Mechanisms of hypoxic coronary vasodilatation in isolated perfused rat hearts.

We pharmacologically investigated the potential involvement of nitric oxide (NO), prostacyclin, adenosine, adenosine triphosphate (ATP)-sensitive K (K(ATP)) channel opening and Ca2+-activated K (K(Ca)) channel opening in coronary vasodilatation during 15 min of hypoxia in isolated rat hearts perfused at a constant pressure of 70 mm Hg. The coronary flow suppressed by 10(-4) M Nomega-nitro-L-arginine methyl ester (L-NAME), which corresponds to the NO-dependent flow, decreased to almost zero during hypoxia. In contrast, the NO-dependent coronary flow amounted to approximately 40% of the total coronary flow during normoxia. The suppression of coronary flow by 10(-5) M 8-phenyltheophylline (8-PT), which corresponds to the adenosine-dependent flow, was remarkable in the middle and the late phases of a 15-min hypoxia. The coronary flow suppressed by 2 x 10(-6) M glibenclamide, which corresponds to the K(ATP) channel opening-dependent flow, depended on the agents added to the perfusate. However, there was a marked increase in coronary flow in the early phase of hypoxia in the heart perfused with the combination of 8-PT, 10(-2) M tetraethylammonium (TEA) and L-NAME. During hypoxia, the coronary flow suppressed by TEA, which corresponds mainly to the K(Ca) channel opening-dependent flow, also depended on the agents added to the perfusate. However, during reoxygenation, there was a transient significant increase in any combination of the agents. Our study suggests that hypoxia almost completely inhibits NO production, and that K(ATP) channel opening immediately after hypoxia and subsequent enhanced adenosine production cause a marked hypoxic coronary vasodilatation. It also suggests that K(Ca) channel opening causes vasodilatation during reoxygenation.     

Anandamide induces endothelium-dependent vasoconstriction and CGRPergic nerve-mediated vasodilatation in the rat mesenteric vascular bed

An endogenous cannabinoid anandamide (N-arachidonoylethanolamide) has been shown to cause vasodilatation in vitro and a brief vasoconstriction followed by prolonged depressor response in vivo. This study investigated the vascular effects of anandamide and underlying mechanisms in rat mesenteric vascular beds. In preparations with an intact endothelium and active tone, anandamide at low concentrations (0.1 - 1 nM) caused a concentration-dependent decrease in perfusion pressure due to vasodilatation, but at high concentrations (10 nM - 1 μM) elicited an initial and sharp increase in perfusion pressure due to vasoconstriction followed by long-lasting vasodilatation in a concentration-dependent manner. Treatment with SR141716A [cannabinoid-1 (CB(1))-receptor antagonist] blunted both the vasoconstrictor and vasodilator responses. Also, removal of the endothelium and indomethacin (cyclooxygenase inhibitor), but not adrenergic denervation with 6-hydoxydopamine (adrenergic neurotoxin), markedly inhibited the vasoconstrictor response to anandamide, while these treatments did not affect vasodilatation. The vasodilatation, but not vasoconstriction, in response to anandamide was markedly attenuated by capsazepine [selective antagonist for transient receptor potential vanilloid-1 (TRPV1)], pretreatment with capsaicin [calcitonin gene-related peptide (CGRP)ergic-nerve depletor], or cold-storage denervation. These results suggest that in rat mesenteric vascular beds, anandamide causes CB(1)-receptor- and prostanoid-mediated endothelium-dependent vasoconstriction and perivascular capsaicin-sensitive CGRPergic nerve-mediated vasodilatation.     

N-nitro L-arginine causes coronary vasoconstriction and inhibits endothelium-dependent vasodilatation in anaesthetized greyhounds.

