In vitro and in vivo evaluation of two ultrashort-acting beta-adrenoreceptor antagonists: ACC-9129 and ACC-9369
✍ Scribed by J. E. Shaffer; A. Vuong; R. J. Gorczynski; W. L. Matier
- Publisher
- John Wiley and Sons
- Year
- 1986
- Tongue
- English
- Weight
- 713 KB
- Volume
- 7
- Category
- Article
- ISSN
- 0272-4391
No coin nor oath required. For personal study only.
✦ Synopsis
ACC-9129 and ACC-9369 were evaluated in guinea pig isolated atria and trachea and in anesthetized dogs and conscious rabbits for beta-blocking potency, duration of action, and intraocular pressure effects. ACC-9129 showed competitive cardioselective beta-blocking activity, with a pA2 of 6.8 in guinea pig right atria and a pA2 of 4.8 in guinea pig trachea. ACC-9369 was also a competitive beta blocker in these tissues, with a pA2 of 8.0 in both atria and trachea (nonselective). Cardiodepression in guinea pig right and left atria occurred at concentrations of 1-3 x M and above for either ACC-9129 and ACC-9369, indicating a large therapeutic index for beta-blocking versus cardiotoxic effects of these compounds. Infusion of ACC-9129 (53 f 7 pglkglmin for 180 min) into anesthetized dogs inhibited isoproterenol-induced tachycardia by 52 f 4% while reducing the hypotensive response by 6 f 3%. ACC-9369 infused at 4.3 f 1.1 pglkglmin (for 180 min) produced 67 f 4% inhibition of the heart rate response and 22 f 9% inhibition of the hypotensive response to isoproterenol. Following termination of a 3-hr infusion of each of these agents at the dose rates shown above, beta blockade was observed to decline such that there was a 50% recovery of the heart rate response to isoproterenol by 9 f 3 min for ACC-9129 and by 20 f 4 min (in six of nine dogs) for ACC-9369. ACC-9369, but not ACC-9129, showed some potential for intrinsic sympathomimetic activity in guinea pig atria and in anesthetized dogs. In conscious rabbits, periocular administration of ACC-9129 (3%) or timolol (0.5%), 4 hr prior to an intravenous infusion of 5% glucose, blunted the increase in intraocular pressure that occurred in the absence of drug; ACC-9369 (3%) was unable to