Abstract

Within the past 15 years, pharmacologists and physiologists have recognized the pivotal role of ATP and related extracellular nucleotides as novel extracellular messengers. The role of extracellular ATP and related nucleotides is a topic of cross interest to many cell biologists since it appears to be involved in a wide spectrum of basic biological and pathophysiological processes that extend from blood flow control, smooth muscle and neuron excitability to immune and inflammatory responses. Moreover, the interest in nucleotides as physiologically relevant signals has gained increasing interest in the past years due to the widespread localization of 15 different nucleotide receptors (not including P2X splice variants nor the adenosine receptor subtypes) belonging either to ionotropic trimer channels (P2X1-7 receptors) or the G-protein coupled receptors subtypes (P2Y1,2,4,6,11,12,13, and14 subtypes). Our research proposal focuses on the auto/paracrine role of ATP and related nucleotides as an extracellular molecule in vascular beds and on the possible putative dysfunction of the autocrine role of ATP in diabetes. Based on our ongoing experiments plus an updated literature search, we and other investigators reason that in vascular beds shear stress induces ATP release/secretion from endothelial cells or from red blood cells or other blood cells involved in blood flow regulation. We propose that the secreted ATP acts as an autocrine signal that activates a complex intracellular pathway to promote the release of endothelial NO, a powerful vasodilator; other endothelial vasoactive agents might be involved in the ATP-induced autocrine signalling. We aim to investigate whether the autocrine role of ATP in streptozotocin (STZ)-induced experimental diabetes is blunted, and discover the putative dysfunctional levels that might affect the ATP response. In fact, preliminary results from our laboratory demonstrate that the rat arterial mesenteric bed of diabetic rats challenged with P2Y1 or the P2Y2 receptor selective ligands, but not acetylcholine, resulted in a markedly reduced release of NO as compared to beds from control rats. Therefore, in this experimental proposal we aim to identify the mechanism(s) and the altered pathway of the endothelial dysfunction in STZ-induced diabetes.