Effects of tetraethylammonium, 4-aminopyridine and bretylium on cardiovascular tissues from normo- and hypertensive rats.
Our objective was to test whether potassium-channel blockade is a potential positive inotropic mechanism for heart failure. Thus we studied the effects of tetraethylammonium, 4-aminopyridine and bretylium on left ventricular action potentials, left ventricular contractility in the absence and presence of hypertrophy, and on isolated blood vessels from Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs). Tetraethylammonium at 10(-3)-10(-2) M, 4-aminopyridine at 10(-4)-10(-3) M and bretylium at 10(-6)-10(-4) M prolonged the action potentials of the WKY left ventricular strip. Similar concentrations of tetraethylammonium, 4-aminopyridine and bretylium augmented the peak force, prolonged the contractions, and did not cause arrhythmias in the absence or presence of isoprenaline on left ventricular strips from 12-month-old WKY. The 12-month-old SHR has hypertrophy of the left ventricle with reduced contractility and prolongation of relaxation. The effects of tetraethylammonium and bretylium were similar on WKY and SHR, whereas the effects of 4-aminopyridine were reduced on SHR left ventricular contractility, which suggests that the function of the transient outward-blocking potassium channel may be impaired in hypertrophy. Bretylium at < or = 10(-4) M had no effect on the portal vein, intralobar or mesenteric arteries. Tetraethylammonium and 4-aminopyridine at > or = 10(-5) M increased the duration or amplitude, or both, of the portal vein contractions. Tetraethylammonium at > or = 10(-2) M and 4-aminopyridine at > or = 3 x 10(-4) M contracted the mesenteric artery, and 4-aminopyridine also contracted the intralobar pulmonary artery. In summary, we have demonstrated that the action potential prolonging effects of potassium-channel blockade is associated with a positive inotropic effect on the rat left ventricle. The non-specific blockers, tetraethylammonium and 4-aminopyridine, do not have potential as positive inotropes in heart failure because of their widespread effects, including vasoconstriction. The potential of bretylium and some of the newer selective potassium-channel blockers as positive inotropes requires further evaluation.
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Cardiovascular Pharmacology Group, Faculty of Medicine and Health Science, The University of Auckland, New Zealand.
Doggrell
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D015761:4-Aminopyridine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001949:Bretylium Compounds / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D011169:Portal Vein / Q000187:drug effects / Q000503:physiopathology; D026902:Potassium Channel Blockers; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D019789:Tetraethylammonium / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D001949:Bretylium Compounds; D026902:Potassium Channel Blockers; D019789:Tetraethylammonium; D015761:4-Aminopyridine; C045166:bretylium