Potential beneficial as well as detrimental effects of chronic treatment with lisinopril and (or) spironolactone on isolated hearts following low-flow ischemia in normal and infarcted rats.

This study was designed to demonstrate potential beneficial as well as detrimental effects of lisinopril and spironolactone given in combination. In patients with congestive heart failure or myocardial infarction, the use of angiotensin-converting enzyme (ACE) inhibitors may inhibit aldosterone production. Spironolactone, a specific aldosterone receptor antagonist may exert other independent and additive effects to those of ACE inhibitors. Given the consequences of aldosterone on ischemic hearts, we evaluated the protective effects of spironolactone or lisinopril and combined spironolactone-lisinopril therapy during low-flow ischemia and reperfusion in isolated rat hearts. Normal and infarcted (left coronary artery ligature) male Wistar rats were submitted to chronic action of drugs (0.8 mg.kg-1.day-1 for lisinopril and 8 or 50 mg.kg-1.day-1 for spironolactone) for 1 month. Hearts were rapidly excised and perfused (constant pressure) for a 40-min period of stabilization followed by a 25-min period of global low-flow ischemia and a 30-min reperfusion. In normal rats, spironolactone decreased ischemic and reperfusion contracture, reduced ventricular tachycardia, suppressed action-potential duration dispersion, and increased reactive hyperemia leading to an improvement of contractile recovery. Lisinopril also decreased ventricular tachycardia and action-potential duration dispersion concomitantly with increased reactive hyperemia and better contractile recovery. These beneficial effects of the drugs were lost when the two treatments were combined (lisinopril and 50 mg.kg-1.day-1 spironolactone), despite a synergistic effect on plasmatic K+ and Mg2+. However, an interaction between the ACE inhibitor and spironolactone potentiating the effects of either drug alone was observed with a lower dose of spironolactone (lisinopril and 8 mg.kg-1.day-1 spironolactone). Similar beneficial effects have been noted in infarcted rat hearts on reactive hyperemia, ventricular tachycardia, and contractile recovery with the combined treatment and for both spironolactone concentrations (8 or 50 mg). Chronic spironolactone treatment produces similar beneficial effects to ACE inhibitor treatment on normal rat hearts during an ischemia-reperfusion protocol. Synergistic effects have been observed with the combined therapy when a lower dose of spironolactone was utilized in normal and infarcted rats. However, in the case of a high dose of spironolactone, the two effective drugs seem to cancel each other but only in normal rats.

Reactive hyperemia during early reperfusion as a determinant of improved functional recovery in ischemic preconditioned rat hearts.

OBJECTIVE: Our study was undertaken to clarify the impact of the shear stress-induced reactive hyperemia (associated with reperfusion) in preconditioning-mediated protection. METHODS: In control rat hearts, a 40-minute preischemic perfusion (constant pressure: 70 mm Hg) period was followed by 25-minute global low-flow ischemia (constant flow: 0.3 mL/min) and 30-minute reperfusion (constant pressure). As preconditioning protocol, hearts underwent 2 cycles of 5-minute no-flow ischemia/5-minute reperfusion. RESULTS: Although coronary vasodilation in response to shear stress is severely impaired after global low-flow ischemia and reperfusion, it is fully preserved by ischemic preconditioning concomitantly with an improvement of left ventricular developed pressure. Restricting coronary peak flow to 100% of baseline at reperfusion reduced left ventricular recovery to the control level. N(G)-nitro-l-arginine methyl ester affects the restoration of reperfusion-reactive hyperemia and the improvement of contractile recovery afforded by ischemic preconditioning. However, if the time course of hyperemia was restored by forcibly reperfusing to 150% of baseline for 10 minutes and, therefore, by restricting final peak flow to 80% of baseline for 20 minutes, contractile function recovered to a high degree despite the presence of N(G)-nitro-l-arginine methyl ester. CONCLUSION: We conclude that wall stretch and shear stress during reperfusion are necessary for the mediation phase of preconditioning.

Mechanisms underlying the coronary vasodilation in the isolated perfused hearts of rats submitted to one week of high carbon monoxide exposure in vivo.

We examined the possible mechanisms for carbon monoxide (CO)-induced effects in hearts isolated from Wistar rats exposed for 1 wk to 530 ppm CO. They were treated by daily intraperitoneal injections of either methylene blue (10 mg/kg), glibenclamide (3 mg/kg), or apamin (125 nmol/kg), known to inhibit vasodilatory mechanisms. Hearts were excised, cannulated, and retrogradely perfused through the coronary artery, using the Langendorff method with a constant perfusion pressure. After stabilization, we investigated the degree of resistance to an in vitro transient global low-flow ischemia. One-week CO exposure induced a significant increase in hematocrit and a cardiomegaly, which were not affected by any of these drugs. An enhancement of coronary flow was observed concomitantly with a decrease in ischemic contracture after CO exposure. However, no improvement of contractile recovery was noted. Since methylene blue did not interact with the CO effects, a cGMP signaling pathway can be excluded. On the contrary, as glibenclamide and to a greater extend apamin blocked the vasodilatory effects of CO, we conclude that K+ channels may be involved in these CO effects.

A 4-AP-sensitive current is enhanced by chronic carbon monoxide exposure in coronary artery myocytes.

A physiological role of carbon monoxide has been suggested for coronary myocytes; however, direct evidence is lacking. The objective of this study was to test the effect of chronic carbon monoxide exposure on the K(+) currents of the coronary myocytes. The effect of 3-wk chronic exposure to carbon monoxide was assessed on K(+) currents in isolated rat left coronary myocytes by the use of the patch-clamp technique in the whole cell configuration. Moreover, membrane potential studies were performed on coronary artery rings using intracellular microelectrodes, and coronary blood flow in isolated heart preparation was recorded. Carbon monoxide did not change the amplitude of global whole cell K(+) current, but it did increase the component sensitive to 1 mM 4-aminopyridine. Carbon monoxide exposure hyperpolarized coronary artery segments by approximately 10 mV and, therefore, increased their sensitivity to 4-aminopyridine. This effect was associated with an enhancement of coronary blood flow. We conclude that chronic carbon monoxide increases a 4-aminopyridine-sensitive current in isolated coronary myocytes. This mechanism could, in part, contribute to hyperpolarization and to increased coronary blood flow observed with carbon monoxide.