[Unusual cause of Takotsubo cardiomyopathy after pacemaker implantation]. / Un cas inhabituel de cardiomyopathie de Takotsubo après implantation de pacemaker.

Since its first description in Japan in 1990, Takotsubo (stress) cardiomyopathy has gained worldwide recognition. The disease is characterized by transient systolic and diastolic left ventricular dysfunction with a variety of wall-motion abnormalities. She predominantly affects elderly women and she is often preceded by an emotional or physical trigger. In the acute phase, the clinical presentation, electrocardiographic findings and biomarker profiles are often similar to those of an acute coronary syndrome. Although, the cause of Takotsubo cardiomyopathy remains unknown, the role of the brain-heart axis in the pathogenesis of the disease has been described. The potential role of catecholamine excess in the pathogenesis of Takotsubo cardiomyopathy has been long debated, and as such beta-blockers have been proposed as a therapeutic strategy. Currently, the treatment is not codified and it adapts according to clinical symptomatology. It seems difficult to summarize all the factors to provoque the cardiomyopathy, we describe a case of Takotsubo after a pacemaker (PM) implantation and to give a recent progress on this heart disease.

[Unusual cause of acute coronary syndrome: Horton's disease]. / Un syndrome coronaire aigu particulier : maladie de Horton.

The pathophysiology of acute coronary syndromes is in most cases due to the erosion or rupture of a plaque with consequent thrombotic obstruction of coronary artery. In a few cases, the mechanism is different, this not modifying the initial management but imposing special techniques for diagnosis and therapeutic management. We report a clinical case of a patient supported for an acute coronary syndrome, in a context of impaired general condition and biological inflammatory syndrome revealing a Horton's disease.

[Coronary artery fistulas, a current problem: Clinical and therapeutic considerations]. / Les fistules coronaires, un problème d'actualité : approche clinique et considérations thérapeutiques.

The coronary fistula is a link between one or more of the coronary arteries and cardiac cavity or great vessel. The exact occurrence is unknown. The majority of these fistulas are congenital in origin. However, they may occasionally be detected after cardiac surgery. For a long time, fistulas are asymptomatic, especially if they are small; the frequency of the symptoms and especially the complications rise with age. The potential complications are: cardiac failure, endocarditis, endarteritis, atrial fibrillation, ventricular arrhythmias, rupture, and thrombosis. The main differential diagnosis is patent arterial duct, while other congenital arteriovenous shunts need to be excluded. Even though echocardiography Doppler can help to differentiate shunts, the coronary angiography remains the main diagnostic tool for the description of the anatomy. For a long time, the surgery was the only therapeutic means, up till now, percutaneous occlusion is the first line therapy of coronary fistulas and that the different devices can be tailored to meet different anatomic and functional characteristics.

BK2 but not BK1 receptors mediating contractile response in human umbilical arteries: role of thromboxane A2.

Bradykinin receptors have been divided into B1 and B2 subtypes. The aim of this study on human umbilical arteries was: i) to compare the recognition properties of the mediating contractions of bradykinin receptors; and ii) to assess the possible role of thromboxane A2 in a bradykinin-induced contraction of smooth muscle. Umbilical arteries were dissected and mounted in organ baths for isometric measurement of force. Our results showed that the B1 agonist [Sar1dPhe8desArg9]-bradykinin had no effect on the concentration-response 10(-9)-3 x 10(-5) mM. Cumulative additions of bradykinin (10(-9)-3 x 10(-5) mM) and of the B2 agonist [Hyp3TyrMe8]-bradykinin (10(-9)-3 x 10(-5) mM) produced dose-dependent contractions. Dose response curves to bradykinin (10(-9)-3 x 10(-5) mM) were not significantly altered by the presence of B1 selective antagonist [des-Arg9, Leu8]-bradykinin (10(-5) mM), or by the selective B2 antagonist [Thi(5,8), D-Phe7]-bradykinin (10(-5) mM). However, Hoe 140 D-Arg-[Hyp3, Thi5,D-Tic7, Oic8]-bradykinin, an antagonist of B2 responses, significantly inhibited bradykinin-induced contraction. The responses to bradykinin were unaffected by indomethacin (10(-4) mM), dazoxiben (10(-5) mM) or even by nordihydroguaiaretic acid (10(-5) mM). However, bradykinin contractions were antagonized in a noncompetitive manner by quinacrine (10(-5) mM). These results showed that bradykinin contracts human umbilical arteries essentially through B2 receptors. Moreover, the responses to bradykinin are unlikely to be mediated by the cyclooxygenase/lipooxygenase pathway. The inhibitory effects of quinacrine may be due to a specific or nonspecific effect at a cellular level on smooth muscle contractility, or due to a direct action to block Ca2+ influx at membrane level.