1. The effect of N-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide biosynthesis, on large coronary artery diameter and coronary blood flow was examined in anaesthetized greyhounds. The effects of L-NNA on the coronary vascular responses to acetylcholine (ACh), glyceryl trinitrate (GTN) and 5-hydroxytryptamine (5-HT) were also assessed. 2. L-NNA (5 mg kg-1), infused into the left circumflex coronary artery, increased systemic mean arterial pressure and decreased the external diameter of the artery. Infusion of L-NNA decreased coronary blood flow in 5 of the 7 dogs tested and increased mean coronary resistance but neither of these effects was statistically significant. There was no change in heart rate. 3. Intra-arterial injection of both ACh (0.01-0.05 micrograms kg-1) and GTN (0.1-0.5 micrograms kg-1) increased large coronary artery diameter and coronary blood flow. Coronary vascular responses to the endothelium-dependent vasodilator ACh were significantly reduced by L-NNA, whereas the responses to the endothelium-independent vasodilator GTN were not significantly affected. 4. 5-HT (0.1 microgram kg-1, injected into the left circumflex coronary artery) decreased coronary artery diameter but increased coronary blood flow. After the administration of L-NNA the 5-HT-induced dilatation of the coronary resistance vessels was significantly attenuated whereas the constriction of the circumflex coronary artery was increased in 3 out of 3 dogs in which diameter could be measured, although the latter effect was not statistically significant. 5. These data indicate that L-NNA causes coronary and systemic vasoconstriction and selectively inhibits endothelium-dependent vasodilatation in the coronary circulation of the anaesthetized greyhound.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bacterial endotoxin rapidly stimulates prolonged endothelium-dependent vasodilatation in the rat isolated perfused heart.

1. The effects of bacterial lipopolysaccharide (Escherichia coli 0111-B4; LPS) on coronary vascular tone were examined in the isolated perfused heart of the rat. The role of nitric oxide and/or prostaglandin products of the cyclo-oxygenase pathway in mediating the actions of LPS were also investigated. 2. Coronary vascular tone was raised and maintained by a continuous perfusion of the thromboxane-mimetic U46619 (5 nM). LPS perfusion (0.1-100 micrograms ml-1) caused a concentration-dependent fall in coronary tone without any significant change in the force of cardiac contractility. 3. At 5 micrograms ml-1, LPS reduced perfusion pressure by 38 +/- 9 mmHg. This effect was rapid in onset, maximal within the first 5 min and sustained for 90 +/- 10 min (n = 6). 4. The vasodilatation induced by LPS was dependent on the presence of an intact endothelium and abolished following endothelial damage caused by air embolism. 5. NG-nitro-L-arginine methylester (L-NAME; 50 microM) or NG-nitro-L-arginine (L-NOARG; 50 microM) blocked the vasodilatation induced by LPS (5 micrograms ml-1). The inhibition caused by these arginine analogues was partially reversed by 1 mM L- but not D-arginine. 6. The vasodilator action of LPS was also completely blocked by the glucocorticoid, dexamethasone (10 microM) but unaffected by indomethacin (10 microM). 7. These results suggest that LPS evokes rapid release of nitric oxide (NO) in the microvasculature of the rat isolated heart presumably via activation of the constitutive L-arginine-NO pathway in the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardioprotective effect of pindolol in ischemic-reperfused isolated rat hearts.

The effects of pindolol and timolol on ischemia reperfusion damage were studied in isolated working rat hearts. Ischemia (15 min) decreased the mechanical function and the energy state, and increased the tissue levels of free fatty acids (FFA). During reperfusion (20 min), the mechanical function did not recover, but the energy state recovered incompletely, whereas FFA increased further. Pindolol (50 microM) accelerated recovery of the mechanical function and the energy state that had been decreased by ischemia during reperfusion, and inhibited the accumulation of FFA during ischemia and reperfusion, especially when it was applied during the whole period of reperfusion. Timolol (50 microM), however, did not accelerate recovery of the mechanical function and the energy state during reperfusion, although it attenuated FFA accumulation during reperfusion. The pindolol-induced recovery of the mechanical function during reperfusion was reduced by timolol. The results suggest that the intrinsic sympathomimetic activity of pindolol may play an important role, at least in part, in producing the cardioprotective effect, especially during reperfusion.     

