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Improvement of relaxation velocity parameters by calcium channel blockers in the aging rabbit myocardium

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Summary

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., 5×10−9 to 4×10−8 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. The data suggest that, in this rabbit model, calcium channel blockers may improve or reverse the age-related reduction in myocardial relaxation.

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References

  1. Gerstenblith G, Fleg JL, Becker LC, Rodeheffer RJ, Rogers WJ, Weisfeldt ML, Lakatta EG (1983) Maximum left ventricular filling rate in healthy individuals measured by gated blood pool scans: Effect of age. Circulation 68 (Suppl): III-101

    Google Scholar 

  2. Miyatake K, Okomoto M, Kinoshita N, Owa M, Nakasone I, Sakakibara H, Nimura Y (1986) Augmentation of atrial contribution to left ventricular inflow with aging as assessed by intracardiac Doppler flowmetry. Am J Cardiol 53:586–589

    Google Scholar 

  3. Bonow RO, Vitale DF, Bacharach SL, Maron BJ,Green MV (1988) Effect of aging on asynchronous left ventricular regional function and global ventricular filling in normal human subjects. J Am Coll Cardiol 11:50–58

    Google Scholar 

  4. Bonow RO, Rosing DR, Bacharach SL, et al (1981) Effect of verapamil on left ventricular systolic function and diastolic filling in patients with hypertrophic cardiomyopathy. Circulation 64:787–796

    Google Scholar 

  5. Bonow RO, Leon MB, Rosing DR, Kent KM, Lipson LC, Bacharach SL, Green MV, Epstein SE (1981) The effects of verapamil and propranolol on left ventricular systolic function and diastolic filling in patients with coronary artery disease: Radionuclide angiographic studies at rest and during exercise. Circulation 65:1337–1350

    Google Scholar 

  6. Iwase M, Sotobata I, Takagi S, Miyaguchi K, Jing HX, Yokota M (1987) Effects of diltiazem on left ventricular diastolic behavior in patients with hypertrophic cardiomyopathy: Evaluation with exercise pulsed Doppler echocardiography. J Am Coll Cardiol 9: 1099–1105

    Google Scholar 

  7. Paulus WJ, Lorell BH, Craig WE, Wynne J, Murgo JP, Grossman W (1983) Comparison of the effects of nitroprusside and nifedipine on diastolic properties in patients with hypertrophic cardiomyopathy: Altered left ventricular loading or improved muscle inactivation? J Am Coll Cardiol 2:879–886

    Google Scholar 

  8. Lorell BH, Turi Z, Grossman W (1981) Modification of left ventricular response to pacing tachycardia by nifedipine in patients with coronary artery disease. Am J Med 71:667–675

    Google Scholar 

  9. Bonow RO (1985) Verapamil-induced improvement in left ventricular diastolic filling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term effects. Circulation 72:853–864

    Google Scholar 

  10. Hanrath P, Schluter M, Sonntag F, Diemert J, Bleifeld W (1983) Influence of verapamil therapy on left ventricular performance at rest and during exercise in hypertrophic cardiomyopathy. Am J Cardiol 52:544–548

    Google Scholar 

  11. Brutsaert DL, Housemans PR, Goethals MA (1980) Dual control of relaxation. Its role in the ventricular function in the mammalian heart. Circ Res 47:637–652

    Google Scholar 

  12. Morcos NC, Henry WL (1987) Direct but reversible effects of cocaine on the myocardium (abstr). J Am Coll Cardiol 11:71A

    Google Scholar 

  13. Morcos NC, Gardin JM, Henry WL (1989) Improvement of relaxation velocity by calcium blocker in aging rabbit myocardium (abstr). J Am Coll Cardiol 13:57A

    Google Scholar 

  14. Langer GA, Brady AJ (1968) The effects of temperature upon contraction and ionic exchange in rabbit ventricular myocardium in relation to control of active state. J Gen Physiol 53:682–713