DOCA-salts induce heart failure in the guinea pig.

Heart failure (HF) is a common clinical problem confronting physicians and is often the final manifestation of many cardiovascular disorders. Despite recent advances in the pharmacological management of HF, it remains a highly lethal and disabling disorder. A number of animal models have been developed to study both the pathophysiology of HF and new therapeutic approaches to this complex syndrome. Only through an improved understanding of the basic biology of the early stages of the syndrome can HF be prevented or at least anticipated. With this in view, we have developed an easily realisable and inexpensive model in the guinea pig, which presents numerous structural, metabolic and biochemical similarities compared with the human heart. Thirty guinea pigs, aged 5 weeks and weighing 300 g were used. After anaesthesia, left nephrectomy was performed. After 1 week the guinea pigs were divided into: (a) control group (n=15), which received an injection of vehicle as well as tap water for 10 weeks; (b) DOCA-salts group (n=15), where the animals were treated with an IM injection of 10 mg DOCA 5 days a week for 10 weeks and with drinking water containing 9 g/l(-1) NaCl and 2 g/l(-1) KCl. Our results demonstrate that the administration of DOCA-salts to guinea pigs for 10 weeks caused a significant increase in blood pressure (BP+30%) associated with left ventricular hypertrophy (LVH), evaluated by LV weight (+37%), LV wall (+36%), by the ratio LV weight/Body weight (+23%) and by an increase in LV volume (+51%). Concerning HF, the latter was clinically evident through an increase in body weight, heart rate and dyspnoea. Indeed, guinea pigs presented pleural and/or pericardial effusion often associated with ascite. This model, which combines pressure and volume overload, results in a slow evolution towards HF. This allows a better understanding of the mechanisms in early LV remodelling which has the potential to develop into HF. Some recent studies have emphasised the value of using guinea pigs. The guinea pig heart muscle presents two major regulatory mechanisms of contractility that are closer to those found in humans, the isomyosin pattern which is predominantly V(3) and the phenomenon of Ca(2+)-induced Ca(2+)-release from the sarcoplasmic reticulum. The DOCA-salts model in the guinea pig is an easy surgical procedure with high post-operative survival, which causes an increase in arterial BP, LVH associated with HF. This model is a useful tool for studying some of the basic mechanisms of cardiovascular diseases.

Guanylate cyclase and not ATP-dependent K(+) channels seems temperature-dependent in smooth muscle relaxation of human umbilical arteries.