Effects of metabolic inhibitors on endothelium-dependent and endothelium-independent vasodilatation of rat and rabbit aorta.

1. Basal release of endothelium-derived relaxing factor (EDRF) rendered endothelium-containing rings of rat aorta 4.7 fold less sensitive to the contractile actions of phenylephrine and depressed the maximum response when compared with endothelium-denuded rings. The responsiveness and maximum response to phenylephrine was, however, similar in rings of rabbit aorta with or without endothelium. 2. Rotenone (1 nM-0.1 microM), an inhibitor of oxidative phosphorylation, induced a profound, irreversible blockade of phenylephrine-induced tone in endothelium-containing and endothelium-denuded rings of rat aorta, but induced only slight inhibition of tone in rings of rabbit aorta. 3. 2-Deoxy glucose (10 mM), an inhibitor of glycolysis, had no effect on phenylephrine-induced contraction in endothelium-denuded rings of rat aorta, but inhibited reversibly the endothelium-dependent depression of contraction in endothelium containing rings. 2-Deoxy glucose had no effect on phenylephrine-induced contraction in rings of rabbit aorta with or without endothelium. 4. Rotenone (0.1 microM) inhibited acetylcholine-induced, endothelium-dependent relaxation of phenylephrine-contracted rings or rat and rabbit aorta. In endothelium-denuded rings of rat aorta, relaxation induced by glyceryl trinitrate of isoprenaline was also inhibited, but relaxation induced by 8-bromo cyclic GMP or dibutyryl cyclic AMP was not. Relaxation induced by verapamil on KCl-contracted, endothelium-denuded rings of rat aorta was also unaffected. 5. 2-Deoxy glucose (10 mM) inhibited acetylcholine-induced, endothelium-dependent relaxation of phenylephrine-contracted rings of rat and rabbit aorta.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary vasoconstriction by locally administered acetylcholine, carbachol and bethanechol in isolated, donor-perfused, rat hearts.

1 Experiments were carried out on rat isolated heart preparations in which the coronary vasculature was perfused through the aorta at a constant flow rate with arterial blood from donor animals. Single doses of drugs were injected into the aortic cannula. 2 Small doses of acetylcholine, carbachol or bethanechol decreased perfusion pressure (PP) without markedly affecting left ventricular pressure (LVP) and heart rate (HR); larger doses of these drugs increased PP (vasoconstriction), and decreased LVP and HR in a dose-dependent manner. 3 Acetylcholine, carbachol and bethanechol had almost no effects when perfused through the aorta in such a way as to exclude the coronary vessels. 4 Coronary vasoconstriction in response to acetylcholine, carbachol and bethanechol was not significantly affected by reserpine pretreatment, phentolamine or hexamethonium, but was antagonized by small doses of atropine. 5 From these results it is concluded that in the coronary vasculature of the rat, the receptors involved in the vasoconstrictor actions of acetylcholine carbachol and bethanechol are muscarinic.     

Pirarubicin-induced endothelium-dependent relaxation in rat isolated aorta.

The mechanism of relaxation produced by pirarubicin [(2"R)-4'-O-tetrahydropyranyladriamycin, THP] has been studied in rat isolated aorta. THP (1.5 x 10(-6)-4.5 x 10(-5) M) markedly relaxed contractions induced by noradrenaline (10(-7) M) in the aorta with endothelium, but not in that without endothelium. The relaxation induced by 1.5 x 10(-5) M THP was inhibited by methylene blue (5 x 10(-6) M), hydroquinone (10(-4) M), phenidone (5 x 10(-5) M), haemoglobin (10(-6) M) and p-bromophenacyl bromide (5 x 10(-5) M), but not by indomethacin (2.5 x 10(-5) M). The relaxation induced by THP (1.5 x 10(-7) -4.5 x 10(-5) M) was inhibited by NG-nitro-L-arginine (10(-5) M), but enhanced by superoxide dismutase (10 units mL-1) or by L-arginine (10(-2) M). However, the THP-induced relaxation was not inhibited by various receptor antagonists such as atropine (10(-6) M), cimetidine (10(-5) M), diphenhydramine (3 x 10(-6) M) and [D-Pro4, D-Trp7,9,10]-substance P(4-11) (1.5 x 10(-6) M). In fifteen anthracycline analogues, THP and 13-dihydropirarubicin (both with a tetrahydropyranyl group) produced endothelium-dependent relaxations. These results suggest that the THP-induced relaxation which is probably mediated by endothelium-derived relaxing factor (EDRF) was not produced by an activation of muscarine, histamine H1 or H2, or substance P receptor, and further that the tetrahydropyranyl group must play an important role in the THP-induced relaxation.     

