Inhibitory effect of propranolol on tetanic contraction in rabbit

The effects of propranolol on electrical and mechanical activity during tetanic stimulation of the diaphragm and leg muscles, and on the heart rate, were studied in the anaesthetized rabbit. Propranolol (from 0.5 mg/kg) reduced the EMG evoked in diaphragm by phrenic nerve stimulation (50/sec) and the EMG and force of contraction during periods of increased respiratory drive obtained by partial tracheal obstruction. The heart rate was lowered by 10–25%. In the indirectly or directly stimulated leg muscles, the drug induced high frequency inhibition of EMG and tetanic contractions (100/sec) without affecting twitch contractions. The inhibitory effect of propranolol on skeletal muscle was probably not caused by β-adrenergic block, but by stabilization of the sarcolemma. The results suggest that the high frequency inhibitory effect might contribute to the fatigue and reduced work capacity frequently observed when high doses of propranolol are given to man and animals.     

Influence of endothelium on drug-induced relaxation of the rabbit aorta

The influence of endothelium on relaxation induced by glyceryl trinitrate (GTN) and isoprenaline (I) has been studied in isolated rabbit aortic ring preparations, in the resting state and after constriction with 5-hydroxytryptamine (5HT). In resting preparations relaxant responses to GTN and I were smaller in the presence of endothelium. In preparations constricted with 5HT relaxant responses to GTN and I were conversely greater in the presence of endothelium. These paradoxical findings are discussed in relation to basal release of endothelium derived relaxant factor.     

Mechanism of barium-induced contraction in the vascular smooth muscle of rabbit aorta.

In a solution containing 1.5 mM Ca2+, cumulative application of 0.3-10.0 mM Ba2+ induced a concentration-dependent contraction of the rabbit aorta. This contraction was reduced by the Ca2+ channel inhibitors, verapamil (10(-6) M), nifedipine (10(-7) M) and lanthanum (2.0 mM), and was potentiated by the Ca2+ channel facilitator, Bay K8644 (10(-7) M). In a Ca2+-free solution containing EGTA (1.0 mM), cumulative application of Ba2+ still induced a concentration-dependent contraction, the maximum contractile tension of which was comparable to that in the presence of 1.5 mM Ca2+. The Ba2+-induced contraction which was not dependent on the external Ca2+ was also inhibited by verapamil, nifedipine and lanthanum and was potentiated by Bay K8644. A high concentration (65.4 mM) of K+ potentiated this Ba2+-induced contraction whereas noradrenaline (10(-6) M) did not have such an effect. In order to deplete the releasable Ca2+ store in the cell, the muscle strip was treated with noradrenaline (10(-6) M) and/or caffeine (20.0 mM) in a Ca2+-free solution. In such a Ca2+-depleted muscle, Ba2+ still induced a contraction of a similar magnitude to that without such treatment. Further, the second application of Ba2+ in a Ca2+-free solution induced a similar contraction to that induced by the first application of Ba2+. These results suggest that Ba2+ depolarizes the cell membrane and opens the voltage-dependent Ca2+ channels resulting in a Ca2+ influx in the presence of Ca2+. In the absence of external Ca2+, Ba2+ may enter the cell through the voltage-dependent Ca2+ channels and induce contraction without mobilizing the Ca2+ store which is sensitive to noradrenaline and caffeine.     

Effects of glibenclamide on cytosolic calcium concentrations and on contraction of the rabbit aorta.

