Structural heterogeneity of the rat pulmonary vein myocardium: consequences on intracellular calcium dynamics and arrhythmogenic potential.

Mechanisms underlying ectopic activity in the pulmonary vein (PV) which triggers paroxysmal atrial fibrillation are unknown. Although several studies have suggested that calcium signalling might be involved in these arrhythmias, little is known about calcium cycling in PV cardiomyocytes (CM). We found that individual PV CM showed a wide range of transverse tubular incidence and organization, going from their virtual absence, as described in atrial CM, to well transversally organised tubular systems, like in ventricular CM. These different types of CM were found in groups scattered throughout the tissue. The variability of the tubular system was associated with cell to cell heterogeneity of calcium channel (Cav1.2) localisation and, thereby, of Cav1.2-Ryanodine receptor coupling. This was responsible for multiple forms of PV CM calcium transient. Spontaneous calcium sparks and waves were not only more abundant in PV CM than in LA CM but also associated with a higher depolarising current. In conclusion, compared with either the atrium or the ventricle, PV myocardium presents marked structural and functional heterogeneity.

[The endothelin system: its involvement in the cardiovascular system]. / Le système endothéline : son implication dans le système cardiovasculaire.

The endothelin (ET)-system is composed of three endothelins, two receptors and two enzymes. The study of this system presents a great interest to understand the cardiovascular physiopathology. The ET-system is involved in cardiac organogenesis, angiogenesis and vascular tone homeostasis. Its role in arterial pulmonary hypertension, arterial hypertension and atherosclerosis has been shown. The numerous ET-system's targets suggest that it could be involved in pathologies which bring together various cardiovascular disorders such as the obstructive sleep apnoea syndrome. Thus, the ET-system generates today a lively interest for experimental and clinical trials.

Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives.

There are three major types of sleep-disordered breathing (SDB) with respect to prevalence and health consequences, i.e. obstructive sleep apnoea syndrome (OSAS), Cheyne-Stokes respiration and central sleep apnoea (CSR-CSA) in chronic heart failure, and obesity hypoventilation syndrome (OHS). In all three conditions, hypoxia appears to affect body functioning in different ways. Most of the molecular and cellular mechanisms that occur in response to SDB-related hypoxia remain unknown. In OSAS, an inflammatory cascade mainly dependent upon intermittent hypoxia has been described. There is a strong interaction between haemodynamic and inflammatory changes in promoting vascular remodelling. Moreover, during OSAS, most organ, tissue or functional impairment is related to the severity of nocturnal hypoxia. CSR-CSA occurring during heart failure is primarily a consequence of cardiac impairment. CSR-CSA has deleterious consequences for cardiac prognosis and mortality since it favours sympathetic activation, ventricular ectopy and atrial fibrillation. Although correction of CSR-CSA seems to be critical, there is a need to establish therapy guidelines in large randomised controlled trials. Finally, OHS is a growing health concern, owing to the worldwide obesity epidemic and OHS morbidities. The pathophysiology of OHS remains largely unknown. However, resistance to leptin, obesity and severe nocturnal hypoxia lead to insulin resistance and endothelial dysfunction. In addition, several adipokines may be triggered by hypoxia and explain, at least in part, OHS morbidity and mortality. Overall, chronic intermittent hypoxia appears to have specific genomic effects that differ notably from continuous hypoxia. Further research is required to fully elucidate the molecular and cellular mechanisms.

[Hypoxic preconditioning: role of transcription factor HIF-1alpha]. / Préconditionnement hypoxique: rôle du facteur de transcription HIF-1alpha.

The delayed form of myocardial preconditioning is of particular interest because of its large window of protection. It involves many signalisation pathways who, along with transcription factors, activate cardioprotective genes. Amongst the latter, the hypoxia inducible factor 1 (HIF-1) whose a subunit is stabilized by hypoxia, appears to play a pivotal role in the delayed preconditioning induced by hypoxia. The stabilisation of HIF-1alpha by inhibitors of prolyl-4-hydroxylases, the enzymes responsible for its degradation in normoxia, reproduces the cardioprotective effects of hypoxia. These enzymes represent promising therapeutic targets for the treatment of various cardiovascular diseases.

