Chronic calcium antagonist therapy: some unexpected results

Area of Science:

• Pharmacology
• Cardiovascular Physiology

Background:

• Calcium antagonists, like verapamil, offer myocardial protection against ischemia and reperfusion injury when used prophylactically.
• Prophylactic use necessitates chronic therapy, raising questions about long-term cardiac adaptations.

Purpose of the Study:

• To investigate the impact of chronic verapamil therapy on cardiac noradrenaline (NA) reserves.
• To determine if long-term verapamil administration alters beta-1 adrenoceptor density in the heart.

Main Methods:

• Sprague-Dawley rats received either placebo or dl-verapamil (V) orally for 6 weeks to achieve plasma V levels of ~100 ng/ml.
• Cardiac catecholamine levels (noradrenaline, adrenaline, dopamine) were quantified using high-performance liquid chromatography.
• Cardiac membranes were isolated to assess beta-1 adrenoceptor density (Bmax) and affinity (KD) via radioligand binding assays.

Main Results:

• Three days of verapamil therapy significantly reduced left ventricular noradrenaline by 45%, reaching a plateau within 11 days.
• Dopamine levels also decreased significantly, while adrenaline remained largely unchanged.
• Chronic verapamil therapy (up to 6 weeks) did not alter the density or affinity of cardiac beta-1 adrenoceptors.

Conclusions:

• Chronic verapamil therapy leads to a substantial depletion of cardiac noradrenaline reserves.
• Despite significant changes in catecholamine levels, beta-1 adrenoceptor density and function remain constant during long-term verapamil treatment.