MLC20 phosphorylation, and the contraction was also sensitive to ONO-RS-082. These results suggest that a part of MLC20 phosphorylation following PKC activation is due to inhibition of MLC20 phosphatase and the phosphorylation is responsible for the contraction. Furthermore, a mechanism independent of [Ca2+]i and phosphorylation may play a significant role in the PKC-dependent contraction. The involvement arachidonic acid is suggested, not only in the inhibition of dephosphorylation but also in the Ca2+-independent regulation of contractile proteins.

Effect of KMD-3213, an α1a-adrenoceptor-selective antagonist, on the contractions of rabbit prostate and rabbit and rat aorta

KMD-3213, (−)-( R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide, a newly synthesized α 1-adrenoceptor antagonist, has been shown to have potent action toward, and to be selective for human cloned and native α 1-adrenoceptors. In the present study, we characterized the inhibitory effect of KMD-3213 on the phenylephrine ( α 1-adrenoceptor-selective agonist)-induced contraction of rabbit prostate, rabbit thoracic aorta and rat thoracic aorta to functionally confirm the tissue selectivity of KMD-3213. The mean pA 2 value for KMD-3213 for the inhibition of the rabbit prostatic contraction was 10.05, whereas the values for the rabbit and rat aortic contractions were 9.36 and 8.13, respectively. The order of mean pA 2 values for the inhibition of the rabbit prostatic contraction was KMD-3213 ≥ tamsulosin > > prazosin, whereas that for the rabbit and rat aortic contractions was tamsulosin > KMD-3213 > prazosin and tamsulosin ≥ prazosin > > KMD-3213, respectively. KMD-3213 produced a sigmoidal inhibition curve for single-dose phenylephrine-induced contractions of rabbit prostate, whereas it produced a non-sigmoidal curve for that of rabbit aorta. KMD-3213 had no effect on isoproterenol-induced chronotropic action in guinea-pig atria, and 5-hydroxytryptamine-, histamine- and acetylcholine-mediated contractions of rabbit aorta. These results indicate that the potency of the inhibitory activity of KMD-3213 depends on the tissue subtype expression and that KMD-3213 preferentially antagonizes prostatic contraction.

Effects of hypertension on hypercholesterolemia-induced changes in contraction of rabbit aorta and carotid artery

Reactivity of aortic and carotid strips from control; hypertensive; hypercholesterolemic; and hypertensive/hypercholesterolemic rabbits was studied. Maximal stress was less in strips from hypertensive/hypercholesterolemic animals. Norepinephrine sensitivity was increased in the carotid artery from hypertensive/hypercholesterolemic animals (EC 50: 0.11 μM; 0.35 μM control). CaCl 2 sensitivity during norepinephrine-induced contractions was enhanced by hypertension and hypercholesterolemia (carotid EC 50: 0.10 mM; 0.38 mM control; aorta EC 50: 0.12 mM; 0.82 mM control) Similar results were obtained during membrane depolarization. 5-hydroxytryptamine sensitivity (EC 50: 0.15μM carotid; 0.18 μM aorta) was decreased during hypertension (EC 50: 0.51 μM carotid; 1.13 μM aorta) and by hypercholesterolemia (EC 50: 1.76 μM carotid; 1.53 μM aorta). Our results support the hypothesis that hypertension and hypercholesterolemia increase vascular sensitivity by increasing Ca 2+ permeability. Our results also suggest that hypertension and hypercholesterolemia selectively decrease 5-hydroxytryptamine-induced contractions.