Compensation of Endothelin-1-Induced Coronary Vasoconstriction

Abstract

The vasodilator capacity of the coronaries was determined by the reactive hyperemia (RH) test in open-chest anesthetized dogs. The myocardial release of adenine nucleosides (adenosine and inosine) was measured by the HPLC-UV method. In group I (n = 9) after the control RH test, a bolus injection of endothelin-1 (ET-1; 1.0 nmol i.c.) was administered and was followed by a second RH test. In group II (n = 9), glibenclamide (GLIB) was infused continuously (1.0 mumol/min i.c.) and RH tests were performed during the control period and then before and after bolus injection of ET-1. In contrast to the significant reduction of the RH response after ET-1 in group I and after GLIB in group II, the nucleoside release into the coronary sinus during the first minute of the RH test was significantly higher (adenosine release 0.05 +/- 0.02 vs. 0.10 +/- 0.04 mumol, and 0.02 +/- 0.00 vs. 0.08 +/- 0.02 mumol; p < 0.05). Injection of ET-1 did not result in further RH reduction in GLIB-pretreated dogs (group II) but significantly increased nucleoside release. High doses of ET-1 activated the metabolic compensatory mechanisms of the myocardium and thereby increased the release of adenine nucleosides into the venous blood of the heart. However, whether these metabolites can exert any significant compensatory vasodilator effects appears doubtful.

Coronary metabolic adaptation restricted by endothelin in the dog heart

“…In agreement with preliminary results obtained in the dog heart (11), the present investigation shows that a single dose of ET-1 is capable of significantly decreasing metabolic adaptive capacity in the coronary vascular bed, and, at the same time, of increasing release from the heart of metabolic mediators. The long-lasting coronary vasoconstriction following ET-1 administration, a major finding of these results (Tables I and II), also confirms a number of previous reports (for reference see (16,26)).…”

“…Because under basal conditions the adenine nucleoside output via the coronary venous drainage of the dog heart is very small [usually it is less than 2 nmol min -1 and 4 nmol min -1 for adenosine and inosine, respectively, (11)], for practical reasons a wellquantified reversible ischemic load (RH) was applied. By plotting hyperemic (postischemic) flow values against nucleoside release, the shift of regression lines appears to provide indirect evidence for the reduced potency under ET-1 influences of endogenous adenosine and inosine as coronary vasodilators.…”

Pericardial concentrations of adenosine, inosine and hypoxanthine in an experimental canine model of spastic ischaemia

“…An experimental model was designed to induce myocardial ischaemia by coronary vasospasm provoked by endothelin-1 (ET-1) in the in situ canine heart. The ET-1 vasoconstrictor effect has certain characteristics that are uncommon in the coronary bed : the vascular effects of a high-dose bolus injection are usually long lasting, occlusive and uncompensated by the autoregulatory processes of the heart [15][16][17]. These features make this peptide the most likely candidate as an endogenous agent eliciting natural coronary spasm [18,19].…”