Early pharmacological preconditioning by erythropoietin mediated by inducible NOS and mitochondrial ATP-dependent potassium channels in the rat heart.

Administration of recombinant human erythropoietin (rhEPO) is known to induce protection against cardiac ischaemia injury improving functional recovery and reducing apoptosis. But the underlying mechanisms are not elucidated. We determined the role of nitric oxide synthases (NOS) as well as ATP-dependent (K(ATP)) and calcium-activated (K(Ca)) potassium channels in the early cardioprotection induced by rhEPO. Wistar male rats were divided into two experimental groups treated by rhEPO (5,000 IU/kg, i.p.) or saline (control group). One hour later, rats were anaesthetized, hearts isolated, retrogradely perfused and submitted to a 30-min no-flow global ischaemia followed by 120 min of reperfusion sequence. Cardiac functional recovery (left ventricular developed pressure, LVDP) was significantly higher in the group treated by rhEPO (LVDP at 30 min reperfusion: 71.7 +/- 2.3 mmHg) compared with the control group (57.4 +/- 5.8 mmHg). We observed the same significant effect on its derivative (dP/dt). The rhEPO-induced improvement in ventricular function was abolished by perfusion prior to ischaemia with either N-nitro-l-arginine methyl ester (l-NAME, a nonspecific NOS inhibitor) or N-(3-(aminomethyl)benzyl)acetamidine (1,400W, a specific inducible NOS inhibitor) or 5-hydroxydecanoic acid (5HD, a mitochondrial K(ATP) channel blocker) but not with paxilline (a K(Ca) channel inhibitor). Thus, in vivo rhEPO administration provides early preconditioning against ischaemic injury in the isolated perfused rat heart that is dependent on iNOS and mitochondrial K(ATP) channels.

Erythropoietin and myocardial protection: what's new?

Erythropoietin (EPO), the principal hematopoietic cytokine produced by the kidney and the liver in fetuses, regulates mammalian erythropoiesis and exhibits diverse cellular effects in non-hematopoietic tissues. The introduction of recombinant human EPO (rhEPO) has marked a significant advance in the management of anemia associated with chronic renal failure. At the same time, experimental studies have unveiled its potential cardioprotective actions. As with other preconditioning agents, administration of exogenous rhEPO can confer myocardial protection against ischemia-reperfusion injury, in terms of reduction in cellular apoptosis and necrosis as well as improvement in myocardial functional recovery. The purpose of this study is to review current information regarding the various protocols used to investigate the effects of rhEPO administration as well as its cardioprotective properties. We also address the potential mechanisms underlying the protective effects of EPO. A better understanding of these mechanisms is essential for the development of clinical applications and the design of novel therapeutical strategies.

Acute intermittent hypoxia improves rat myocardium tolerance to ischemia.

In this study, we investigated the influence of depth and duration of intermittent hypoxia (IH) on the infarct size development in isolated rat heart. The role of nitric oxide synthase (NOS) and ATP-sensitive K+ (K(ATP)) channel was also studied. Wistar male rats were exposed to IH [repetitive cycles of 1 min, 40 s with inspired oxygen fraction (FI(O2)), 5 or 10%, followed by 20-s normoxia], during 30 min or 4 h. Another group was exposed to 4 h of continuous hypoxia with 10% FI(O2). Twenty-four hours later, their hearts were isolated and subjected to a 30-min no-flow global ischemia-120-min reperfusion sequence. For some hearts, N(omega)-nitro-L-arginine methyl ester (L-NAME) (a nonselective inhibitor of NOS) or 5-hydroxydecanoic acid (5-HD) (a selective mitochondrial K(ATP) blocker) was infused before ischemia. Infarct size (in percentage of ventricles) was significantly reduced by prior IH for 4 h (10% FI(O2)) (21.8 +/- 3.1 vs. 33.5 +/- 2.5% in sham group). This effect was abolished by L-NAME or 5-HD. Infarct size was not different in groups subjected to either 30 min of IH or to continuous hypoxia compared with sham group. In contrast, IH for 4 h (5% FI(O2)) significantly increased infarct size (45.1 +/- 3.6 vs. 33.5 +/- 2.5% in sham group). Acute IH for 4 h with a minimal FI(O2) of 10% induced a delayed preconditioning against myocardial infarction in the rat, which was abolished by NOS inhibition and mitochondrial K(ATP) channel blockade. Depth, duration, and intermittence of hypoxia appeared to be critical for cardioprotection to occur.