The effects of K(+) channel opener, nicorandil [N-(2-hydroxyethyl)-nicotinamide nitrate], on isolated human umbilical arteries were investigated at two temperatures: 37 degrees C and 25 degrees C. The purpose of this investigation was: (1) to confirm the relaxant effect of nicorandil, (2) to elucidate the influence of endothelium and temperature on nicorandil-induced relaxation, (3) to determine which of guanylate cyclase or ATP-sensitive K(+) channels was implicated in temperature-induced relaxation of smooth muscles. Rings, 3-mm-wide, were suspended in organ chambers for isometric force measurement. All solutions were aerated with 95% O(2)-5% CO(2) and maintained at 37 degrees C or 25 degrees C (cooling), pH 7.4. The presence of an intact endothelium was confirmed by immunohistochemistry. During the first set of experiments after contraction with 5-hydroxytryptamine (5-HT 10(-5) M), nicorandil (10(-9)-10(-4) M) was added to the organ chambers with controls and in with rings incubated with L-arginine, N-nitro-L-arginine (L-NNA) an inhibitor of nitric oxide (NO) synthase, [1-H-(1,2,4) oxadiazole (4,3-a) quinoxalin-1-one] (ODQ), a specific inhibitor of guanylate cyclase, or glibenclamide, an antagonist of nicorandil, all at 10(-5) M. In another set of experiments, rings were contracted with 5-HT (10(-5) M) and relaxed with 3-morpholinosydnonimine [SIN-1 (10(-9)-3x10(-5) M) or cromakalim (10(-9)-3x10(-5) M)]. Our results showed that nicorandil induced concentration-dependent relaxation. At 37 degrees C, in the control, the maximum relaxation was 90+/-5%, and 60+/-8% at 25 degrees C (P<0.01). However, the relaxation at 37 degrees C or 25 degrees C remained unchanged after pretreatment with L-arginine, L-NNA, this suggests that the same concentration of drugs used in this type of vessel does not appear to modulate the relaxant effect of nicorandil. On the other hand, we observed that the relaxant effect of SIN-1 was 72+/-5% at 37 degrees C and only 28+/-7% at 25 degrees C (P<0.01). However, relaxations with cromakalim were partly influenced by cooling. In the presence of ODQ, the nicorandil-induced relaxation observed at 37 degrees C or 25 degrees C was less than that in the control and in the rings incubated with glibenclamide. These results for human umbilical arteries indicate that cooling decreases the relaxation response of smooth muscles and that this is partly due to a decreased response to guanylate cyclase.

5-hydroxytryptamine induces vasoconstriction of the human umbilical artery: effects of hypoxia and nicorandil.

Human umbilical arteries are known to be modulated by oxygen partial pressure. To further understand the underlying mechanisms, rings were suspended in organ chambers for the measurement of isometric force. The effects of 5-hydroxytryptamine (10(-9) to 10(-5) M) were first investigated before and after hypoxic conditions (5% O(2)-5% CO(2) in N(2)). Then after pretreatment, we tested indomethacin (10(-5) M), N-nitro-L-arginine (L-NNA, 10(-5) M) and nicorandil (10(-5) M) each separately, then each of the three substances together with hypoxia. In separate experiments the contractions to 5-hydroxytryptamine (10(-9) to 10(-5) M) were effectuated in a glucose-free medium, and mitochondrial respiration was inhibited by cyanide (2 mM). Hypoxic conditions significantly reduced the contractive response to 5-hydroxytryptamine. Contractions were enhanced after indomethacin, but remained unchanged after L-NNA. Pretreatment with nicorandil decreased the contraction. Furthermore, hypoxia and nicorandil dramatically decreased the contraction to 5-hydroxytryptamine. In glucose-free medium under normoxia or in hypoxic conditions, 5-hydroxytryptamine did not induce any contraction. Moreover, cyanide (2 mM) remained without effect on the contraction obtained by 5-hydroxytryptamine. These results suggest that hypoxia and nicorandil attenuate vasoconstrictor responses to 5-hydroxytryptamine in human umbilical arteries. Furthermore, these findings suggest that prostacyclin acts as a functional antagonist to vasoconstriction whereas nitric oxide does not. Finally, glycolysis seems to be involved rather than mitochondrial metabolism.

[Nitric oxide (NO), vascular protection factor. NO related cardiovascular diseases]. / Le monoxyde d'azote (NO), facteur de protection vasculaire. Pathologies cardiovasculaires liées au NO.

