Cardiac electrophysiological effects of pinacidil and related pyridylcyanoguanidines: relationship to antihypertensive activity.
It has been suggested that certain direct acting vasodilators increase potassium conductance (gK) of smooth muscle membranes. A similar increase of gK in cardiac tissue would be expected to selectively shorten the action potential duration (APD). The present studies were conducted to determine whether a series of pyridylcyanoguanidine antihypertensive agents, including pinacidil, might shorten the APD of canine Purkinje fibers and ventricular muscle, and if so, whether this effect can be correlated with their antihypertensive activities in anesthetized spontaneously hypertensive rats (SHR). Cardiac Purkinje fiber APD was decreased by most compounds. P-1075, the most potent compound of the series (EC50 = 3.7 x 10(-8) M), reduced the APD of Purkinje fibers by a maximum of 91 +/- 2% at 10(-6) M with no change in the maximum rate of rise (Vmax) or conduction time of the action potential. Similar selective effects on APD were noted in ventricular muscle cells. Shortening of APD was not altered by muscarinic blockade with atropine (3 x 10(-6) M) or adenosine receptor blockade with isobutyl methylxanthine (3 x 10(-5) M). In chloralose-anesthetized SHR, the pyridylcyanoguanidines reduced mean arterial blood pressure (BP) and left ventricular dP/dtmax with an order of potency similar to their effect on APD95. The most potent compound was again P-1075 with an ED50 of 8 micrograms/kg i.v. for its effect on BP. When the ED50 for BP reduction in vivo was compared with the EC50 for Purkinje fiber APD shortening in vitro, an excellent correlation was obtained (r = 0.97, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
Smallwood
J K
JK
Department of Cardiovascular Pharmacology, Lilly Research Laboratories, Indianapolis, Indiana 46285.
Steinberg
M I
MI
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D020110:Pinacidil; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D006146:Guanidines; D009570:Nitriles; D011725:Pyridines; D020110:Pinacidil