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Objectives: While there are many suggested reasons for the marked gender bias in cardiovascular events, much of the available data indicate that circulating estrogens are cardioprotective. The possibility that endogenous androgens may be detrimental to the cardiovascular system has received relatively less attention. We investigated the short-term modulatory effects of various concentrations of testosterone on vascular function in isolated porcine coronary artery rings. Results: The higher concentrations (>1 μM) of testosterone relaxed U46619-contracted coronary artery rings in an endothelium-independent manner. This direct effect was insensitive to the testosterone receptor antagonists, flutamide and cyproterone acetate. Short-term exposure (20 min) to low levels of testosterone (1–100 nM), which were ineffective on their own on vascular function, significantly diminished relaxation to bradykinin and calcium ionophore A23187 but not those produced by levcromakalim and sodium nitroprusside. The inhibitory effect observed with 1 nM testosterone was only partially reversed by flutamide and cyproterone acetate and unaltered in the presence of actinomycin D and cycloheximide. Conclusions: These results demonstrate that acute treatment with testosterone, at concentrations that have no effect on their own, reduces vasorelaxation. Furthermore, they suggest that this modulatory action may be in part independent of the classical testosterone receptor since it was not completely sensitive to the anti-androgens and was not inhibited by the transcriptional and translational inhibitors. These findings support the postulation that testosterone may have unfavorable influences on vascular function.

Objective: The aim was to examine the effect of selenium supplement on endothelium dependent relaxation in rat aortic rings. Methods: Rats were supplemented with selenium for 3 d (intraperitoneal injection of 4.33 μmol sodium selenite·kg−1 body weight·d−1). Saline injections served as controls. Rat aortic ring was precontracted with phenylephrine and endothelium dependent relaxation was produced by the addition of acetylcholine. Results: Acetycholine-induced endothelium dependent relaxation was enhanced in aortic rings from rats after receiving selenium supplement as compared to control rats. For comparison, endothelium independent vasodilators (sodium nitroprusside and cromakalim) were investigated. Selenium supplement did not affect the relaxation produced by these vasodilators. N-nitro-L-arginine methyl ester (L-NAME) abolished acetylcholine induced relaxation in aortic rings from animals with selenium supplement while indomethacin had no effect on the relaxation. Direct addition of selenium or glutathione peroxidase and glutathione into the organ bath had no effect on acetylcholine induced endothelium dependent relaxation. Conclusions: The enhanced relaxation after selenium supplement was due to an increase in the release of nitric oxide since L-NAME was effective in blocking the relaxation. The lack of an effect by indomethacin indicated little role for cyclo- oxygenase products in this system. Our results suggest that the effect of selenium supplement on endothelium dependent relaxation is mediated by cellular changes that cannot be mimicked by the direct addition of selenium or the selenium dependent enzyme glutathione peroxidase. Cardiovascular Research 1994; 28 :345-348

Study objective – The aim was to evaluate the arrhythmogenic effect of a free radical generating system, FeCl3/ADP, using two different approaches. Design – Ventricular arrhythmias were studied in isolated rat hearts subjected to regional ischaemia and reperfusion without or with simultaneous treatment with nicergoline (0.4 mg·litre−1). In the second part of this study the electrophysiological effects of FeC13/ADP (0.1/1.0 μM) were investigated in normal Purkinje fibres and in Purkinje fibres from dog surviving infarction, by using conventional microelectrode method. Experimental materials – Hearts were obtained from male Sprague-Dawley rats, weight 250-300 g. Purkinje fibres were dissected from hearts of mongrel dogs of either sex (10-15 kg) with or without prior myocardial infarction. Measurements and results – FeC13/ADP (0.1/1.0 μM and 1.0/1.0 μM respectively) weakly changed the incidence of reperfusion induced arrhythmias. In nicergoline pretreated hearts, in which the incidence of reperfusion arrhythmias was reduced, FeC13/ADP (0.1/1.0 μM and 1.0/1.0 μM) did not change the incidence and the duration of reperfusion arrhythmias. In normal Purkinje fibres, FeC13/ADP (0.1/1.0 μM) induced a decrease in action potential duration without any pronounced effect on Vmax, diastolic potential, and activation potential. In Purkinje fibres from post infarct myocardium, FeCl3/ADP decreased action potential duration, diastolic potential, and activation potential. Conclusions – Free radical generation did not antagonise the antiarrhythmic activity of α adrenergic blockade. Free radical generation induced slow and minor changes in electrophysiological activity of Purkinje fibres both from normal and ischaemic hearts. Our data suggest that free radical generation may not be the only mechanism involved in the genesis of reperfusion arrhythmias.

