Effects of adenosine and its analogues on isolated intracerebral arterioles: Extraluminal and intraluminal application

Abstract

We evaluated the responses of brain parenchymal arterioles to intraluminal and extraluminal application of adenosine and its analogues. Intracerebral arterioles (28.4- to 60.3-μ diameter) were isolated from Sprague-Dawley rats, cannulated with micropipettes, and perfused in vitro. Both extraluminal and intraluminal adenosine, 5′-(N-ethylcarboxamido)adenosine (NECA), R-N6-(phenylisopropyl) adenosine (R-PIA), and S-N6-(phenylisopropyl)adenosine (S-PIA) elicited concentration-dependent dilation of these arterioles, but intraluminal application was less potent and efficacious than extraluminal application. Inosine was not vasoactive. A common order of agonist potency (NECA>adenosine>R-PIA≥S-PIA) was determined for both extraluminal and intraluminal application. Theophylline (10 μM) caused a rightward shift of the adenosine concentration-response curve and a 50-fold reduction in potency. Intraluminal theophylline was one sixth as effective as extraluminal theophylline in antagonizing the extraluminal adenosine response, whereas intraluminal 8-sulfophenyltheophylline, a polar theophylline derivative, was ineffective. Polyadenylic acid (PolyA, 1 μM), an adenosine polymer that does not penetrate the endothelium, induced a dilation of 44.2±5.3% when applied extraluminally but had no effect when infused intraluminally. The dilator effect of PolyA was antagonized by theophylline. We conclude that (1) intraluminal adenosine and its analogues are effective dilators of intracerebral arterioles, (2) the dilator effects of both intraluminally and extraluminally applied adenosine are predominantly mediated by A2-type receptors, and (3) adenosine receptors mediating vasodilation are not present on the luminal surface of the endothelium.