[Cardiac and vascular effects of cannabinoids: toward a therapeutic use?]. / Effets cardiaques et vasculaires des cannabinoïdes: vers une utilisation thérapeutique en cardiologie?

Interest in cannabinoid pharmacology developed rapidly since the discovery of cannabinoids receptors and endocannabinoids. Modulation of this system is becoming a hot topic in cardiovascular pharmacology mainly at the light of recent findings. Among them, cardiac effects of cannabinoids were described with respect to their probable participation to the well-studied preconditioning phenomenon. Beneficial effects of post-infarction cannabinoids administration against ischemia-reperfusion injury were also reported. Concerning their vascular effects the situation is more complex some studies reporting pressor effects while others depressor ones. It was also proposed that the endothelium-derived hyperpolarizing factor released by various vasodilators may be an endocannabinoid an hypothesis still discussed. Finally, pathological situations concerning the cardiovascular system and including brain ischemia, hemorrhagic and endotoxic shocks were reported to be linked with endocannabinoids. However, the clinical use of cannabinoid receptors agonists or antagonists will depend on the development of non psychoactive compounds.

Chronic intermittent hypoxia increases infarction in the isolated rat heart.

Coronary heart disease is frequently associated with obstructive sleep apnea syndrome and treating obstructive sleep apnea appears to significantly improve the outcome in coronary heart disease. Thus we have developed a rat model of chronic intermittent hypoxia (IH) to study the influence of this condition on myocardial ischemia-reperfusion tolerance and on functional vascular reactivity. Wistar male rats were divided in three experimental groups (n = 12 each) subjected to chronic IH (IH group), normoxia (N group), or control conditions (control group). IH consisted of repetitive cycles of 1 min (40 s with inspired O(2) fraction 5% followed by 20 s normoxia) and was applied for 8 h during daytime, for 35 days. Normoxic cycles were applied in the same conditions, inspired O(2) fraction remaining constant at 21%. On day 36, mean arterial blood pressure (MABP) was measured before isolated hearts were submitted to an ischemia-reperfusion protocol. The thoracic aorta and left carotid artery were also excised for functional reactivity studies. MABP was not significantly different between the three experimental groups. Infarct sizes (in percent of ventricles) were significantly higher in IH group (46.9 +/- 3.6%) compared with N (26.1 +/- 2.8%) and control (21.7 +/- 2.1%) groups. Vascular smooth muscle function was similar in aorta and carotid arteries from all groups. The endothelium-dependent relaxation in response to acetylcholine was also similar in aorta and carotid arteries from all groups. Chronic IH increased heart sensitivity to infarction, independently of a significant increase in MABP, and did not affect vascular reactivity of aorta and carotid arteries.

Heat stress protects against electrophysiological damages induced by acute doxorubicin exposure in isolated rat hearts.

The use of anthracycline antibiotics as anticancer agents is limited by their cardiac toxicity. Heat stress (HS) is known to confer protection against various myocardial injuries such as ischemia-reperfusion induced damage. This cardioprotective mechanism is associated with an increase in endogenous antioxidative defenses and heat stress proteins (HSPs) synthesis. The aim of this study was thus to investigate whether HS could protect against acute doxorubicin cardiotoxicity using the isolated rat heart model. Rats were either heat stressed (42 degrees C for 15 min) or sham anesthetized. 24 h later, their hearts were isolated and retrogradely perfused at constant flow. Following 30-min of stabilization, hearts were perfused during 70 min with modified-Krebs solution containing 6 mg/l doxorubicin. Control hearts were perfused under identical conditions but without doxorubicin. Different hemodynamic and electrophysiological parameters were assessed in hearts from the four experimental groups. Doxorubicin exposure decreased left ventricular developed pressure (approximately -60% of baseline) and increased coronary perfusion pressure (approximately +230% of baseline). Prior HS did not modify these effects. Incidence of ventricular fibrillation (VF) was significantly enhanced by doxorubicin exposure (66% vs 0% in control group). Moreover, the ventricular action potential duration (APD) was significantly shortened in the presence of doxorubicin. Prior HS prevented both increase in VF incidence and shortening of APD. We conclude that prior heat stress protects myocardium against electrophysiological injury, but not against hemodynamic damage, induced by acute doxorubicine exposure. Further investigations are required to elucidate the precise mechanisms involved in this effect.