ALTERATIONS OF THE ENDOTHELIUM: Because of its anatomic position between circulating blood and smooth muscle cells, the vascular endothelium is a prime target for cardiovascular diseases such as hypertension, hypercholesterolemia, diabetes or ischemia. The morphological changes occurring in the endothelium have been known for many years, but it was only recently that the functional alterations have been described. IMPACT OF NO: Under physiological conditions, the vascular endothelium plays a protective role by secreting relaxation factors. In the disease state, the synthesis and release of NO may be reduced or even abolished. The exact significance of endothelium-dependent vasodilatation disorders remains a topic of research, but the properties of NO strongly suggest it is involved in several diseases. For some diseases it is still a question as to whether the observed anomalies are the cause or the consequence of the underlying disease. DISEASE-SPECIFIC CHANGES: NO is known to be reduced in atherosclerosis, either because of less synthesis or accelerated degradation. In different experimental modules of hypertension, the baseline level of NO release appears to be decreased. Conversely, NO release can be normal, reduced or increased in diabetes. In heart failure, there appears to be not only a permanent alteration in NO secretion, but also an increase in factors stimulating vascular contraction, contributing to an altered capacity for vascular adaptation in these patients.

[Nitric oxide (NO), vascular protection factor. Biology, physiological role and biochemistry of NO]. / Le monoxyde d'azote (NO), facteur de protection vasculaire. Biologie, rôles physiologiques et biochimie du NO.

VASOMOTRICITY: The vascular endothelium plays a key role in vasomotricity by producing a number of factors which modulate smooth muscle relaxation and contraction. Nitric oxide (NO) has been found to be one of the most important relaxation factors. NO SYNTHESIS: Nitric oxide is synthesized from L-arginine by NO-synthetase whose activity is regulated by intracellular calcium concentration and modulated by pharmacological compounds such as acetylcholine, 5-hydroxytryptamine, bradykinin and ADP as well as the sheer forces produced by blood flow. MODE OF ACTION: NO stimulates soluble guanylate cyclase in smooth muscles. Its action is mediated by increased intracellular cGMP which provokes smooth muscle relaxation. ACTIONS OF NO: The physiological role of NO produced by the vascular endothelium is quite complex and incompletely elucidated. NO helps maintain adequate blood supply to tissues by reacting rapidly to changes in pharmacological and mechanical stimuli. It opposes the direct vasoconstrictor effect of certain factors in the blood stream and its action on platelets and endogenous fibrinolysis helps prevent thrombus formation.

[Nitric oxide (NO), vascular protection factor. NO: role in aging]. / Le monoxyde d'azote (NO), facteur de protection vasculaire. NO: rôle dans le vieillissement.

AGING PROCESS: There is a large body of experimental and clinical data demonstrating that endothelial dysfunction is encountered not only in disease states such as atherosclerosis, hypertension, heart failure or diabetes, but also in the normal physiological process of aging. Currently available data show that endothelium-dependent function declines with age. The fact that this same decline is observed in patients with hypertension suggests that age is an independent factor capable of provoking changes in the vascular endothelium. CAUSAL MECHANISMS: It is often suggested that altered NO synthesis from L-arginine and/or increased production of contraction factors play a role in the aggravation of endothelial and parietal lesions and would thus affect the natural history of the disease process. HUMAN STUDIES: Ongoing studies in man tend to confirm experimental data obtained in animal models; treatment protocols could be adapted using compounds aimed at restoring normal endothelial function.

Effects of magnesium on human umbilical arteries: role of intracellular calcium stores.

The purpose of this investigation on human umbilical arteries was: (1) to analyze the effects of magnesium (Mg2+) in the prevention of contractions induced by 5-hydroxytryptamine (5-HT), KCl, Bay K 8644 and BaCl2; (2) to determine whether the presence of Mg2+ could modulate the response to caffeine in Ca2+-free medium at 25 and 37 degreesC, and (3) to examine the influence of Mg2+ and temperature in the release of intracellular calcium induced by 5-HT in Ca2+-free medium. Human umbilical arteries were dissected and mounted in organ baths for isometric measurement of force. Our results showed: (1) Mg2+ is a potent inhibitor of smooth muscle contraction of human umbilical arteries caused by 5-HT, KCl, Bay K 8644 and BaCl2, and that this effect might be due to the inhibition of the transmembrane calcium influx. (2) The relaxant effect of Mg2+ did not seem to be mediated by a blockade of the release of calcium from an intracellular store. (3) Moreover, our results suggest an effect of temperature independent from the action of Mg2+ on 5-HT-induced contraction.

