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

Abstract

It has been shown that the adenosine concentration in the pericardial fluid of the normal heart is higher by one order of magnitude than that of the venous plasma. A further increase in the pericardial adenosine concentration was also demonstrated in myocardial ischaemia or hypoxia. It was proposed that pericardial nucleoside levels may represent the interstitial concentrations of the adenine nucleosides. An experimental model was designed to determine the intrapericardial concentrations of adenosine, inosine and hypoxanthine during coronary spasm provoked by intracoronary administration of endothelin-1 (ET-1; 0.08+/-0.02 nmol/g of myocardial tissue). In the in situ dog heart (n=10), adenosine, inosine and hypoxanthine concentrations were determined by HPLC in fluid samples collected from the closed pericardial sac before and after ET-1 administration, and from the systemic arterial blood. Systemic blood pressure, heart rate and standard ECG were registered continuously. We found that the nucleoside concentrations in the infusate samples increased significantly during coronary spasm [adenosine, 1.49+/-0.44 compared with 0.37+/-0.07 microM (P<0.05); inosine, 27.43+/-11.51 compared with 0.47+/-0.11 microM (P<0.05); hypoxanthine, 21.17+/-6.49 compared with 4.91+/-1.24 microM (P<0.05)], while a significant decrease in blood pressure and an elevation in ECG ST segments were observed. The levels of the purine metabolites did not change in the systemic blood. The data indicate that changes in adenine nucleoside levels measured in pericardial infusate samples reflect activation of coronary metabolic adaptation in this model of spastic ischaemia, and that pericardial nucleoside levels may characterize alterations in interstitial adenine nucleoside concentrations.

Potential influence of the pericardial space on myocardial function: Cardiac interactions of adenosine and endothelin-1

“…The closed pericardium model and our pericardial sampling method were suitable for characterizing the alteration of pericardial concentrations of both ET-1 and adenine nucleosides. This pericardial model was successfully established in our research laboratory in order to investigate the interstitial concentrations of endogenous regulators, such as adenine nucleosides, endothelin-1, natriuretic peptides, angiotensin II and catecholamines [27][28][29][30]. These findings support the hypothesis that the pericardial fluid may have the potential to mirror the compounds of myocardial interstitium and allow a new possibility to investigate the myocardial interaction of adenosine and ET-1.…”

“…The question arises, whether locally elevated levels of adenine nucleosides can influence myocardial function and whether cardioprotective effects of nucleosides can be provoked from the pericardial space? Our data suggest that the residual pericardial concentrations of ADO and INO measured at the end of the incubation periods are at the same order of magnitude or interestingly, even higher than their concentrations under severe myocardial ischemia [28]. The low pericardial turnover rate offers the opportunity of pericardial administration of adenine nucleosides for local pharmaco-therapeutic interventions.…”

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

“…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.…”

“…[11][12][13] Notably, physiological concentrations of certain regulatory agents were found to be several magnitudes higher in the pericardial fluid than in the peripheral and coronary venous blood. 2,3,7,14,15 These elevated pericardial levels reflect their myocardial derivation and suggest a teleological role for the pericardial space as a functionally distinct compartment with potential (patho)physiological function in cardiac regulation. Moreover, the pericardial space offers the opportunity to examine the effects and interactions among the aforementioned agents, whose pericardial concentrations may be elevated in cardiovascular pathologies.…”

“…Moreover, the pericardial space offers the opportunity to examine the effects and interactions among the aforementioned agents, whose pericardial concentrations may be elevated in cardiovascular pathologies. 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.…”