MAP-kinase dependent activation of kinin B1 receptor gene transcription after heat stress in rat vascular smooth muscle cells.

The mechanism involved in the induction of kinin B1 receptors in pathological situations is not completely defined. In this study, we evaluated whether p42/p44 mitogen activated protein (MAP) and p38 stress activated protein (SAP) kinases were implicated in the activation of the gene encoding for the B1 receptor after heat stress in rat vascular smooth muscle cells (SMCs). Rat vascular SMCs were incubated with either vehicle, or 4(4-fluorophenyl)-2-(4 methylsulfinylphenyl)-5-(4pyridil)imidaz (SB 203580) (10 microM), a selective inhibitor of the p38 SAP kinase pathway or 2-(2amino-3-methoxyphenyl)4H-1-benzopyran-4-one (PD 98059) (25 microM), a selective inhibitor of the p42/p44 MAP kinase pathway and submitted or not to heat stress (42 degrees C, 20 min). Five hours later, B1 receptor mRNA was detected using a semi-quantitative RT-PCR technique. In the meantime, we characterised p42/p44 MAP kinase activation after heat stress by immunodetection. A basal expression of B1 receptor mRNA was detected in rat vascular SMCs. This expression was increased by heat stress. However, in cells previously incubated with either SB 203580 or PD 98059 and submitted to heat stress, this increase in B1 receptor mRNA was not detected. Moreover, we showed by immunodetection that heat stress was followed by a transient phosphorylation of p42/p44 MAP kinases. In conclusion, both p42/p44 and p38 kinases play a crucial role in the mechanism leading to B1 receptor mRNA induction after heat stress.

Role of nitric oxide synthases in the infarct size-reducing effect conferred by heat stress in isolated rat hearts.

Nitric oxide (NO) donors are known to induce both delayed cardioprotection and myocardial heat stress protein (HSP) expression. Moreover, heat stress (HS), which also protects myocardium against ischaemic damages, is associated with a NO release. Therefore, we have investigated the implication of NO in HS-induced resistance to myocardial infarction, in the isolated rat heart model. Rats were divided in six groups (n=10 in each group), subjected or not to heat stress (42 degrees C internal temperature, 15 min) and treated or not with nitro-L-arginine-methylester (L-NAME) a non-selective inhibitor of NO synthase isoforms, or L-N(6)-(1-imino-ethyl)lysine (L-NIL), a selective inhibitor of the inducible NO synthase. Twenty-four hours after heat stress, their hearts were isolated, retrogradely perfused, and subjected to a 30-min occlusion of the left coronary artery followed by 120 min of reperfusion. Infarct-to-risk ratio was significantly reduced in HS (18.7+/-1.6%) compared to Sham (33.0+/-1.7%) hearts. This effect was abolished in L-NAME-treated (41.7+/-3.1% in HS+L-NAME vs 35.2+/-3.0% in Sham+L-NAME ) and L-NIL-treated (36.1+/-3.4% in HS+L-NIL vs 42.1+/-4.6% in Sham+L-NIL) groups. Immunohistochemical analysis of myocardial HSP 27 and 72 showed an HS-induced increase of these proteins, which was not modified by L-NAME pretreatment. We conclude that NO synthases, and in particular the inducible isoform, appear to play a role in the heat stress-induced cardioprotection, independently of HSP 27 and 72 levels. Further investigations are required to elucidate the precise role of HSPs in this adaptive response.

Endothelial kinin B(1)-receptors are induced by myocardial ischaemia-reperfusion in the rabbit.

