Effect of verapamil withdrawal on cardiac β₁-adrenoceptor density

Summary

Ischaemia imposes a progression of damage on the myocardium, starting with a loss of adenosine triphosphate, creatine phosphate, potassium and active tension-generating capacity. These changes progress until the tissue is incapable of maintaining ionic homeostasis, is depleted of purine precursors and shows evidence of structural disorganization. Upon reperfusion the ischaemia-induced damage is exaggerated, primarily because of the accompanying uncontrolled gain in calcium, increasing tissue osmolarity and release of endogenous noradrenaline. When used prophylactically, calcium antagonists attenuate many of the deleterious effects of ischaemia and reperfusion. We have previously shown that long-term administration of verapamil to rats (50 mg/kg daily, orally) depletes their cardiac stores of noradrenaline (NA) (3.9 ± 0.3 μg/g dry wt in controls vs 0.9 ± 0.1 μg/g dry wt NA after 6 weeks of therapy). This loss of NA was not accompanied by a change in β₁-adrenoceptor density (35.5 ± 1.9 fmol/mg protein for controls vs 31.2 ± 2.3 fmol/mg protein after 6 weeks of therapy). Verapamil withdrawal after 6 weeks of therapy resulted in a restoration of ventricular NA levels; within 2 days they had recovered to 75% of their original values. The density of the β₁-adrenoceptor was unaltered. Withdrawal of verapamil results in rapid repletion of cardiac NA, with an initial but transient reduction in β₁-adrenoceptor density. The absence of β₁-adrenoceptor “up-regulation” under these conditions probably contributes to the absence of withdrawal problems upon cessation of verapamil therapy.