Biomedical subjects

R Domenech

Publications and source records attributed to R Domenech.

18 recordsLinked to original sources

PubMed2001

Mitochondrial ATP dependent potassium channels mediate non-ischemic preconditioning by tachycardia in dogs.

Brief episodes of tachycardia without myocardial ischemia prior to a coronary occlusion decrease myocardial infarct size in dogs. This non-ischemic preconditioning is mediated by adenosine. Because ischemic preconditioning is mediated through ATP dependent potassium channels, particularly the mitochondrial ones, we studied whether non-ischemic preconditioning is also mediated through these channels. In anesthetized dogs heart rate was kept constant at 120 cycles/min and aortic pressure changes were damped. Myocardial infarction was induced by occlusion of the anterior descending coronary artery for 60 min and reperfusion for 270 min. In a control group the infarct size (necrotic volume/risk region volume x 100) was 15.8+/-1.5%. Preconditioning with five periods of tachycardia, 5 min in duration each at 213 cycles/min with intervening periods of 5 min of basal heart rate at 120 cycles/min, reduced the infarct size by 45.6% (p < 0.05) with respect to the control group. This effect was completely reverted by the blockade of ATP dependent potassium channels with glibenclamide or 5 hydroxydecanoate (a specific blocker of mitochondrial ATP dependent potassium channels) prior to preconditioning. These effects were not due to differences in collateral flow, risk region size or hemodynamic variables between the groups. These results show that mitochondrial ATP dependent potassium channels mediate non-ischemic preconditioning by tachycardia in dogs.

Adenosine↗

PubMed1998

Non-ischemic myocardial preconditioning.

The reduction of infarct size produced by brief ischemic episodes prior to a sustained occlusion of a coronary artery, called ischemic preconditioning, is a well known phenomenon that occurs in several species, but its mechanism is still under investigation. Recent reports support the idea that this protection can also be obtained by non-ischemic maneuvers like distention of the left ventricle and metabolic stimulation of myocardial cells. The features of non-ischemic preconditioning (temporal limitation, second window, tolerance development, remote preconditioning and efficiency of the protection), as opposed to those of ischemic preconditioning, are still to be determined. Neither is it known if non-ischemic preconditioning occurs in humans. From a physiological point of view the protective effect of an increase in metabolic rate of the heart means a constant feed-back mechanism in the myocardial cell that counteracts the presumptive damage consequent to the increase in metabolism. Therefore, in the presence of a sudden coronary occlusion the metabolic rate of the heart immediately before the occlusion would have a dual role of increasing the degree of ischemia and of protecting against it.

Animals↗

PubMed1997

[Metalloproteinases in vascular wall remodelling].

Metalloproteinases (MTP) are enzymes that degrade the extracellular matrix, mainly collagen tissue. Normally these enzymes are expressed in vascular walls as proenzyme together with inhibitors of the active enzymes. By effect of different cytokines, produced by an inflammatory process in the vascular wall, these proenzymes are activated to an extent that surpasses the action of the inhibitors and degrade collagen. This action may partly explain the rupture of atherosclerotic plaques ("vulnerability") and also the remodelling of the vessel wall with "compensatory enlargement" of the vessel (increase in the outer size of the vessel) that allows the plaques to develop inside the arterial wall without protruding into the vessel lumen for many years. The occlusion of saphenous vein in aortocoronary bypass grafts is due to fibromuscular proliferation and atheroma development and therefore the participation of MTP in the occlusion of these vessels is a reasonable hypothesis. However, the structural features of saphenous vein bypass grafts are different from those of atheroma in native coronary arteries. Mainly the compensatory enlargement of the vessels does not occur because of intense fibrous tissue development including the adventitia and therefore the new tissue in the wall is forced to protrude into the vessel lumen. The reason for this difference in the vessel wall remodeling is not clear and the article by Grez et al in this issue of this Journal is an starting and promising study in this regard.

Arteries↗

PubMed1996

Effect of transthoracic electric current on the coronary circulation of the dog.