    Google Scholar 

  15. Schlant RC (1974) Normal physiology of the cardiovascular system. In: Hurst JW, Logue RB, Schlant RC, Wenger NK (eds) The Heart,New York, McGraw Hill Book Co, pp 79–109

    Google Scholar 

  16. Yin FCP, Spurgeon HA, Weisfeldt ML, Lakatta EG (1980) Mechanical properties of myocardium from hypertrophied rat hearts: A comparison between hypertrophy induced by senescence and by aortic banding. Circ Res 46:292–300

    Google Scholar 

  17. Bhatnagar GM, Walford GD, Beard ES, Humphreys SH, Lakatta EG (1984) ATPase activity and force production in myofibrils and twitch characteristics in intact muscle from neonatal, adult and senescent rat myocardium. J Moll Cell Cardiol 16:203–218

    Google Scholar 

  18. Weisfeldt ML, Lakatta EG, Gerstenblith G (1988) Aging and cardiac disease. In: Braunwald E (ed) Heart Disease. Philadelphia, WB Saunders, pp 1650–1662

    Google Scholar 

  19. Spurgeon HA, Steinbach MF, Lakatta EG (1983) Chronic exercise prevents characteristic age-related changes in rate cardiac contraction. Am J Physiol 244:H513–H518

    Google Scholar 

  20. Spurgeon HA, Thorne PR, Yin FCP, Shock NW, Weisfeldt ML (1977) Increased dynamic stiffness of trabeculae carneae from senescent rats. Am J Physiol 232:H373–H380

    Google Scholar 

  21. Sanderson JE, Gibson DJ, Brown DJ, Goodwin JF (1977) Left ventricular filling in hypertrophic cardiomyopathy: An angiography study. Br Heart J 39:661–670

    Google Scholar 

  22. Sanderson JE, Traill TA, St. John Sutton MG, Brown DJ,Gibson DJ, Goodwin JF (1978) Left ventricular relaxation and filling in hypertrophic cardiomyopathy: An echocardiographic study. Br Heart J 40:596–601

    Google Scholar 

  23. St. John Sutton MG, Tajik AJ, Gibson DJ, Brown CJ, Seward JB, Giuliani ER (1978) Echocardiographic assessment of left ventricular filling and septal and posterior wall dynamics in idiopathic hypertrophic subaortic stenosis. Circulation 57:512–520

    Google Scholar 

  24. Hanrath P, Mathey DJ, Siegert R, Bleifeld W (1980) Left ventricular relaxation and filling different forms of left ventricular hypertrophy: An echocardiographic study. Am J Cardiol 45:15–23

    Google Scholar 

  25. Bonow RO, Frederick TM, Bacharach SL, et al (1983) Atrial systole and left ventricular filling in patients with hypertrophic cardiomyopathy: Effect of verapamil. Am J Cardiol 51:1386–1391

    Google Scholar 

  26. Mirsky I, Cohn PF, Levine JA, et al (1974) Assessment of left ventricular stiffness in primary myocardial disease. Circulation 50:128–136

    Google Scholar 

  27. Gottsman MS, Lewis BS (1974) Left ventricular volumes and compliance in hypertrophic cardiomyopathy. Chest 66:498–505

    Google Scholar 

  28. Gaasch WH, Levine HJ, Quinones MA, Alexander JK (1976) Left ventricular compliance: Mechanisms and clinical implications. Am J Cardiol 38:645–653

    Google Scholar 

  29. Grossman W, McLaurin LP (1976) Diastolic properties of the left ventricle. Ann Intern Med 84:316–326

    Google Scholar 

  30. Grossman W, Berry WH (1980) Diastolic pressure-volume relations in the diseased heart. Fed Proc 39:148–155

    Google Scholar 

  31. Alvares RF, Shaver JA, Gamble WH, Goodwin JF (1984) Isovolumic relaxation period in hypertrophic cardiomyopathy. J Am Coll Cardiol 3:71–81

