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In mature spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), acetylcholine and the calcium ionophore A-23187 release endothelium-derived contracting factors (EDCFs), cyclooxygenase derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine are most likely prostacyclin and prostaglandin (PG)[H.sub.2], whereas those released by A-23187 remain to be identified. Isometric tension and the release of PGs were measured in rings of isolated aortas of WKY and SHR. A-23187 evoked the endothelium-dependent release of prostacyclin, thromboxane [A.sub.2], [PGF.sub.2[alpha]], [PGE.sub.2], and possibly [PGH.sub.2] ([PGI.sub.2] [much greater than] thromboxane [A.sub.2] = [PGF.sub.2[alpha]] = [PGE.sub.2]). In SHR aortas, the release of prostacyclin and thromboxane [A.sub.2] was significantly larger in response to A-23187 than to acetylcholine. In response to the calcium ionophore, the release of thromboxane [A.sub.2] was significantly larger in aortas of SHR than in those of WKY. In both strains of rat, the inhibition of cyclooxygenase-1 prevented the release of PGs and the occurrence of endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, abolished the A-23187-dependent production of thromboxane [A.sub.2] and inhibited by approximately one-half the endothelium-dependent contractions. U-51605, an inhibitor of PGI synthase, reduced the release of prostacyclin elicited by A-23187 but induced a parallel increase in the production of [PGE.sub.2] and [PGF.sub.2], suggestive of a [PGH.sub.2] spillover, which was associated with the enhancement of the endotbelium-dependent contractions. These results indicate that in the aorta of SHR and WKY, the endothelium-dependent contractions elicited by A-23187 involve the release of thromboxane [A.sub.2] and prostacyclin with a most likely concomitant contribution of [PGH.sub.2]. arteries; endothelial factors; hypertension; TP receptors; spontaneously hypertensive rats; Wistar-Kyoto rats

In mature spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), acetylcholine and the calcium ionophore A-23187 release endothelium-derived contracting factors (EDCFs), cyclooxygenase derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine are most likely prostacyclin and prostaglandin (PG)H2, whereas those released by A-23187 remain to be identified. Isometric tension and the release of PGs were measured in rings of isolated aortas of WKY and SHR. A-23187 evoked the endothelium-dependent release of prostacyclin, thromboxane A2, PGF2α, PGE2, and possibly PGH2 (PGI2 ⪢ thromboxane A2 = PGF2α = PGE2). In SHR aortas, the release of prostacyclin and thromboxane A2 was significantly larger in response to A-23187 than to acetyicholine. In response to the calcium ionophore, the release of thromboxane A2 was significantly larger in aortas of SHR than in those of WKY. In both strains of rat, the inhibition of cyclooxygenase-1 prevented the release of PGs and the occurrence of endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, abolished the A-23187-dependent production of thromboxane A2 and inhibited by approximately one-half the endothelium-dependent contractions. U-S 1605, an inhibitor of PGI synthase, reduced the release of prostacyclin elicited by A-23187 but induced a parallel increase in the production of PGE2 and PGF2α, suggestive of a PGH2 spillover, which was associated with the enhancement of the endothelium-dependent contractions. These results indicate that in the aorta of SHR and WKY, the endothelium-dependent contractions elicited by A-23187 involve the release of thromboxane A2 and prostacyclin with a most likely concomitant contribution of PGH2. [ABSTRACT FROM AUTHOR]

This study was designed to determine whether the endothelium-dependent hyperpolarizations evoked by acetylcholine in guinea-pig carotid artery involve a cytochrome P450 metabolite and whether they are linked to the activation of two distinct populations of endothelial KCa channels, SKCa and IKCa.The membrane potential was recorded in the vascular smooth muscle cells of the guinea-pig isolated carotid artery. All the experiments were performed in the presence of N?-L-nitro arginine (100?µM) and indomethacin (5?µM).Under control conditions (Ca2+: 2.5?mM), acetylcholine (10?nM to 10?µM) induced a concentration- and endothelium-dependent hyperpolarization of the vascular smooth muscle cells. Two structurally different specific blockers of SKCa, apamin (0.5?µM) or UCL 1684 (10?µM), produced a partial but significant inhibition of the hyperpolarization evoked by acetylcholine whereas charybdotoxin (0.1?µM) and TRAM-34 (10?µM), a nonpeptidic and specific blocker of IKCa, were ineffective. In contrast, the combinations of apamin plus charybdotoxin, apamin plus TRAM-34 (10?µM) or UCL 1684 (10?µM) plus TRAM-34 (10?µM) virtually abolished the acetylcholine-induced hyperpolarization.In the presence of a combination of apamin and a subeffective dose of TRAM-34 (5?µM), the residual hyperpolarization produced by acetylcholine was not inhibited further by the addition of either an epoxyeicosatrienoic acid antagonist, 14,15-EEZE (10?µM) or the specific blocker of BKCa, iberiotoxin (0.1?µM).In presence of 0.5?mM Ca2+, the hyperpolarization in response to acetylcholine (1?µM) was significantly lower than in 2.5?mM Ca2+. The EDHF-mediated responses became predominantly sensitive to charybdotoxin or TRAM-34 but resistant to apamin.This investigation shows that the production of a cytochrome P450 metabolite, and the subsequent activation of BKCa, is unlikely to contribute to the EDHF-mediated responses in the guinea-pig carotid artery. Furthermore, the EDHF-mediated response involves the activation of both endothelial IKCa and SKCa channels, the activation of either one being able to produce a true hyperpolarization.British Journal of Pharmacology (2005) 144, 477-485. doi:10.1038/sj.bjp.0706003 [ABSTRACT FROM AUTHOR]

