Facilitation of calcium blocking and membrane effects by intrinsic sympathomimetic activity

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Abstract
The interactions between ICI 118, 587 (Corwin®) a β1-selective partial adrenergic agonist, and atenolol (Tenormin®), propranolol (Inderal®) and verapamil were examined first in anaesthetised dogs pretreated with syrosingopine and vagotomised. ICI 118,587 was administered iv in cumulative doses of 0.1 to 1000 μg·kg−1. In four animals, heart rate increased from 102±4 to 188±12 beats·min−1 with a KA of 2.5±0.9 μg·kg−l. ICI 118,587 was then administered to five groups each of four animals pretreated with atenolol (250 μg·kg−1 and 500 μg·kg−1iv), propranolol (250 μg·kg−1 and 500 μg·kg−1) or verapamil (200 μg·kg−l plus 5 μg·kg−1 min−1 iv). Both atenolol and propranolol shifted the dose response curve to the right but verapamil did not. Atenolol did not lower the maximal heart rate response to ICI 118,587. Both propanolol and verapamil slowed heart rate significantly (P−5 mol·litre−1. Tension was recorded at Lmax over a [Ca2+] range of 0.5 to 8 × 10−3 mol·litre−1. The pA2 for verapamil against Ca2+ in the presence of atenolol and ICI 118,587 was 5.25±0.10 and 6.57±0.22 respectively. The pA2 for propranolol against Ca2+ in the presence of atenolol and ICI 118,587 was 4.60±0.08 and 5.85±0.26 respectively. The in vitro data confirm the in vivo observations that partial agonist activity (ISA) appears to unmask the calcium blocking activity of verapamil and the membrane activity (MSA) of propranolol.