Developmental changes in endothelium-dependent pulmonary vasodilatation in pigs.

1. We compared in vitro endothelium-dependent vasorelaxant responses to acetylcholine (ACh) and the endothelium-independent vasodilator response to sodium nitroprusside (SNP) in prostaglandin F2 alpha (PGF2 alpha)-precontracted muscular pulmonary arteries (PA) from pigs aged 5 min to 2 h (neonatal), 3-10 days, 3-8 weeks and adults. 2. In the pulmonary artery (PA) rings from neonatal animals, the vasodilator response to ACh was negligible. However, responses to ACh were present in all PA rings from older animals, being greatest at 3-10 days and then decreasing with age (P less than 0.001, ANOVA). ACh (30 microM) induced a 1 +/- 1%, 92 +/- 9%, 62 +/- 5% and 51 +/- 6% reduction of the PGF2 alpha-generated tension in neonatal, 3-10 days, 3-8 weeks and adult groups, respectively. 3. The relaxant response to SNP was present in the PA rings from all age groups and increased with age (P less than 0.001, ANOVA). SNP (1 microM)-induced relaxation was 55 +/- 9%, 73 +/- 7%, 97 +/- 5% and 93 +/- 6% in neonatal, 3-10 days, 3-8 week and adult groups, respectively. 4. Removal of the vascular endothelium abolished the relaxant response to ACh but had no effect on the response to SNP in any groups. 5. NG-monomethyl-L-arginine (30 microM), a nitric oxide synthesis inhibitor, inhibited the response to ACh but not to SNP. The lipoxygenase inhibitor, nordihydroguaiaretic acid, had no significant effect on responses to ACh or SNP in any group.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of vasopressin in isolated rat hearts

The roles of cGMP, prostaglandins, the entry of extracellular Ca2+ through slow channels, endothelium and V1 receptors in the negative inotropic, chronotropic and coronary vasoconstrictor responses to arginine vasopressin (AVP) have been investigated in isolated perfused rat hearts. The bolus injection of 5 x 10(-5) M AVP produced a significant decrease in contractile force, heart rate and coronary flow. AVP also significantly decreased contractile force, heart rate and coronary flow in hearts pretreated with an inhibitor of soluble guanylate cyclase methylene blue (10(-6) M), an effective drug for removing endothelium saponin (500 micrograms/ml), an inhibitor of cyclooxygenase indomethacin (10(-5) M) or a calcium channel antagonist verapamil (5 x 10(-7) M). The potent V1 receptor antagonist [Deamino-Pen1, Val4, D-Arg8]-vasopressin (9 x 10(-5) M) did not alter effects of AVP but the very potent V1 receptor antagonist [beta-Mercapto-beta, beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8]-vasopressin (8 x 10(-5) M) abolished these effects. Our results suggest that AVP produces negative inotropic, chronotropic and coronary vasoconstrictor effects in isolated perfused rat hearts. cGMP, prostaglandin release and Ca2+ entry does not involve in the effects of AVP. These effects are endothelium independent and mediated by V1 receptors. The use of V1 receptor antagonist [beta-mercapto-beta, beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8]-vasopressin may be beneficial for preventing the negative inotropy, chronotropy and coronary vasoconstriction induced by AVP.     

