Pharmacological properties of 5-[(6,7,8-trimethoxy-4-quinazolinyl) amino]-1-pentanyl nitrate maleate in cardiovascular system.

Effects of 5-[6,7,8-trimethoxy-4-quinazolinyl)amino]-1-pentanyl nitrate maleate (KT-1, CAS 47487-05-8), whose chemical structure has both a prazosin and a nitrate moiety, on cardiovascular system were investigated in in vivo and in vitro experiments. KT-1 i.v. decreased aortic pressure, renal blood flow, left ventricular enddiastolic pressure and resistances of total peripheral, vertebral, coronary and renal vasculatures and increased aortic blood flow, vertebral blood flow, coronary blood flow, peak positive left ventricular dP/dt and heart rate in anesthetized open-chest dogs. These cardiovascular effects of KT-1 were similar to those of glyceryl trinitrate (nitroglycerin, GTN). Nitrate-deleted KT-1 from its chemical structure (denitro KT-1) equimolar to KT-1 produced no marked changes in these cardiovascular parameters, but 3 or 10 times large doses of denitro KT-1 showed relatively long persisting vasodilator effects. In isolated dog coronary artery preparations contracted with KCl, the order of relaxant potency was GTN greater than KT-1 greater than denitro KT-1. In isolated dog mesenteric artery preparations, phenylephrine produced concentration-dependent contractions which were significantly inhibited by prazosin and KT-1 but not by denitro KT-1. In anesthetized open-chest dogs, phenylephrine produced pressor responses which were significantly inhibited by KT-1 but not by GTN or denitro KT-1. In isolated rat thoracic aorta strips, in contrast to GTN, KT-1 hardly developed a tachyphylaxis. Thus, KT-1 showed cardiovascular effects similar to those of both nitrates and a1-adrenoceptor blocking agents with no development of a tachyphylaxis.