Novel functions of cardiovascular P2 receptors

Sammanfattning: The aim of the thesis was to examine the expression and function of the extracellular nucleotide P2 receptors in the cardiovascular system. In the cardiovascular system nucleotides are released during shear stress, hypoxia, ischemia, from endothelial cells, smooth muscle cells, aggregating platelets, inflammatory cells and erythrocytes. We demonstrate that ATP, ADP, UTP and UDP induce vascular relaxation in human blood vessels stimulating P2Y1, P2Y2 and P2Y6 receptors on endothelial cells. ADP, acting on the P2Y1 receptor was the most potent vasodilator and the response was mediated via equal amounts of NO, EDHF and prostaglandins. We show that ADP gives contraction in human blood vessels and reveal functional expression of P2Y12 receptors on the VSMC. In vessels having an intact endothelium, ADP induces vasodilatation but a dysfunctional endothelium leads to ADP induced contraction. Stable drugs with antagonistic effects on P2Y12 receptors, affecting both platelets and VSMC, could be of double therapeutic benefit in their prevention of both thrombosis and vasospasm. Increased ATP release has been shown during cardiac ischemia. We found increased levels of UTP in patients with myocardial infarction and the amounts correlated to the ATP level (1:10). ATP, UTP and UDP stimulated potent inotropic effects acting on the heart muscle cells. The pyrimidine effects were mediated via P2Y2/4 and P2Y6 receptors acting via PLC pathways. Expression of P2Y2, P2Y4 and P2Y6 was verified using real-time PCR. ATP induced inotropic effects mediated via two pathways, PLC and adenylyl cyclase pathway, suggesting a P2Y11-like receptor in mouse. Responses to UDP and a P2Y11 agonist were decreased in mice with cardiomyopathy. Antagonists for P2Y2/4, P2Y6 and P2Y11 receptors could be beneficial in the treatment of hypertension and heart failure. Finally, by designing and synthesizing new chemical compounds, two new P2X1 receptor potentiating substances were found. The clinical use of a P2X1 receptor potentiator could be to increase blood pressure in orthostatic hypotension, counteract urinary incontinence, or even male infertility.