    Google Scholar 

  32. Betocchi S, Bonow RO, Bacharach SL, Rosing DR, Maron BJ, Green MV (1986) Isovolumic relaxation period in hypertrophic cardiomyopathy: Assessment by radionuclide angiography. J Am Coll Cardiol 7:74–81

    Google Scholar 

  33. Bonow RO, Dilsizian V, Rosing DR, Maron BJ, Bacharach SL, Green MV (1985) Verapamil-induced improvement in left ventricular diastolic filling and increased exercise tolerance in patients with hypertrophic cardiomyopathy: Short- and long-term effects. Circulation 72:853–864

    Google Scholar 

  34. Newman H, Cugrue D, Oakley CM, Goodwin JF, McKenna WJ (1985) Relation of left ventricular function and prognosis in hypertrophic cardiomyopathy: An angiographic study. J Am Coll Cardiol 5:1064–1074

    Google Scholar 

  35. Hanrath P, Mathey DJ, Kramer P, Sonntag F, Bleifeld W (1980) Effect of verapamil on left ventricular isovolumic relaxation time and regional left ventricular filling in hypertrophic cardiomyopathy. Am J Cardiol 45:1258–1264

    Google Scholar 

  36. Eickhorn P, Grimm J, Caugh R, Hess O, Karoll J, Krayenbuehl HP (1982) Left ventricular relaxation in patients with left ventricular hypertrophy secondary to aortic valve disease. Circulation 65:1395–1404

    Google Scholar 

  37. Lorell BH, Paulus WJ, Grossman W, Wynne J, Cohn PF (1982) Modification of abnormal left ventricular diastolic properties by nifedipine in patients hypertrophic cardiomyopathy. Circulation 65:499–507

    Google Scholar 

  38. Bonow RO, Vitale DF, Maron BJ, Bacharach SL, Frederick TM, Green MV (1987) Regional left ventricular asynchrony and impaired global left ventricular filling in hypertrophic cardiomyopathy: Effect of verapamil. J Am Coll Cardiol 9:1108–1116

    Google Scholar 

  39. Rodeheffer RJ, Gerstenblith G, Becker LC, Fleg JL, Weisfeldt ML,Lakatta EG (1984) Exercise cardiac output is maintained with advancing age in healthy human subjects: Cardiac dilation and increased stroke volume compensate for a diminished heart rate. Circulation 69:203–213

    Google Scholar 

  40. Gerstenblith G, Frederiksen J, Yin FCP, Fortuin NJ, Lakatta EG, Weisfeldt ML (1977) Echocardiographic assessment of a normal adult aging population. Circulation 56: 273–278

    Google Scholar 

  41. Nixon JV, Hallmark H, Page K, Raven PR, Mitchell JH (1985) Ventricular performance in human hearts aged 61 to 73 years. Am J Cardiol 56:932–937

    Google Scholar 

  42. Lima JAC, Weiss JL, Guzman PA, Weisfeldt ML, Reid PR, Traill TA (1983) Incomplete filling and incoordinate contraction as mechanisms of hypotension during ventricular tachycardia in man. Circulation 68:928–938

    Google Scholar 

  43. Walsh RA (1987) The effects of calcium-entry blockade on left ventricular systolic and diastolic function. Circulation 75 (Suppl V):V43–V55

    Google Scholar 

  44. Gilmer DJ, Kark P (1980) Pulmonary edema precipitated by nifedipine. Br Med J 280:1420–1421

    Google Scholar 

  45. Brooks N, Callel M, Pidgeon J, Balion R (1980) Unpredictable response to nifedipine in severe cardiac failure. Br Med J 281:1324

    Google Scholar 

  46. Robson RH, Vishwanath MC (1982) Nifedipine and beta-blockade as a cause of cardiac failure. Br Med J 284:104–106

    Google Scholar 

  47. Elkayam U, Weber L, Toskan B, Berman D, Rahimtoola SH (1986) Comparison of hemodynamic responses to vasodilation due to calcium channel antagonism with nifedipine and direct-acting agonism with hydralazine in chronic refractory congestive heart failure. Am J Cardiol 54:126–131