Kinin B1-receptors are induced by various inflammatory stimuli. Since myocardial ischaemia-reperfusion results in inflammation, we questioned whether it could induce B1-receptor-dependent responses to des-Arg9-bradykinin (DBK). Thirty-six rabbits were submitted either to a 30 min coronary occlusion followed by a 3 h reperfusion or to a sham operation. The response to DBK was then tested in vivo on mean arterial pressure (MAP) and in vitro on isolated hearts and arterial rings. DBK induced a dose-dependent decrease in MAP in the ischaemia-reperfusion group (DBK, 10 microg kg(-1), intra-arterial: -12 +/- 2 vs. -5 +/- 2 mm Hg in the sham group, P < 0.02), which was significantly antagonised by [Leu8]-des-Arg9-bradykinin (LBK), a B1-receptor antagonist. Following ischaemia-reperfusion, isolated hearts responded to DBK by a decrease in coronary perfusion pressure greater than that of the sham group. DBK dose-dependently decreased the isometric force of isolated carotid rings (DBK, 10(-5) M: -9 +/- 2 vs. -1 +/- 2% in the sham group, P < 0.02) and mesenteric arteries (DBK, 10-6 M: -38 +/- 7% vs. -3 +/- 2 % in the sham group, P < 0.001). The vascular effects of DBK seen after ischaemia-reperfusion were significantly antagonised by LBK. The presence of B1-receptors in ischaemia-reperfusion animals was confirmed by immunolocalisation and Western blot analysis. This study demonstrates that myocardial ischaemia-reperfusion induces a global induction of functional kinin B1-receptors in the endothelium.

Delayed myocardial protection induced by endotoxin does not involve kinin B(1)-receptors.

Endotoxin is known to confer a delayed protection against myocardial infarction. Lipopolysaccharide (LPS) treatment also induces the de novo synthesis of kinin B(1)-receptors that are not present in normal conditions. The aim of this study was to evaluate whether LPS-induced B(1)-receptors are implicated in the reduction of infarct size brought about by LPS. Rabbits were submitted to a 30-min coronary artery occlusion and 3-h reperfusion sequence. Six groups were studied: pretreated or not (control animals) with LPS (5 microgram kg(-1) i.v.) 24 h earlier and treated 15 min before and throughout ischaemia - reperfusion with either the B(1)-antagonist R-715 (1 mg kg(-1) h(-1)), the B(1)-agonist Sar-[D-Phe(8)]-des-Arg(9)-bradykinin (15 microgram kg(-1) h(-1)) or vehicle (saline). Infarct size and area at risk were assessed by differential staining and planimetric analysis. The presence of B(1)-receptors in LPS-pretreated animals was confirmed by a decrease in mean arterial pressure in response to B(1) stimulation. LPS-pretreatment significantly reduced infarct size (6.4+/-1.7%, of area at risk vs 24.1+/-2.5% in control animals, P<0.05). This protection was not modified by B(1)-receptor antagonism (7.4+/-2.2%, NS) or stimulation (5.2+/-1.2%, NS). Neither antagonist nor agonist modified infarct size in control animals. In conclusion, these data suggest that LPS-induced myocardial protection in the rabbit is not related to concomitant de novo B(1)-receptor induction.

SB 203580, a mitogen-activated protein kinase inhibitor, abolishes resistance to myocardial infarction induced by heat stress.

Heat stress (HS) is known to confer protection against ischemia-reperfusion injury, including mechanical dysfunction and myocardial necrosis. However, the mechanisms involved in this cardioprotection are yet to be elucidated. Mitogen-activated protein (MAP) kinase cascades have been demonstrated to be involved in cellular response to different stresses. In particular, p38 MAP kinase is known to be activated by HS. Therefore, we investigated the implication of this kinase in HS-induced resistance to myocardial infarction, in the isolated rat heart model, using SB 203580 (SB) to selectively inhibit p38 MAP kinase. Rats were treated with SB (2.83 mg/kg, i.p.) or vehicle (1% DMSO in saline, i.p.) before they were either heat stressed (42 degrees C for 15 minutes) or sham anesthetized. Their hearts were isolated 24 hours later, retrogradely perfused, and subjected to a 35-minute occlusion of the left coronary artery followed by 120 minutes of reperfusion. The infarct-to-risk ratio was significantly reduced in HS (16.9 +/- 2.0%) compared with sham (41.6 +/- 2.5%) hearts. This reduction in infarct size was abolished in the SB 203580-treated group (37.8 +/- 1.9% in HS + SB vs. 42.0 +/- 1.9% in sham + SB). Risk zones were similar between experimental groups. Western blot analysis of the myocardial HSP72 showed an HS-induced increase of this protein, which was not modified by the p38 MAP kinase inhibitor, SB 203580. We conclude that activation of p38 MAP kinase appears to play a role in the functional cardioprotection associated with the heat stress response, which seems to be unrelated to the HSP72 level. Further investigations are required to elucidate the precise role of the p38 MAP kinase and heat stress proteins in this adaptative response.