1. Using fluorometry of fura-2 and rabbit aortic strips, we studied the effects of glibenclamide (GLB), a sulphonylurea anti-diabetic drug and an inhibitor of opening of K+ channels, on cytosolic calcium concentrations ([Ca2+]i) and on force development. 2. Both high K(+)-depolarization and noradrenaline (NA) increased [Ca2+]i and force, in a concentration-dependent manner, in the presence of extracellular Ca2+ (1.25 mM). However, force development in relation to [Ca2+]i ([Ca2+]i-force relationship) observed with NA was much greater than that observed with K(+)-depolarization. 3. Pretreatment with GLB (10(-6)-10(-4) M) for 10 min partially inhibited, in a concentration-dependent manner, both [Ca2+]i elevation and the force development induced by 118 mM K(+)-depolarization or NA 10(-5) M in the presence of extracellular Ca2+. The [Ca2+]i-force relationship induced by both 118 mM K+ physiological salt solutions and by NA 10(-5) M in the GLB-treated strips overlapped that obtained in the non-treated strips, thereby suggesting that GLB has no effect on the Ca2(+)-sensitivity of the intracellular contractile apparatus. Only high concentrations (10(-4) M) of GLB decreased [Ca2+]i and the force, when applied after the force induced by 118 mM K+ PSS or NA 10(-5) M reached the maximum level. 4. In the absence of extracellular Ca2+, NA induced a transient increase in [Ca2+]i and in the force and these increases were inhibited when the vascular strips were pretreated with GLB for 10 min. The [Ca2+]i-force relationship obtained in the GLB-treated strips overlapped that in the non-treated ones.(ABSTRACT TRUNCATED AT 250 WORDS)     

Possible mechanisms of inhibition with atropine against noradrenaline-induced contraction in the rabbit aorta.

1. In the rabbit isolated aorta, atropine (3 x 10(-6) M-10(-4) M) inhibited contractile response to noradrenaline without affecting contraction to KCl. 2. In the presence of contraction to noradrenaline, atropine (3 x 10(-7) M-10(-4) M) caused concentration-dependent relaxation. Pretreatment with theophylline (10(-3) M) potentiated the relaxant action of atropine. Relaxation to atropine was not affected by the specific guanosine 3':5'-cyclic monophosphate phosphodiesterase inhibitor, M & B 22,948 (10(-4) M), tetraethylammonium (10 mM), indomethacin (10(-5) M), propranolol (10(-7) M), nifedipine (10(-6) M) or removal of the endothelium. 3. Relaxation to either atropine or prazosin was not affected by preincubation with prazosin and atropine, respectively. 4. In Ca(2+)-free medium containing EGTA and nifedipine, atropine (10(-7) M-10(-4) M) inhibited the residual noradrenaline response more than the subsequent Ca(2+)-induced contraction. Pretreatment with either theophylline (10(-3) M), forskolin (3 x 10(-7) M) or a low concentration of prazosin (3 x 10(-9) M) also inhibited the residual contraction to noradrenaline and Ca2+. The effect of combined treatment of atropine and any of these agents was much greater than with each individual agent. 5. Atropine (10(-6) M-10(-4) M) also inhibited increases in the level of inositol monophosphates (IP) in response to noradrenaline. Theophylline (10(-3) M) and a low concentration of prazosin (3 x 10(-9) M) also inhibited IP formation. Combined with atropine, the effect was much greater than with each of these agents individually. 6. Atropine did not affect adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels in the aorta and also failed to displace specific [3H]-prazosin binding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory actions of amiodarone on the isolated rabbit heart and aorta

1. The inhibitory actions of amiodarone on the isolated rabbit heart and aorta have been studied. 2. Amiodarone inhibited vasopressin- and ergonovine-induced coronary spasm, starting from a concentration of 10(-7) M which did not affect myocardial contractility to 10(-4) M, which decreased myocardial contractility. 3. Sinus node activity was largely unaffected even when the highest dose of 10(-4) M was used. 4. Amiodarone did not modify the smooth muscle contraction in rabbit aorta strips precontracted with noradrenaline or potassium. 5. Comparison with other inhibitors of the cardiovascular system (alpha- and beta-blockers, nitrates, calcium entry blockers) points out a peculiar pharmacological profile of amiodarone and indicates some doubts about its presumed anti-adrenergic properties.     

Inhibitory effects of cyclic AMP-elevating agents on norepinephrine-induced phosphatidylinositide hydrolysis and contraction in rat aorta.