OBJECTIVE: In vitro experiments have shown that an electric field changes coronary vascular resistance (CVR) tone and damages the vascular endothelium. The effect of transthoracic electric current in dogs on the vasodilatory responses mediated through the endothelium and reactive hyperemia were studied. The manner of delivery of the electric current was similar to that used clinically during cardiac resuscitation. DESIGN: Eight mongrel dogs of either sex weighing between 15 and 22 kg were anesthetized with sodium pentobarbital. The lungs were mechanically ventilated and the thorax was opened. Circumflex coronary flow was measured with an electromagnetic flowmeter. Mean aortic pressure and the heart rate were kept constant and left ventricular systolic and diastolic pressures did not change during the procedures. The changes in CVR produced by different intracoronary doses of acetylcholine and reactive hyperemia to 10 and 30 s of circumflex coronary occlusion were measured before and after the transthoracic delivery of five synchronized electric shocks, 300 J each 1 min apart. MAIN RESULTS: CVR decreased by 32.8 +/- 2.1% (P < 0.01) from the effects of the electric shocks in spite of no changes in heart rate, ventricular systolic and diastolic pressures nor left ventricular oxygen consumption. After the delivery of the electric shocks, the vasodilatory response to acetylcholine decreased by a mean value of 35.9 +/- 2.6% for the different doses (P < 0.001) and reactive hyperemia decreased by 42.5 +/- 5.5% (P < 0.001) and by 31.5 +/- 9.6% (P < 0.02) for the 10 and 30 s occlusion duration, respectively. The intracoronary infusion of sodium nitroprusside decreased the coronary vascular resistance to a minimal value lower than that obtained by the maximal dose of acetylcholine but similar to before and after the passage of the electrical current revealing the preservation of the coronary vasodilatory reserve after the electrical shocks. CONCLUSIONS: These results show that transthoracic electrical shocks as used clinically induce coronary vasodilation but simultaneously produce endothelial dysfunction.

Acetylcholine↗

PubMed1995

In memoriam Professor Mario Penna, MD.

In memoriam Mario Penna. Born in Ovalle, Chile, February 12, 1924. MD, University of Chile. Professor of Pharmacology, Faculty of Medicine, University of Chile. Chairman, Department of Pharmacology; Director, Department of Experimental Medicine, Eastern Division, University of Chile. President, Latin American Association of Pharmacology. Member of the Advisory Committee of this journal, under its previous name of "Archivos de Biología y Medicina Experimentales", between 1966 and 1987. Deceased in Santiago, Chile, June 25, 1994.

Cardiology↗

PubMed1995

Relative participation of adenosine and endothelium derived mediators in coronary reactive hyperemia in the dog.

The metabolites that mediate coronary reactive hyperemia have not been definitely identified. Although adenosine and endothelium derived substances seem to be involved, their relative contributions have not been defined yet. In the canine coronary circulation, we studied the relative participation of adenosine, nitric oxide and prostacyclin in reactive hyperemia, by measuring the changes produced by interfering with the synthesis or action of these metabolites. The dose-response curve for flow changes vs intracoronary administration of adenosine was displaced to the right after the inhibition of nitric oxide synthesis with N-omega-nitro-L-arginine, revealing that nitric oxide release partly mediates the vasodilator action of adenosine. The inhibition of PGI-2 synthesis with indomethacin did not modify reactive hyperemia. Interference with adenosine action, by administration of adenosine deaminase plus theophylline, decreased reactive hyperemia by 31.0 +/- 4.0% (p < 0.001). Inhibition of nitric oxide synthesis decreased reactive hyperemia by a larger (p < 0.005) magnitude, 41.0 +/- 3.9% (p < 0.001), revealing the existence of other stimuli for nitric oxide release in reactive hyperemia besides adenosine. Simultaneous inhibition of nitric oxide and PGI-2 syntheses and of adenosine action reduced reactive hyperemia, but the effect was not additive, reaching 49.5 +/- 4.5% of control. Since nitric oxide and adenosine are the most important mediators in reactive hyperemia so far described, our results suggest that other metabolites, acting directly or through mediators other than adenosine or nitric oxide, are responsible for about 50% of coronary reactive hyperemia.

Adenosine↗

PubMed1994

Aging differentially modifies arterial sensitivity to endothelin-1 and 5-hydroxytryptamine: studies in dog coronary arteries and rat arterial mesenteric bed.