Protective effects of melatonin against ischemia-reperfusion injury in the isolated rat heart.

There has been increased interest in melatonin recently, since it was shown to be a potent scavenger of toxic free radicals. Melatonin has been found to be effective in protecting against pathological states due to reactive oxygen species release. The present study was performed in order to determine whether melatonin or 5-methoxy-carbonylamino-N-acetyl-tryptamine (5-MCA-NAT), a structurally related indole compound, protect against ischemia-reperfusion injury in the isolated rat heart. Wistar rats were treated in vivo with either melatonin (1 or 10 mg/kg, i.p.) or 5-MCA-NAT (10 mg/kg, i.p.) or their vehicle, 30 min before their hearts were excised and perfused according to the Langendorff technique. Two different protocols were then applied. In the first one, a regional ischemia (5 min)-reperfusion (30 min) sequence was performed in order to record incidence and duration of reperfusion arrhythmias. In the second one, infarct size was assessed after a regional ischemia (30 min)-reperfusion (120 min) sequence. Results show a spectacular protection against ischemia-reperfusion injuries (on arrhythmias as well as on infarct size) in rats pre-treated with 10 mg/kg of melatonin or 5-MCA-NAT. In conclusion, both melatonin and its structural analog, 5-MCA-NAT, appear to confer protection against ischemia-reperfusion injury in the isolated rat heart. This observation suggests that melatonin could have a potential clinical application in the treatment of myocardial ischemia, even if the mechanisms underlying this protection remain to be determined.

Nitric oxide and its role in the induction of kinin B(1)-receptors after heat stress in the rat.

Kinin B(1)-receptors are inducible-receptors. They are absent under basal conditions but expressed following pathophysiological stresses. This study was designed to examine a possible role of nitric oxide (NO) in the mechanism underlying B(1)-receptor induction after heat stress (HS). Rats were divided into six groups, subjected or not to HS (42 degrees C internal temperature, 20 min) without or with treatment with nitro-L-arginine-methylester (L-NAME), a nonselective inhibitor of NO synthase (NOS) isoforms, or L-N(6)-(1-imino-ethyl)lysine (L-NIL), a selective inhibitor of the inducible NOS. Twenty-four hours after HS, rats were injected with bradykinin and [des-Arg(9)]-bradykinin and hypotensive responses were recorded. In six additional groups, B(1)-receptor mRNAs were detected in aorta 5 h after HS or sham treatment. Bradykinin, a B(2)-receptor agonist, induced a hypotension of a similar magnitude in all the groups studied. [des-Arg(9)]-bradykinin, a B(1)-receptor agonist, induced no response in sham rats. In rats previously subjected to hyperthermia, this agonist induced a hypotensive response, which was, respectively, decreased and increased by pretreatment with L-NAME and with L-NIL prior to hyperthermia. RT-PCR results confirmed these in vivo observations. In conclusion, this study suggests a role for NO in B(1)-receptor induction after HS as well as a possible interaction between NOS isoforms.

Heat stress-induced protection of endothelial function against ischaemic injury is abolished by ATP-sensitive potassium channel blockade in the isolated rat heart.

