Key result
PY 108-068 yields ~50-fold selectivity for negative chronotropy over inotropy, limiting reflex tachycardia.
Why the study?
The negative ino- and chronotropic effects of the new calcium antagonist PY 108-068 and its ability to inhibit reflex tachycardia compared with other calcium antagonists were investigated to explore potential therapeutic advantages.
The wide separation between the negative chronotropic and negative inotropic effects of PY 108-068 suggests a targeted action that could be therapeutically advantageous for managing tachycardia.
Supports preclinical selectivity testing for chronotropic calcium blockade; leaves open human translation for reflex tachycardia.
The negative ino- and chronotropic effects of the new calcium antagonist, PY 108-068 (PY), were investigated and compared with several other calcium antagonists in paced left and spontaneously beating right atria of guinea pigs. The concentrations that decreased, by 25% (EC25), the contractile force and heart rate (HR), were determined. For PY, the concentration needed for the negative inotropic EC25 was 50 times higher than the concentration that diminished the HR by 25%. This ratio was also determined for the following calcium antagonists: nisoldipine, 27; verapamil, 2.8; gallopamil, 2.2; fendiline, 1.6; diltiazem, 3.4; and nifedipine, 0.35. The results obtained with PY and nifedipine were verified in rabbit right atria and papillary muscle. The separation between the two EC25 values was 23 for PY and 0.07 for nifedipine. Nitroglycerin had no effects on guinea pig and rabbit cardiac tissue in vitro. Conscious rabbits with chronically implanted catheters were used to determine if PY inhibits reflex tachycardia in vivo. The effects of nitroglycerin on blood pressure (BP) and HR served as a standard by which the effects of PY and nifedipine were compared. All three compounds lowered BP dose dependently and had similar initial effects on HR. While HR increased dose dependently with nitroglycerin and nifedipine, no such dose dependence was found with PY. PY thus inhibited reflex tachycardia in conscious rabbits. The wide separation between negative chronotropic and negative inotropic effects of PY implies that the calcium channels involved may be different. The selective action of PY could present a therapeutic advantage.
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Hof et al. (1983) studied Reflex tachycardia. PY 108-068 vs. Other calcium antagonists and nitroglycerin was evaluated on Negative inotropic and chronotropic EC25 concentrations. PY 108-068 showed a 50-fold separation between its negative inotropic and negative chronotropic EC25 concentrations, inhibiting reflex tachycardia in vivo without proportional negative inotropy.
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