[Effects of nicorandil, a potassium agonist, on the human umbilical artery. Role of the vascular endothelium]. / Effets du nicorandil, un agoniste potassique sur l'artère ombilicale humaine. Rôle de l'endothélium vasculaire.

The umbilical arteries play an important role in the foetal circulation. These vessels, which have no sympathetic tone, are a valuable model for the study of a direct pharmacological effect on vascular smooth muscle. The aims of this study were to determine if the potassium-channel reopener, nicorandil, could relax the smooth muscle of the human umbilical artery, if glibenclamide, an inhibitor of ATP-dependant potassium channels, can influence the action of nicorandil and, finally, to evaluate the role of the vascular endothelium. Rings of human umbilical artery 3 mm wide were placed in glycosated, oxygenated (95% O2, 5% CO2) Krebs-Henseleit solution, at 37 degrees C, pH 7.4 for isometric myography. The rings were contracted with 10(-5) M 5-hydroxytryptamine (5-HT). After stabilisation, a dose-effect graph of nicorandil (10(-9) to 3 x 10(-4) M) was constructed. In another series of experiments, the rings were incubated with NG nitro-L-arginine (NLA) at 10(-4) M, an inhibitor of NO-synthase, for 15 minutes and then contracted with 5-HT (10(-5) M) and relaxed with nicorandil at the same dosage. In yet another series of experiments, glibenclamide (10(-4) M) was added to the bath 15 minutes before contraction with 5-HT (10(-5) M). The vessel was then relaxed by incremental doses of nicorandil from 10(-9) to 3 x 10(-4) M. During this study, no significant difference was observed with respect to the contractions to 5-HT; moreover, the maximal relaxations obtained by nicorandil before and after glibenclamide were no significant. On the other hand, only the relaxations obtained after incubation with NLA were significant (p < 0.005). Furthermore, the pD2 did not differ significantly between the different groups of vascular rings. The authors conclude that nicorandil is a powerful dilatator of human umbilical artery. Glibenclamide has an inhibitory effect on nicorandil but only at low concentrations and in a non-competitive manner. The endothelium seems to modulate the vascular tone because relaxation is greater in the presence of an inhibitor of NO-synthase: in this type of vessel, the presence of the endothelium predisposes to the liberation of contractile factors.

Induction of hypertension and cardiac hypertrophy in guinea pig by DOCA salt.

Experimental hypertension can be induced in rats by uninephrectomy, administration of deoxycorticosterone acetate (DOCA) and sodium chloride. We developed this model in the guinea pig, because it presents an isoenzymic myosin pattern and calcium-induced calcium release similar to those of humans. Unilateral nephrectomy was performed in 33 guinea pigs, after which they were given DOCA (300 mg/kg pellets, s.c.; n = 11, or 10 mg, i.m.; n = 12, 5 days a week for 5 weeks). One week after surgery, drinking water was supplemented with NaCl 9 g/l and KCl 2 g/l for 5 weeks. Control guinea pigs (n = 10) were nephrectomized but not treated. Five weeks after surgery, hemodynamic measurements were recorded and the animals sacrificed to assess the degree of left ventricular hypertrophy. Left ventricular hypertrophy was considered significant if the ratio of left ventricular weight/body weight was > 2.3 and if the thickness of the left ventricle free wall was > 3.5 mm. Results showed that the systolic, diastolic and mean blood pressures of the treated groups were 36% higher than in the control group. Cardiac hypertrophy occurred within 5 weeks, and resulted in an increase in left ventricle weight and in left ventricular hypertrophy. The possibility of using the DOCA salt model of experimental hypertension in the guinea pig could help to elucidate the mechanisms responsible for hypertension and induced left ventricular hypertrophy, and thus improve prevention and treatment.