The protection conferred by heat stress (HS) against myocardial ischaemia-reperfusion injury, in terms of mechanical function preservation and infarct size reduction, is well documented and mechanisms underlying these effects have been extensively explored. However, the effect of HS on coronary circulation is less known. The aim of this study was thus to investigate the role of ATP-sensitive potassium (K(ATP)) channels in the protection against ischaemic injury afforded by HS to the coronary endothelial function. Twenty-four hours after whole body hyperthermia (42 degrees C for 15 min, H groups) or sham anaesthesia (Sham groups), isolated perfused rat hearts were subjected to a 15 min stabilization period followed by a 30 min infusion of either 0.3 microM glibenclamide (Gli, a K(ATP) channel blocker) or its vehicle (V). Hearts were then exposed to a low-flow ischaemia (30 min)-reperfusion (20 min) (I/R) or normally perfused (50 min), after which coronaries were precontracted with 0.1 microM U-46619. Finally, the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 microM) was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). In hearts from Sham-V and Sham-Gli groups, I/R selectively diminished 5-HT-induced vasodilatation without affecting the vasodilatation to SNP. In V-treated groups, prior HS preserved the vasodilatation produced by 5-HT. This HS-induced protection was abolished by Gli treatment. In conclusion, these results suggest that K(ATP) channel activation contributes to the preservation of coronary endothelial function conferred by heat stress against ischaemic insult.

Myocardial meta-[125l]iodobenzylguanidine uptake in awake genetically hypertensive rats at different ages: an autoradiographic study.

The purpose of this work was to evaluate changes in myocardial meta-[125I]iodobenzylguanidine ([125I]MIBG) uptake and distribution with age in awake spontaneously hypertensive rats (SHR) with respect to Wistar-Kyoto (WKY) rats. Rats were randomly divided into two groups, one for measuring myocardial [125I]MIBG uptake and distribution 4 h after its injection and the second for evaluating myocardial catecholamine concentrations. Mean arterial blood pressure, cardiac hypertrophy index (heart/body weight ratio), and heart rate were significantly higher with increasing age in SHR compared with matched WKY rats. Myocardial catecholamine concentrations and turnover did not differ between the two strains and were significantly decreased with increasing age. Myocardial [125I]MIBG uptake determined by gamma counting was similar in WKY rats and SHR and did not vary significantly with age when expressed as uptake density. However, in both strains of rats, [125I]MIBG uptake determined by autoradiography was significantly greater at the base of the heart than at the apex and midventricular levels, and the uptake values of young rats were significantly higher than those of older rats. In 21-week-old WKY rats and SHR, the highest [125I]MIBG uptake values were found in the right ventricle. Thus, quantitative autoradiography allowed detection of significant changes in myocardial [125I]MIBG uptake and showed its heterogeneous distribution in the rat heart.

Histamine H3-receptor stimulation is unable to modulate noradrenaline release by the isolated rat heart during ischaemia-reperfusion.

The aim of this study was to evaluate the ability of H3-histaminergic prejunctional receptors to modulate the noradrenaline release induced by myocardial ischaemia in the rat, and the effects of an eventual modulation on haemodynamic, biochemical and electrophysiological parameters. Isolated rat hearts were perfused according to the Langendorff technique. Control hearts (n = 13) were not treated; two groups were treated with the H3-agonist R-alpha-methyl-histamine at 0.3 microM (n = 14) and 1 microM (n = 11) and one group, used as positive control, was treated with the selective alpha 2-agonist Mivazerol at 0.5 microM (n = 14) added to the perfusion medium. Noradrenaline, lactate and transaminase output in the coronary effluent, as well as various haemodynamic and electrophysiological parameters, were measured during global and total ischaemia (30 min) and reperfusion (30 min). alpha 2-receptor stimulation increased ischaemia-induced noradrenaline release during reperfusion (195 +/- 13 vs. 145 +/- 12 pmol.g-1 in control group, P < 0.05). In contrast, R-alpha-methyl-histamine, at both doses, did not significantly modify these parameters. Both treatments did not affect ischaemia- and reperfusion-induced haemodynamic (decrease in heart rate or in left ventricular developed pressure), biochemical (lactate and GOT release) and electrophysiological (arrhythmias or increase in action potential duration) alterations. Unlike other species, the rat appears to be insensitive to H3-histaminergic receptor modulation of ischaemia-induced noradrenaline release, although a modulation can be seen with other prejunctional receptor agonists.