PT  - JOURNAL ARTICLE
AU  - Priola, Donald V.
AU  - Spurgeon, Harold A.
AU  - Blauw, Alfred S.
AU  - Cannon, Walter B.
AU  - Dung, Eugene
TI  - MECHANISM OF THE INOTROPIC ACTION OF BRETYLIUM TOSYLATE ON THE HEART
DP  - 1973 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 121--132
VI  - 187
IP  - 1
4099  - http://jpet.aspetjournals.org/content/187/1/121.short
4100  - http://jpet.aspetjournals.org/content/187/1/121.full
SO  - J Pharmacol Exp Ther1973 Oct 01; 187
AB  - There is some question as to whether the effects of bretylium (BT) on the heart are mediated only through norepinephrine release. The following experiments were performed in order to determine whether BT has a significant direct inotropic action on the heart. BT (0.1-100 mg/kg) was administered to normal dogs and to dogs whose hearts had been chronically denervated. The animals were placed on total heart bypass. Right ventricular and left ventricular isovolumic contractility were evaluated along with heart rate. In terms of both transient and sustained responses, low doses of BT (<20 mg/kg, cumulative) increased contractility in the normal animals but did not change or actually decreased it in the denervated animals. High doses of the drug (<20 mg/kg, cumulative) increased contractility in both groups. The positive inotropic responses in the denervated animal were abolished by beta receptor blockade but were unaffected by adrenalectomy. In the normal animals, low doses of BT produced tachycardia whereas high doses resulted in bradycardia. In the denervated animals, bradycardia was produced by BT at all dose levels. It was concluded that the positive inotropic and chronotropic effects of BT at low doses require the presence of intact sympathetic nerve endings; i.e., the drug acts primarily by causing release of norepinephrine from these neuronal storage sites. At high doses, BT produces a direct positive inotropic effect, probably through stimulation of beta adrenergic receptors. The direct chronotropic actions of BT appears to be negative, perhaps through an effect on the electrogenic pacemaker membrane itself. © 1973 by The Williams & Wilkins Company