Study objective – The aim of the study was to investigate the electrophysiological effects of acetylcholine in Purkinje fibres surviving infarction. Design – Infarction in canine hearts was produced by coronary occlusion. Ischaemic tissue was removed and surviving Purkinje fibres were compared for effects of increasing concentrations of acetylcholine (1-100 μM) with control Purkinje fibres from normal hearts and normal Purkinje fibres treated with barium. Subjects – Experimental animals were mongrel dogs of either sex, weight 10-15 kg, n = 14 (control), 9 (infarction group), 11 (Ba treated group). Measurements and main results – Acetylcholine caused concentration dependent shortening of action potential duration in normal Purkinje fibres and in fibres surviving infarction, but had no effect when potassium conductance was decreased with Ba. Acetylcholine induced a small hyperpolarisation in normal Purkinje fibres and in fibres surviving infarction perfused with a 4 mM potassium solution without affecting action potential amplitude or dV/ dtmax. Reduction in K concentration to 1 and 2 mM caused a greater depolarisation of diastolic potential in normal fibres than in fibres surviving infarction or Ba treated fibres. Acetylcholine produced hyperpolarisation under these conditions in normal fibres only. Acetylcholine decreased automaticity in normal fibres only at high concentration (100 μM). A lesser effect was seen in Ba treated fibres and in fibres surviving infarction. Conclusions – Since Ba treated Purkinje fibres had similar action potential characteristics to those seen in Purkinje fibres surviving infarction and responded in the same way to the modifications of K concentration, a decrease in K conductance might be the underlying mechanism for some of the electrophysiological changes in fibres surviving infarction. The results also suggest that after 24 h ischaemia, surviving Purkinje fibres have a different sensitivity to acetylcholine from normal fibres.

Aims The present study examined the hypothesis that prostaglandin E2 (PGE2) through activation of prostaglandin E (EP) receptor contributes to endothelium-dependent contractions. Methods and results Western blotting revealed that the protein expression of EP1 receptor was significantly down-regulated in the aorta of the spontaneously hypertensive rat (SHR), but there was no significant difference in the expression of EP2, EP4, and total EP3 receptors between preparations of Wistar Kyoto rats (WKY) and SHR. Isometric tension studies showed that low concentrations of PGE2 caused endothelium-dependent relaxations in WKY but not in aortas of the SHR. High concentrations of PGE2 evoked contractions predominately through the activation of thromboxane-prostanoid (TP) receptors in the WKY, but involves the dual activation EP and TP receptors in the SHR. SQ29,548, BAYu3405 and Terutroban (TP receptor antagonists), and AH6809 (non-selective EP receptor antagonist) abolished, while SC19220 (preferential EP1 receptor antagonist) did not inhibit endothelium-dependent contractions. Both SC19220 and AH6809 significantly inhibited contractions to U46619 (TP receptor agonist). Conclusion The present study demonstrates that the contraction caused by PGE2 in the SHR aorta is dependent on the activation of EP1 and TP receptors, but that endothelium-dependent contractions do not require the former. Thus, PGE2 is unlikely to be an endothelium-derived contracting factor in this artery. The ability of AH6809 to inhibit endothelium-dependent contractions can be attributed to its partial antagonism at TP receptors. Nevertheless, the impairment of PGE2-mediated relaxation may contribute to endothelial dysfunction in the aorta of the SHR.