1. Exposure of rat aorta to forskolin, dibutyryl cyclic AMP, rolipram or isobutylmethylxanthine partially prevented the increased inositol monophosphate accumulation due to norepinephrine, while the contractile responses to norepinephrine were almost completely inhibited. 2. Inhibition of the increased phosphatidylinositide synthesis due to norepinephrine could not account for the decreased inositol monophosphate accumulation. 3. Although the increased inositol monophosphate accumulation due to norepinephrine was partially inhibited by the cyclooxygenase inhibitor, indomethacin, the inhibitory effects of the cyclic AMP-elevating agents were still observed in the presence of indomethacin. 4. Inhibition of agonist-induced phosphatidylinositide hydrolysis may contribute, at least in part, to the vasodilatory effects of the cyclic AMP-elevating agents.     

Inhibitory effect of aclarubicin on endothelium-dependent relaxation of rat aorta.

The effects of aclarubicin on endothelium-dependent and -independent vasorelaxations were investigated in aortic strips from rats. Aclarubicin (5.9-23.6 microM) inhibited endothelium-dependent relaxation and the increment of the cyclic GMP level in aortic strips in response to acetylcholine but not the endothelium-independent relaxation and the increase of cyclic GMP level in response to sodium nitroprusside. Aclarubicin also inhibited endothelium-dependent relaxations in response to ATP and calcium ionophore A23187. These results suggest that aclarubicin can inhibit endothelium-dependent relaxation by acting somewhere distal to receptor stimulation in vascular endothelial cells.     

Mobilization of stored calcium for phasic contraction induced by norepinephrine in rabbit aorta.

In Ca-free solution norepinephrine (NE) produced only a phasic contraction in the media-intima layer of rabbit aorta. The second application of NE was almost ineffective. Incubation of the muscle with Ca for a short period (Ca loading) restored the ability to produce a phasic contraction in Ca-free solution. Various ions and compounds were applied to the muscle prior to the Ca loading or prior to NE application and it was found that these treatments variously affected the NE-induced phasic contraction. The data suggest that the NE-induced phasic contraction in Ca-free solution results from Ca release from cellular sites and that a hyperbolic relationship exists between the amount of Ca at these sites and the magnitude of the contraction. These sites take up extracellular Ca by a process sensitive to La3+ but not to D600; the Ca influx stimulated by high K solution, which is sensitive to D600 and also contributes to refilling of these sites; NE releases this stored Ca by a process sensitive to procaine, caffeine and theophylline and, in this manner, elicits a phasic contraction.     

Local formation of angiotensin II in the rat aorta: effect of endothelium.

1. The local formation of angiotensin II (AII) from its precursors, angiotensin I (AI) and tetradecapeptide (TDP) renin substrate, was studied in intact (with endothelium) and rubbed (without endothelium) aortic rings of the rat. 2. AI and TDP renin substrate maximally contracted intact tissues in a similar way to AII. The same observations were made in rubbed tissues. 3. The maximal response and the sensitivity of the aorta to these agonists were greater in rubbed than in intact tissues. 4. In intact preparations, methylene blue increased the contractile response to AII and TDP to the same extent as endothelium removal. 5. In intact preparations, AII receptor blockade completely suppressed all contractile responses, converting enzyme inhibition completely blocked the responses to AI and TDP, and renin inhibition partially blocked the responses to TDP. 6. In rubbed preparations, AII receptor blockade completely inhibited all contractile responses, converting enzyme inhibition completely suppressed the responses to AI but only partially inhibited those to TDP, and renin inhibition partially blocked the responses to TDP. 7. In conclusion, the formation of AII from TDP and its blockade by a converting enzyme inhibitor and a renin inhibitor shows that converting enzyme and a renin-like aspartic proteinase are present in the aortic wall. Furthermore, the results show that the endothelium is not essential for the conversion of the TDP to AII, but modulates the responses to locally formed AII through the release of endothelium-derived relaxing factor (EDRF).     