Combined antihypertensive effect of GSY and metoprolol,based on endothelium-dependent vasodilatation function

OBJECTIVE To investigate the synergistic effect on dilating blood vessels and anti-hypertension of GYS combined with metoprolol.METHODS ① Spontaneously hypertensive rats(SHR)were administered orally with the vehicle,GSY,metoprolol or GSY combined with metoprolol for 4weeks.Blood pressure,which included SBP,DBP and MBP was measured by a noninvasive method every week.At the end of4 weeks,blood was drawn from the ophthalmic venous plexus to determine blood fat levels(serum TC,TG,LDL-c,HDL-c),liver function(serum ALT,AST),and kidney function(serum BUN,UA and Cr)by the ACCUTE(TBA-40FR)automatic.② The aortae of normal SD rats were prepared and cleaned from periadventitial fat and surrounding connective tissue and cut transversely into 4-mm width rings.To observe different concentration of GYS,metoprolol or GSY combined with metoprolol causing relaxation of the isolated aortic rings precontracted until a stable plateau by noradrenaline(NA)directly or in the presence of eNOS inhibitor L-NAME and cyclooxygenase inhibitor indomethacin(INDO)respectively.③ The concentrations of plasma GSY was determined by the HPLC after rats administered orally with GSY or GSY combined with metoprolol for single-dose.DAS data processing software calculated the pharmacokinetic parameters of GSY.RESULTS There was a significant synergism between GYS and metoprolol in lowering blood pressure and the concentrations of serum TC and LDL-c of SHR.The relaxant effect of GYS combined with metoprolol on the aortic rings precontracted by NA could be attenuated by L-NAME or INDO.The AUC0-tof GSY significantly increased after in conjunction with metoprolol.CONCLUSION GYS combined with metoprolol increases the concentrations of plasma GSY and synergistically lowers blood pressure based on endothelium-dependent vasodilatation function(EDVF).     

The effect of NG-nitro-L-arginine methyl ester upon basal blood flow and endothelium-dependent vasodilatation in the dog hindlimb.

1. The role played by the endothelium-derived relaxing factor (EDRF), nitric oxide (NO) in the regulation of blood flow to the skeletal muscle vasculature of the dog skinned hindlimb has been determined by examining the effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) upon (i) basal iliac artery blood flow, (ii) vasodilator responses to endothelium-dependent and -independent agonists and (iii) reactive hyperaemic responses to arterial occlusion. 2. L-NAME (0.1-3 mg min-1) infused directly into the iliac artery dose-dependently reduced basal iliac artery blood flow by a maximum of 48.6 +/- 6.9% (n = 4) and also increased mean systemic arterial blood pressure by 25.6 +/- 5.0 mmHg (n = 4) (at 3 mg min-1 L-NAME). 3. Over the same dose range, L-NAME also inhibited the peak vasodilator responses to intra-arterially administered, submaximal bolus doses of the endothelium-dependent agonists, bradykinin (3-300 ng) and acetylcholine (30-300 ng) by approximately 40%. In contrast, peak vasodilator responses to the endothelium-independent agonists, sodium azide (3-30 micrograms) and adenosine (0.3-1 mg), and peak reactive hyperaemic responses to arterial occlusion (60 s) were largely unaffected by L-NAME. 4. The dose-related effects of L-NAME on basal iliac artery blood flow, mean systemic arterial blood pressure and endothelium-dependent vasodilator responses were significantly attenuated by pretreatment with L-arginine (100 mg min-1) followed by co-infusion of L-arginine (100 mg min-1) with L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)     