While alterations in cholesterol and lipoprotein profiles partly account for menopause being a risk factor for coronary heart disease, recent studies have suggested that 17 beta-estradiol may have vascular effects. Our aims were to study the short-term effects of 17 beta-estradiol on vascular function in isolated porcine coronary artery rings. Concomitantly, we sought to determine if physiological concentrations of 17 beta-estradiol could acutely potentiate relaxation17 alpha- and 17 beta-estradiol at pharmacological (1 microM) concentrations produced relaxation in U46619-pre-contracted porcine coronary artery rings. Relaxation evoked by 17 beta-estradiol was not reversed by the estrogen receptor antagonists tamoxifen and ICI 182780. Following 20 min exposure to a physiological concentration of 17 beta-estradiol (1 nM), which on its own had no effect, relaxation elicited by cromakalim, levcromakalim and sodium nitroprusside, but not bradykinin or calcium ionophore A23187, were significantly enhanced. This potentiating action was also insensitive to tamoxifen and ICI 182780. Our data provide evidence for an acute indirect relaxant action of 17 beta-estradiol and suggest that it may be via a tamoxifen- and ICI 182780-insensitive estrogen receptor. While this response was only observed at pharmacological concentrations, the potentiation of cromakalim, levcromakalim and sodium nitroprusside relaxation was evident in the presence of a physiological concentration (1 nM) of 17 beta-estradiol.These results demonstrate that short-term exposure to 17 beta-estradiol, at concentrations that have no effect on their own, can enhance vasorelaxation. These vascular effects may partly account for some of the acute effects of 17 beta-estradiol on blood flow.

Objective: The aim was to examine the formation of lipid peroxidation products and the alteration in phospholipid content in low density lipoprotein (LDL) after oxidative modification by CuSO4, and subsequently, to determine the ability of the modified LDL to impair endothelium dependent relaxation in rat aortic rings. Methods : Blood samples were obtained from normal human volunteers. LDL was prepared by sequential ultracentrifugation and it was oxidatively modified in the presence of 5 μM CuSO4. Lipid peroxidation products (thiobarbituric acid reactive substancec, TBARS), and alterations in electrophoretic mobility and phospholipid content were determined in normal (native) and oxidised LDL. Endothelium dependent relaxation was produced by acetylcholine (10−8-10−5 M) in phenylephrine precontracted rat aortic rings. Results : LDL incubated for 24 h with 5 μM CuSO4, at 20°C and 37°C with constant agitation displayed higher amounts of TBARS than the respective native LDL. While the amounts of TBARS in LDL modified at 20°C and 37°C were similar, the former condition resulted in statistically smaller changes of phospholipid contents. LDL with higher lysophosphatidylcholine content showed greater impairment of endothelium dependent relaxation in rat aortic rings than LDL with lower lysophosphatidylcholine content. Conclusions : The raised lysophosphatidylcholine level in oxidatively modified LDL was related to the ability of the LDL to impair endothelium dependent relaxation. However, lipid peroxidation products assessed by TBARS did not relate to the phospholipid changes in LDL and therefore cannot be used to predict the vascular effects of LDL after oxidative modification. Cardiovascular Research 1994; 28 :1476-1481

Ventricular arrhythmias following myocardial infarction may originate from subendocardial Purkinje fibres in the infarcted area. The role of potassium and sodium-calcium exchange currents on action potential duration was therefore investigated in Purkinje fibres surviving infarction and in normal Purkinje fibres. Barium was used to reduce potassium conductance and replacement of sodium chloride by lithium chloride was used to reduce the sodium-calcium exchange current. Barium (1 x 10(-5) to 3 x 10(-5) M) produced a concentration dependent lengthening of action potential duration in normal Purkinje fibres but these concentrations had no effect in Purkinje fibres surviving infarction. The resting membrane potential, activation voltage, amplitude and Vmax were decreased in Purkinje fibres surviving infarction and in barium treated fibres v normal Purkinje fibres. These results show that action potential characteristics of barium treated normal Purkinje fibres closely resemble those seen in Purkinje fibres surviving infarction. A similar reduction of action potential duration was seen in normal Purkinje fibres, fibres surviving infarction and barium treated fibres when the sodium "window" current was decreased by lignocaine. Without any effect on the Vmax, the replacement of sodium chloride by lithium chloride resulted in a similar effect on the action potential duration in normal Purkinje fibres and fibres surviving infarction. The results show that the longer action potential duration found in Purkinje fibres surviving infarction can be explained by a decrease of the potassium conductance and not by an increase of the sodium "window" current or the sodium-calcium exchange current.