PF9404C, a new slow NO donor with beta receptor blocking properties

1 PF9404C is the S-S diesteroisomer of a novel blocker of beta adrenergic receptors with vasodilatory properties. It causes a concentration-dependent relaxation of rat aorta helical strips pre-contracted with 10(-6) M noradrenaline (NA; IC50 33 nM). It was equipotent to nitroglycerin (NTG; IC50 49 nM), but much more potent than isosorbide dinitrate (ISD; ICS, 15,000 nM). 2 Oxyhaemoglobin (10 mu M) shifted to the right the concentration-response curve for the relaxation induced by PF9404C (IC50 530 nM) or NTG (IC50 61 nM). 3 Either methylene blue (MB) or ODQ (1 mu M each) largely prevented the vasorelaxing responses to increasing concentrations of PF9404C or NTG. 4 In rat aorta smooth muscle cells, PF9404C increased the formation of cyclic GMP from 3 pmol mg(-1) protein in basal conditions, to 53 pmol mg(-1) protein in 10 mu M PF9404C. Neither metoprolol nor carvedilol enhanced cyclic GMP. 5 In the electrically driven guinea-pig left atrium, PF9404C blocked the inotropic effects of isoprenaline in a concentration-dependent manner. Its IC50 (30 nM) was similar to that for S-propranolol (22.4 nM) and lower than the IC(50)s for metoprolol (120 nM) and atenolol (192 nM). The beta-adrenergic ligand (-)-[H-3]-CGP12177 (0.2 nM) was displaced from its binding to rat brain membranes with K-i of 7 nM, 17 nM, 170 nM and 1.2 mu M respectively for PF9404C, S(-)propranolol, metoprolol, and atenolol. 6 The data are consistent with the idea that the S-S diesteroisomer PF9404C, is a potent vasorelaxing agent, as well as a blocker of cardiac beta adrenergic receptors. The mechanism of its vasorelaxing effects involves the slow generation of NO. This molecule can, therefore, exhibit antihypertensive and cardioprotective actions through a double mechanism, NO donation and beta blockade.