红景天苷对大鼠离体心脏缺血-再灌注损伤的保护作用及机制研究

目的研究红景天的主要成分红景天苷对大鼠离体心脏缺血－再灌注损伤的保护作用及其可能的作用机制。方法将大鼠随机分为对照组和红景天苷组2组,取各大鼠离体心脏,按Langendorff预灌注10min,夹闭30min,再灌注120min,期间实时测定血流动力学指标：左室舒张末期压（LVEDP）、左室发展压（LVDP）、左室收缩压最大变化速率（＋dP／dtmax）、左室舒张压最大下降速率（－dP／dtmin）。复灌末,心脏用1％三苯四氯化磷酸盐缓冲液（TTC）孵育15min,通过TTC染色法测定大鼠心肌梗死面积。实验结束后,测定丙二醛（MDA）含量及心肌组织超氧化物歧化酶（SOD）和一氧化氮合酶（NOS）活力。结果与对照组相比,红景天苷组的LvEDP下降,而LVDP、＋dP／dtmin、－dP／dtmin均上升。给药后,大鼠离体心脏的血流动力学指标有所好转。红景天苷组梗塞面积（14．7±5．5）％明显低于对照组（28．4±4．6）％（P＝0．00012）。生化指标测定结果表明红景天苷组可降低磷酸肌酶（CK）活性和MDA含量,提高SOD和NOS的活性。结论红景天苷对大鼠离体心脏缺血－再灌注损伤的保护作用,这可能是它能抑制氧化应激所致的。     

Effects of captopril on the ACE-tissular system and on models of experimental ischaemia in isolated rabbit hearts.

In this study the authors evaluated the effect of captopril on coronary flow (CBF) dP/dT ratio and on reperfusion ventricular hyperkinetic arrhythmia (VHA) in 15 isolated and perfused (Langendorff's procedure) rabbit hearts following acute experimental ischaemia. The final goal was to determine whether pretreatment with captopril (administered before induced ischaemia or during the perfusion period) could protect the heart from the effects induced by acute ischaemia. Acute ischaemia was produced through 15-min ligation of the anterior descending coronary artery at its origin. After the ischaemic period, the hearts were subjected to a perfusion procedure for 45 min. Isolated hearts were connected to an intraventricular transducer system to evaluate intraventricular pressure curves, associated with a monitoring electrocardiogram system. Renin activity was detected by the RIA method from perfusion fluid samples. The 15 isolated and perfused rabbit hearts were subgrouped into 3 experimental groups as follows: Experiment No. 1: in this model the effects of acute induced ischaemia were evaluated in 5 rabbits without treatment and used as controls. At the end of the ischaemic period a relevant percent decrease in CBF (-36%) and in Dp/dT ratio (-33%) was found; after perfusion period a further percent decrease in CBF (-41%) and in Dp/dT ratio (-41%) was observed. Renin activity increased significantly only during the ischaemic period. In all the rabbits ventricular premature beats (VPB) were found and in 3 rabbits ventricular fibrillation (VF) was also detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary vasoconstriction and PGI2 release by leukotrienes in isolated guinea pig hearts

In isolated, perfused guinea pig hearts, leuokotrienes C₄ and D₄ (0.1–100 ng) dose-dependently decreased coronary flow rate and left ventricular systolic pressure. The leukotrienes (10–100 ng) released prostacyclin, but not thromboxane A₂, from the heart. In isolated atria, they (10⁻⁸–10⁻⁶ M) showed slight positive inotropism. Thus, it is concluded that leukotrienes C₄ and D₄ are potent coronary vasoconstrictors, and might play a role in coronary vasospasm during cardiac anaphylaxis.     

ATP mediates coronary vasoconstriction via P2x-purinoceptors and coronary vasodilatation via P2y-purinoceptors in the isolated perfused rat heart