Pelanserin inhibition of serotonin-induced phosphatidylinositol turnover and contraction in rabbit aorta

Stimulation of rabbit aortic rings with serotonin or quipazine increased the incorporation of [³²P]Pi into phosphatidylinositol (Pl) and induced a dose-related contraction. The effects of serotonin and quipazine were blocked by 5-HT₂ antagonists with the following order of potency: pelanserin = ketanserin ? methysergide. Indorenate, a 5-HT₁ agonist, failed to modify phosphatidylinositol labeling in rabbit aorta but elicited a very weak contraction at high concentrations. Pelanserin blocked epinephrine-stimulated phosphatidylinositol labeling, being two orders of magnitude less potent than prazosin. The results demonstrate that pelanserin is a potent antagonist of the stimulation of Pl labeling and vasoconstrictor effects of 5-hydroxytryptamine and suggest that 5-HT₂ blockade is involved as its major pharmacologic action.     

Effects of lysophosphatidylcholine and endothelium on isolated rabbit aortic ring contraction by serotonin

在离体兔胸主动脉环模型上观察溶血性磷脂酰胆碱（ＬＰＣ）促血管收缩作用的机理以及血管内皮对ＬＰＣ促血管收缩作用的影响．１０μｍｏｌ·Ｌ－１ＬＰＣ预温育３０ｍｉｎ可显著增强兔胸主动脉环对５－羟色胺（５－ＨＴ）的收缩反应,使０．１μｍｏｌ·Ｌ－１５－ＨＴ诱导的峰值张力增加到约２．５倍,ＥＣ５０降低,收缩曲线左移．而蛋白激酶Ｃ（ＰＫＣ）抑制剂显形孢菌素（ｓｔａｕｒｏｓｐｏｒｉｎｅ,１００ｎｍｏｌ·Ｌ－１）能抑制ＬＰＣ的促血管收缩作用,ＥＣ５０恢复;去除血管内皮或加入１００μｍｏｌ·Ｌ－１左旋单甲基精氨酸（Ｌ－ＮＭＭＡ）预处理均可显著增强ＬＰＣ的促血管收缩作用,Ｌ－ＮＭＭＡ的作用更强（Ｐ＜０．００１）．结果提示,ＬＰＣ可能通过ＰＫＣ途径促进５－ＨＴ介导的血管收缩,血管内皮可能在其中起调控作用．     

Effects of Bay K 8644 on 45Ca uptake and efflux and on contraction in the rabbit aorta.

Contractions induced by K+, noradrenaline and 11,9-epoxymethano prostaglandin H2 (11,9-epoxymethano PGH2) were accompanied by a large, moderate and negligible stimulation of 45Ca uptake in rabbit aortic rings, respectively. Bay K 8644, 14 and 56 nM, enhanced both the contraction and the 45Ca uptake stimulated by all 3 agonists. In the absence of agonists, Bay K 8644 (14 and 56 nM) caused a small contraction and increase in 45Ca uptake. 45Ca efflux was increased by noradrenaline, and Bay K 8644 augmented this. In Ca-free solution, contractions induced by noradrenaline or 11,9-epoxymethano PGH2 were not augmented by Bay K 8644. Nifedipine (0.1 microM) antagonized 45Ca uptake stimulated by K+ or noradrenaline. Nifedipine also reduced the stimulant effect of Bay K 8644 on 45Ca uptake in the presence of all three agonists. It is concluded that, in the rabbit aorta, Bay K 8644 enhances the opening of Ca channels both during depolarization and in the presence of receptor-specific agonists and is also able to open Ca channels under basal conditions. Bay K 8644 appears not to reduce Ca efflux or enhance Ca release from intracellular stores.     