The influence of age on vascular reactivity to endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT) was studied in coronary artery rings from dogs of 9 years of age or younger, and dogs older than 9 years. ET-1 caused concentration-dependent contractions that developed about 100% of the 70 mM KCl-induced tension in the younger dogs; those from older dogs did not generate more than 20%. In contrast, 5-HT developed only about 20% of the KCl-induced tension in rings from young dogs, whereas in the older animals, it developed up to 120% of the KCl tension. No significant difference in the tension developed by 70 mM KCl was noted between both groups of dogs. Mechanical denudation of the endothelial cell layer caused a modest, yet significant, leftward shift of the ET-1 and 5-HT concentration-response curves only in the younger dogs. N omega-Nitro-L-arginine (15 microM) shifted the ET-1 concentration-response curves to the left in rings from both groups of dogs. Rings precontracted with 20 mM KCl relaxed in a concentration-dependent fashion with acetylcholine; its sensitivity was about threefold less in the older group of dogs. To validate the changes in vascular reactivity with age, a parallel study was performed perfusing the arterial mesenteric bed of rats of 3, 7, and 30 weeks of age. In this experimental model, the efficacy of ET-1 significantly decreased with age and that of 5-HT was significantly increased. The vasomotor reactivity of noradrenaline was modestly affected by aging, whereas the acetylcholine-induced vasorelaxation was significantly reduced with age.

Acetylcholine↗

PubMed1994

Endothelium-derived relaxing factor participates in the transmural distribution of coronary bloodflow.

OBJECTIVE: To study the role of endothelium-derived relaxing factor (EDRF)--which participates in the regulation of coronary vascular tone, but has an unknown role in the transmural distribution of coronary flow--in transmural coronary flow distribution during steady basal flow and during reactive hyperemia in the left ventricular wall of the dog. DESIGN: Sixteen mongrel dogs of either sex weighing between 14 and 24 kg were anesthetized with sodium pentobarbital. The lungs were mechanically ventilated and the thoraces were opened. Circumflex coronary flow was measured with an electromagnetic flowmeter, and its transmural distribution across four layers of the left ventricular wall was measured with radioactive microspheres. Measurements were done during steady basal flow and during peak reactive hyperemia before and after the inhibition of the EDRF synthesis with N-omega-nitro-L-arginine (NNLA). Mean aortic and systolic left ventricular pressures and heart rate were kept constant, and left ventricular end-diastolic pressure increased by only 3.3 mmHg during reactive hyperemia. MAIN RESULTS: NNLA produced a mean decrease of steady basal flow of 22.3 +/- 0.9% (P < 0.01). Flow decreased in all layers of the wall; the decrease, however, was proportionally less in the subendocardium (P < 0.05). During reactive hyperemia (before NNLA), flow was redistributed to the subendocardium (compared with steady basal flow). Administration of NNLA reduced the magnitude of peak reactive flow to all layers in the wall, showing a relative enhancement of flow in the subendocardium. CONCLUSIONS: These results suggest that the EDRF participates in the regulation of coronary bloodflow and its distribution across the left ventricular wall.

Animals↗

PubMed1993

Role of endothelium-derived relaxing factor on coronary blood flow regulation in the dog.

The endothelium plays a key role in the regulation of vasoreactivity. To assess its importance on coronary flow regulation, we studied the participation of endothelium-derived relaxing factor-nitric oxide (EDRF-NO) on coronary reactive hyperemia and on the hyperemia that occurs secondary to an increase in myocardial oxygen consumption. In 15 dogs, the reactive hyperemic response decreased substantially after inhibition of EDRF-NO synthesis with N-omega-nitro-L-arginine (P < 0.01). In contrast, the hyperemia secondary to an increase in myocardial oxygen consumption, characterized by a linear correlation between myocardial oxygen consumption and coronary flow, did not change significantly after inhibition of EDRF-NO production (regression analysis, P > 0.1). Thus EDRF-NO synthesis by the endothelium is an important mechanism mediating the reactive hyperemic response but it does not seem to be essential for the metabolic regulation of coronary vascular resistance during hyperemia induced by an increased metabolic demand on the myocardium.

Animals↗

PubMed1991

Effect of endothelin on total and regional coronary resistance and on myocardial contractility.

Endothelin is a 21-amino acid peptide produced by the endothelium and has a potent vasoconstrictor effect. Because of the importance of the endothelium on vasomotor regulation, we studied the effect of endothelin on total and regional coronary vascular resistance and on myocardial contractility in the intact heart of anesthetized dogs. Intracoronary administration of 2 to 80 pmol/kg of endothelin produced a dose-dependent increase in coronary resistance, ischaemic decrease in myocardial contractility and atrium-ventricular blockade. The increase in resistance was greater towards the outer layer of the left ventricular wall. When the coronaries were perfused at a constant rate and vasoconstriction was prevented with adenosine or nitroglycerine, endothelin did not produce inotropic changes. These results show that endothelin is a potent vasoconstrictor of the resistance coronary vessels, producing a redistribution of transmural blood flow and a decrease in myocardial contractility secondary to ischaemia.

Animals↗

PubMed1987