The effect of ATP and its analogues on the perfusion pressure of the rat coronary vasculature and the left ventricular pressure of the isolated Langendorff perfused rat heart was examined. The response to ATP was generally biphasic, causing an increase followed by a decrease in perfusion pressure. The rank order of potency of the analogues for eliciting the vasoconstriction component was alpha,beta-methyleneATP greater than 2-methylthioATP greater than ATP, which resembles the pattern previously observed for the P2x-purinoceptor. In causing vasodilation, the rank order of antagonist potency was 2-methylthioATP greater than ATP, with alpha,beta-methyleneATP being without effect; this is a characteristic of P2y-purinoceptors. 1,3-Dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX) antagonised some of the vasodilatory effects of ATP, showing that some of the effect is due to breakdown to adenosine. Reactive blue 2, a putative P2y-purinoceptor antagonist was found to be five times more effective at antagonising the vasodilatory responses to 2-methylthioATP than to adenosine or the vasoconstriction responses to alpha,beta-methyleneATP. We suggest that ATP exerts its biphasic effects in the coronary vasculature of the rat by interacting with P2x- and P2y-purinoceptors and partly via P1-purinoceptors after breakdown to adenosine. Reactive blue 2 was more effective at antagonising responses mediated via P2y-purinoceptors than by P2x- or P1-purinoceptors.     

Effect of levonorgestrel and ethinyloestradiol on vasoconstriction in rat isolated vasculature

Female Sprague-Dawley rats were injected s.c. with 0.2 micrograms day-1 ethinyloestradiol (EE2) or 2.0 micrograms day-1 levonorgestrel (NG), procedures previously shown to increase systolic blood pressure. Increases in perfusion pressure to clonidine, phenylephrine, noradrenaline (NA) and angiotensin II (AII) were observed in rat isolated tail arteries, and to NA in the isolated mesenteric vasculature from steroid and vehicle-treated rats. NG treatment for four weeks produced increases in sensitivity to phenylephrine and NA in rat tail arteries; at 6 weeks the increases in sensitivity had largely disappeared but the maximum responses to clonidine and phenylephrine were increased. No change in sensitivity to AII was observed with NG. In contrast, EE2 treatment for six weeks produced increases in sensitivity to AII, and a decrease in sensitivity and maximum response to clonidine but not to phenylephrine or NA, in tail arteries. Responses to NA in the mesenteric vasculature were increased after 6 weeks NG treatment but unaffected after 12 weeks EE2 treatment. It is concluded that NG treatment stimulates alpha-adrenoceptor number, affinity or receptor-linked Ca2+ events which may contribute to its previously demonstrated hypertensive effect. The increased responsiveness to AII but not the decrease in alpha 2-adrenoceptor responsiveness may be associated with the chronic hypertension induced by EE2.     

Palytoxin-induced endothelium-dependent relaxation in the isolated rat aorta

Summary The effects of a potent marine toxin, palytoxin (PTX), were investigated on the contractile responses in the isolated rat aorta with or without endothelium. PTX in the concentrations of 10^–13–10^–11 mol/l showed little effect on the resting tension of the vessel with or without endothelium. PTX, 10^–10 mol/l, induced a small contraction in the aorta without endothelium but not in the aorta with endothelium. When added during the sustained contraction induced by 10^–7 mol/l norepinephrine, 10^–12 mol/l PTX sometimes (6 out of 43 strips) augmented the norepinephrine-induced contraction whereas 10 ^–11–10^–10 mol/l PTX induced a biphasic response which was composed of a transient augmentation followed by a relaxation. These effects of PTX were not observed in the aorta without endothelium. Influencesof atropine (10^–6 mol/l), indomethacin (2.5 × 10^–5 mol/l), methylene blue (5 × 10^–6 mol/l), hydroquinone (10^–4 mol/l), phenidone (5 × 10^–5 mol/l), hemoglobin (10^–6 mol/l) and p-bromophenacyl bromide (5 × 10^–5 mol/l) on the PTX (10^–10 mol/l) induced responses were examined. Methylene blue, hydroquinone, phenidone, hemoglobin and p-bromophenacyl bromide inhibited both the PTX-induced augmentation and relaxation of the norepinephrine-induced contraction. The endothelium-dependent relaxation due to 3 × 10^–7 mol/l carbachol was inhibited by atropine, methylene blue, hydroquinone, phenidone, hemoglobin and p-bromophenacyl bromide. These results suggest that PTX acts on the endothelium, modifies the synthesis or release of endothelium-derived relaxing factor and thus changes the contractile response to norepinephrine in rat aorta. Send offprint requests to H. Nagase at the above address