The antipsychotic agent risperidone has been shown to cause QT prolongation. In rabbit heart preparations, we have demonstrated that risperidone markedly lengthened action potential duration and blocked the delayed rectifier current, IKr. The current study was designed to investigate the risperidone effects: (i) on the main K+ repolarizing currents on human atrial myocytes, using whole-cell patch clamp recordings; (ii) on action potentials recorded from human atrial and ventricular myocardium using conventional microelectrodes. We found that: (1) risperidone (3–30 μM) reduced significantly the sustained current, Isus, and 30 μM decreased significantly the transient outward current Ito but was without effect on the inward rectifier current IK1; (2) risperidone (0.3–10 μM) lengthened significantly the final repolarization of the atrial action potential and risperidone (10 μM) markedly lengthened the final repolarization in ventricular myocardium. This study showed that risperidone exerts direct electrophysiological effects on human preparations but only at relatively high concentration. [Copyright &y& Elsevier]

The present study was designed to determine whether or not an increase in endothelial intracellular concentration of calcium ([Ca2+]i) evokes endothelium-dependent contractions in the aorta from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Acetylcholine, adenosine triphosphate (ATP) and the calcium ionophore, A 23187, produced endothelium-dependent relaxations in isolated aortic rings of both WKY and SHR. These relaxations in response to the three agonists were significantly smaller in the SHR when compared with the WKY. Endothelium-dependent contractions to acetylcholine, ATP and A 23187 were observed only in the aorta isolated from the SHR. In the presence of NG-nitro-L-arginine, an NO synthase inhibitor, the endothelium-dependent contractions in response to acetylcholine, ATP and A 23187 were potentiated significantly in the aorta SHR and were unmasked in that of WKY. However, the contractions were still significantly greater in SHR than in WKY. These contractions were abolished by indomethacin and valeryl salicylate (two cyclo-oxygenase inhibitors) as well as by S 18886 (a TP-receptor antagonist), indicating that the endothelium-dependent contraction produced by the three agonists share the same characteristics. The results of the present study indicate that the release/generation of endothelium-derived contracting factor, requires an increase in endothelial [Ca2+]i. [ABSTRACT FROM AUTHOR]

Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1–3 μM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03–0.3 μM) reduced significantly the current density of the delayed rectifier current and at 30 μM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events. [Copyright &y& Elsevier]

Objectives: Action potential prolongation related to the alteration of several membrane currents is constantly reported in heart failure (HF) but reports about its role in arrhythmogenesis are sparse. Our aim was to determine, by analogy with long QT syndromes, whether prolonged repolarization is associated with increased dispersion or linked to bradycardia-dependent ventricular arrhythmias in pacing-induced cardiomyopathy. Methods: QT intervals, action potentials and transmural activation-to-recovery intervals (ARIs) along with whole-cell delayed rectifier (IK) and transient outward (Ito1) K+ currents were recorded in left ventricle from pigs with HF and controls. HF was obtained after 14 days of rapid pacing at 250 ms. Results: Repolarization was delayed as indexed by corrected QT intervals (13.7% increase, P<0.01) or ARIs (252±4 to 340±7 ms, P<0.01). ARIs were uniformly prolonged with disappearance of the transmural gradient, spatial dispersion of repolarization decreased by 50% (P<0.05). Ito1 density was reduced in HF from 1.35±0.1 to 0.57±0.04 pA/pF subepicardially, from 1.05±0.19 to 0.55±0.08 pA/pF midmyocardially and from 1.04±0.1 to 0.48±0.04 pA/pF subendocardially. IK density was significantly decreased in HF pigs vs. controls: subepicardially from 0.46±0.04 to 0.22±0.02 pA/pF; midmyocardially from 0.46±0.05 to 0.25±0.03 pA/pF; and subendocardially from 0.49±0.04 to 0.20±0.04 pA/pF following depolarization at +50 mV. Electrocardiogram (ECG) monitoring at the time of death did not disclose any polymorphic ventricular tachyarrhythmia. Conclusion: Despite a profound alteration in K+ currents, repolarization is uniformly prolonged in this model with no proclivity to develop bradycardia-dependent arrhythmias. [Copyright &y& Elsevier]