Endothelin-1-induced elevations in purine metabolite concentrations — autoregulatory protection in the canine pericardium?

Abstract

Pericardial fluid accumulates the cardioprotective purine metabolites, as well as the endogenous vasoconstrictor agent endothelin-1 (ET-1). The aim of the present study was to characterize the pericardial concentrations of the purine metabolites adenosine, inosine and hypoxanthine before and after intrapericardial administration of ET-1 to the in situ heart. The closed pericardial sac of anaesthetized dogs (n=9) was cannulated for ET-1 administration and for obtaining native pericardial fluid and control pericardial infusate samples (C1 and C2), as well as consecutive pericardial infusate samples (samples I, II and III) obtained 15 min after intrapericardial administration of 150 pmol/kg ET-1. In an additional five dogs, using the same protocol, ventricular epicardial and endocardial monophasic action potential recordings were performed to assess local ischaemic electrophysiological changes. Significant elevations of pericardial purine metabolite concentrations (measured by HPLC) were found in sample II compared with sample C2: adenosine, 4.5+/-1.7 compared with 0.5+/-0.1 microM (P<0.05); inosine, 18.3+/-2.8 compared with 0.9+/-0.2 microM (P<0.001); hypoxanthine, 38.1+/-8.0 compared with 13.4+/-2.6 microM (P<0.01). Systemic blood pressure, left ventricular pressure and contractility, and systemic plasma levels of the purine metabolites remained unchanged during the ET-1 effect, while significant ECG ST elevations (ST(max) 0.68+/-0.01 mV; P<0.001) were observed. In the five dogs analysed electrophysiologically, the left ventricular epicardial monophasic action potential duration and upstroke velocity decreased significantly at time point II compared with C2, while the endocardial monophasic action potential duration and upstroke velocity did not show ischaemia-related changes. The results suggest that intrapericardial administration of ET-1 induces subepicardial ischaemia, with parallel activation of coronary metabolic adaptive and cardiac self-protective mechanisms in the epimyocardial layer of the heart.

Comparison of Elimination and Cardiovascular Effects of Adenine Nucleosides Administered Intrapericardially or Intravenously in Anesthetized Dog

“…34 Earlier study has shown that IP administration of ET-1 does not cause transmural ischemia, which was demonstrated by the different alterations of the endocardial and epicardial MAP tracings: significant shortening of the epicardial but not the endocardial MAP duration was observed. 19 Moreover, significant inotropic action of IP INO was not detected in the present study, similarly to the IP application of ET-1. 19 In the present study, only weak cardiovascular effects were observed during IP administration of adenine nucleosides.…”

“…19 Moreover, significant inotropic action of IP INO was not detected in the present study, similarly to the IP application of ET-1. 19 In the present study, only weak cardiovascular effects were observed during IP administration of adenine nucleosides. One possible explanation to this finding is that no transmural penetration through the left ventricular wall occurred by the agents' IP administration.…”

“…We have previously demonstrated that ET-1 applied intracoronarially and IP caused significant elevations in the concentrations of pericardial but not plasma purine metabolites, suggesting a local effect of ET-1 on myocardial production and release of adenine nucleosides. 14,19 Furthermore, the pericardial concentration of the vasoconstrictor ET-1 and the vasodilator ADO increased in response to IP administration of catecholamines (dopamine and norepinephrine). 17 Several investigations also suggest that pericardial delivery of different endogenous or exogenous agents can influence myocardial function in certain cardiovascular pathologies.…”

“…Previous studies demonstrated that certain regulatory agents applied into the pericardial space may exert characteristic cardiovascular effects, 19,[28][29][30] raising the possibility of pharmacotherapeutic intervention via the pericardium. Formerly, we found that IP infusion of endothelin-1 (ET-1) induced ventricular arrhythmias associated with prolongation of QT time and monophasic action potentials (MAP) duration.…”

“…2,5,8,9,11,12,15,16 We previously investigated the pericardial interactions among adenine nucleosides, endothelin-1, natriuretic peptides, angiotensin II, and catecholamines 14,17,18 using a closed-pericardium model. 19 In these experiments, we intended to describe the convoluted regulatory loops and to reveal their complex interactions within the heart. Adenosine (ADO) and its metabolite inosine (INO) play a crucial role in the regulation of vascular reactivity, metabolic adaptation, inflammation, monocyte/macrophage/lymphocyte function, ischemic preconditioning, and angiogenesis.…”