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Improvement of relaxation velocity parameters by calcium channel blockers in the aging rabbit myocardium
N C Morcos1, J M Gardin, N Tomita
1Department of Medicine, University of California, Irvine.
Insights
Calcium channel blockers, like nifedipine, can improve age-related declines in heart muscle relaxation. This study found beneficial effects on myocardial relaxation in older rabbits at clinically relevant doses.
Area of Science:
- Cardiology
- Pharmacology
- Gerontology
Background:
- Normal aging is associated with reduced left-ventricular diastolic function, impacting myocardial relaxation and filling rates.
- Calcium channel blockers are known to improve left-ventricular diastolic function in various heart conditions.
- The mechanism of action for calcium channel blockers may involve direct myocardial effects or vasodilation.
Purpose of the Study:
- To investigate the direct effect of calcium channel blockers on age-related reductions in myocardial relaxation.
- To assess the impact of nifedipine on myocardial relaxation parameters in aging rabbits.
Main Methods:
- Isolated interventricular septa and left-ventricular walls from young and old rabbits were studied.
- Myocardial relaxation parameters, including maximum relaxation velocity ([-dT/dt]/T) and relaxation time (tR/T), were measured.
- Nifedipine was infused at varying concentrations to evaluate its effects on relaxation.
Main Results:
- Older rabbits exhibited significantly impaired myocardial relaxation compared to younger rabbits.
- Low-dose nifedipine (within the clinical therapeutic range) improved relaxation velocity and shortened relaxation time in older rabbit septa.
- These beneficial effects in older rabbits approximated the relaxation parameters of younger rabbits without drug treatment.
Conclusions:
- Calcium channel blockers, specifically nifedipine, can directly improve age-related myocardial relaxation deficits.
- The beneficial effects are observed at concentrations within the clinically therapeutic range.
- These findings suggest a potential therapeutic role for calcium channel blockers in managing age-related diastolic dysfunction.
Abstract:
Normal aging in man is known to be associated with a reduction in left-ventricular diastolic function, including the rates of relaxation and filling. Calcium channel blockers have been reported to improve left-ventricular diastolic function in patients with various forms of heart disease. Clinically, the action of calcium channel blockers may be related to either a direct myocardial effect or may be secondary to the peripheral or coronary vasodilation effects. The purpose of this study is to investigate a possible direct effect of calcium channel blockers on modulation of the reported age-related reduction in myocardial relaxation. The direct effects on myocardial relaxation of the dihydropyridine calcium channel blocker, nifedipine, were studied in isolated, perfused interventricular septa and left-ventricular wall from eight young (ages 9 to 18 months) and 14 old (ages 3 to 5 years) rabbits. Septa were perfused with oxygenated Ringer's solution and paced at 48 beats/min. Maximum relaxation velocity per unit of developed tension [-dT/dt]/T, and relaxation time per unit of developed tension tR/T were continuously measured before and after infusion of calcium channel blockers. In absence of drugs, the older rabbits demonstrated a mean [-dT/dt]/T which was 32% lower (p < 0.003) and a mean tR/T which was 45% higher (p < 0.005) than the younger rabbits. When nifedipine was introduced at concentrations > 10(-8) M equivalent to doses above the therapeutic free-plasma concentration in humans, all contraction and relaxation parameters were depressed. However, at lower doses, equivalent to doses in the clinical therapeutic range, [-dT/dt]/T was increased in the older rabbit septa by 18% in the presence of nifedipine. tR/T was shortened in the older rabbit septa by 17% in the presence of nifedipine. Myocardial relaxation in older rabbits after drug infusion approximated these parameters in the younger rabbits prior to drug infusion (P = NS). Calcium channel blockers had similar beneficial effects on the relaxation properties of the myocardium in younger rabbits. All beneficial effects were observed at concentrations of calcium channel blockers which were within and below the clinically therapeutic range of plasma free drug concentration, i.e., 5 x 10(-9) to 4 x 10(-8) M. Potential differences in relaxation effects related to different segments of the myocardium and different mechanical recording vectors were evaluated. Isolated left ventricle preparations from aging rabbits demonstrated improvements in tR/T and [-dT/dt]/T similar to those observed in the septum. Furthermore, improvement in mechanical function along the y-axis and x-axis vectors of the septum was similar.(ABSTRACT TRUNCATED AT 400 WORDS)