    Google Scholar 

  48. Gertz MA, Falk RH, Skinner M, Cohen AS, Kyle RA (1985) Worsening of congestive heart failure in amyloid heart disease treated by calcium blocking agents. Am J Cardiol 55 (13 Pt 1):1645

    Google Scholar 

  49. Henry PD (1980) Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem. Am J Cardiol 46:1047–1058

    Google Scholar 

  50. Newman RK, Bishop VS, Peterson F, Leroux EJ, Horwitz LD (1977) Effect of verapamil on left ventricular performance in conscious dogs. J Pharmacol Exp Ther 201:723–730

    Google Scholar 

  51. Walsh RA, Badke FR, O'Rourke RA (1981) Differential effects of systemic intracoronary calcium channel blocking agents on global and regional left ventricular function in conscious dogs. Am Heart J 102:314–350

    Google Scholar 

  52. Nakaya H, Schwartz A, Millard RW (1983) Reflex chronotropic and inotropic effects of calcium channel blocking agents on conscious dogs: Diltiazem, verapamil and nifedipine compared. Circ Res 52:302–311

    Google Scholar 

  53. Porter CB, Walsh RA, Badhe FR, O'Rourke RA (1983) Differential effects of diltiazem and nitroprusside on left ventricular function in experimental chronic volume overload. Circulation 68:685–692

    Google Scholar 

  54. Lossnitzer K, Janke J, Hein B, Stawch M, Fleckenstein A(1975) Disturbed myocardial calcium metabolism: A possible pathogenic factor in the hereditary cardiomyopathy of the Syrian hamster. In: Fleckenstein A, Rona G (eds) Recent Advances in Studies on Cardiac Structure and Function. Baltimore, University Park Press, pp 207–217

    Google Scholar 

  55. Walsh RA, O'Rourke RA (1985) Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs. J Clin Invest 75:1426–1434

    Google Scholar 

  56. Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166

    Google Scholar 

  57. Kentish JC, Nayler WG (1978) Calcium-dependent tension generation in chemically-skinned cardiac trabeculae. J Physiol (London) 284:90P–91P

    Google Scholar 

  58. Sassen LM, Bezstarosti K, Verdouw PD, Lamers JM (1991) Effects of nisoldipine on recovery of coronary blood flow, sarcoplasmic reticulum function and other biochemical parameters in post-ischemic porcine myocardium. Biochem Pharmacol 41:43–51

    Google Scholar 

  59. Movsesian MA, Ambudkar IS, Adelstein MS, Shamoo AE (1985) Stimulation of canine cardiac sarcoplasmic reticulum Ca2+ uptake by dihydropyridine Ca2+ antagonists. Biochem Pharmacol 34:195–201

    Google Scholar 

  60. Wang T, Tsai LI, Schwartz A (1984) Effects of verapamil diltiazem, nisoldipine and felodipine on sarcoplasmic reticulum. Eur J Pharmacol 100:253–261

    Google Scholar 

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  1. N. C. Morcos M.D., Ph.D.

    Present address: Department of Medicine, Division of Cardiology, University of California, Medical Sciences I, Room C 388, 92717, 714/456-6545, Irvine, CA, USA

Authors and Affiliations

  1. Department of Medicine, Division of Cardiology, University of California, Medical Sciences I, Room C 388, 92717, 714/456-6545, Irvine, CA, USA

    J. M. Gardin, N. Tomita & W. L. Henry

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  1. N. C. Morcos M.D., Ph.D.
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Morcos, N.C., Gardin, J.M., Tomita, N. et al. Improvement of relaxation velocity parameters by calcium channel blockers in the aging rabbit myocardium. Basic Res Cardiol 87, 437–451 (1992). https://doi.org/10.1007/BF00795056

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