Histamine increases interstitial adenosine concentration via activation of ecto-5'-nucleotidase in rat hearts in vivo

Abstract

We examined whether histamine enhances the production of interstitial adenosine via stimulation of ecto-5'-nucleotidase (a key enzyme responsible for adenosine production) using microdialysis techniques in in situ rat hearts. The microdialysis probe was implanted in the left ventricular myocardium of anesthetized rats and perfused in the presence of adenosine 5'-monophosphate (AMP). Histamine (10-500 microM) administered into the perfusate had a tendency to increase the adenosine concentration. In the presence of prazosin (50 microM), an antagonist of alpha1-adrenoceptors, or of chelerythrine (10 microM), a protein kinase C (PKC) inhibitor, and in reserpinized rats, histamine failed to increase the AMP-primed dialysate adenosine concentration. Accumulation of norepinephrine in the extracellular fluid elicited by pargyline (100 microM), a monoamine oxidase inhibitor, significantly increased histamine-induced adenosine production. Okadaic acid (50 microM), an inhibitor of protein phosphatase, enhanced the histamine-induced increase in adenosine concentration. Norepinephrine is known to activate alpha1-adrenoceptors and PKC. Taken together, the results demonstrate that histamine-released norepinephrine activates both alpha1-adrenoceptors and PKC, which increased ecto-5'-nucleotidase activity and augmented release of adenosine in rat hearts.