Rapid effect of progesterone on the contraction of rat aorta in-vitro

Progesterone induced rapid relaxation of KCl-induced contraction of rat aortic rings. The relaxant effect of progesterone on aortic rings was concentration-dependent (over the range of 10(-10) to 10(-5) M) and partially dependent on the endothelium. Application of a nitric oxide (NO) synthase antagonist N(G)-monomethyl-L-arginine (L-NMMA, 10(-5) M) after progesterone treatment partially inhibited the relaxant effects of progesterone. This suggested that part of the effect was through the production of nitric oxide. Washing out the steroid hormone in the bath solutions could quickly reverse the inhibitory effects of progesterone on phasic tension generation in aortic rings. Five minutes after washout, the tension generation in aortic rings was completely restored. Cultured endothelial cells from rat aorta increased release of NO into culture media in response to a 60-min exposure to progesterone. Aldosterone and dexamethasone were also tested, and failed to relax KCl-induced contraction of aortic rings. These data suggest that the vascular effects of progesterone are not mediated by a genomic action of this steroid, and that the vascular effects are mediated partially through endothelial NO production.     

辛伐他汀对高脂血症兔主动脉内皮细胞非神经性M受体的影响

目的:探索辛伐他汀降脂治疗对介导内皮依赖性血管舒张的内皮细胞非神经性M3受体基因表达的影响。方法:高脂饮食饲喂诱发兔高脂血症模型,同时设置辛伐他汀每日5mg·kg-1降脂干预,15周后,取兔血浆测定血脂指标,取主动脉环测定内皮依赖性和非内皮依赖性血管舒张活性,并取主动脉内皮细胞以RT-PCR方法检测M3亚型的表达。结果:高脂饲喂15周造成高脂血症兔模型,同时应用辛伐他汀干预可有效地降低血脂水平,提高血管的内皮依赖性舒张活性,提高介导内皮依赖性舒张活性的内皮非神经性M3基因的表达。结论:辛伐他汀可以逆转高脂血症状态下内皮非神经性M3受体的表达,改善血管的舒张活性。     

Direct pharmacological comparison of the muscarinic receptors mediating relaxation and contraction in the rabbit thoracic aorta.

The purpose of the present studies was to directly compare the pharmacology of the muscarinic cholinergic receptors coupled to carbachol-induced relaxation and contraction of the intact and the endothelium-denuded rabbit thoracic aorta, respectively. The order of potencies of agonists for producing relaxation in the intact aorta was similar to that for producing contraction in the denuded aorta. In both preparations, the partial agonists pilocarpine, McN-A-343, and RS86 functioned as antagonists, indicating a lack of receptor reserve in both preparations. Further, the pA2 values for antagonists in both tissues were virtually identical and were consistent with the pharmacology of M3 receptors.     

Inhibitory effect of dichlorvos on arterial smooth muscle contraction

The effect of the organophosphate pesticide, dichlorvos, on the contractile responses of isolated rat tail arteries has been studied. Dichlorvos (10(-8)-10(-4) M) had no effect on baseline tension, but relaxed 10(-7) M norepinephrine (NE), 10(-7) M 5-HT or 100 mM KCl contractions dose-dependently. Dichlorvos also inhibited CaCl2 dose-response curves in K+-depolarized strips, as well as depressing both phasic and tonic components of NE-induced contractions. The results suggest a direct relaxant effect of dichlorvos on arterial smooth muscle by a mechanism probably related to interference with Ca2+ supply.     

The pharmacological modulation of thrombin-induced cerebral thromboembolism in the rabbit.

1. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium-labelled platelets and 125I-labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. 2. Thrombin (100 iu kg-1, i.c.) - induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg-1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. 3. Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg-1) 5 min prior to thrombin (100 iu kg-1, i.c.) had no effect on platelet accumulation. 4. An inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 100 mg kg-1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg-1, i.c.) when administered 5 min prior to thrombin. 5. Defibrotide (32 or 64 mg kg-1 bolus i.c. followed by 32 or 64 mg kg-1 h-1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg-1, i.c.) did not significantly modify the cranial platelet accumulation response. 6. Cranial platelet accumulation induced by thrombin (100 iu kg-1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg-1, i.c., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 micrograms kg-1, i.v. bolus) or recombinant tissue plasminogen activator (rt-PA; 100 micrograms kg-1, i.c. bolus followed by 20 micrograms kg-1 min-1, i.c., infusion for 45 min) administered 20 min after thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)