Summary
In the first part of this presentation, data is reported on the hemodynamic effects of forskolin given to patients with dilated cardiomyopathy in a concentration of 3 µg/kg/min and 4 µg/kg/min. At the lower dosage, forskolin had no effect on dP/dtmax, cardiac index, ejection fraction, or myocardial oxygen consumption. With small dosages of dobutamine, however, an increase of all four parameters has been observed in the same group of patients. Systemic vascular resistance and left ventricular enddiastolic pressure fell with forskolin given at the lower concentration. Forskolin administered at a dosage of 4 µg/kg/min induced an increase in dP/dtmax by 19% and a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. Therefore, forskolin may serve as a vasodilating substance in lower concentrations, but cannot be used as a positive inotropic compound because of the subjective symptoms.
In the second part, a study is reported in which an anti-ischemic effect of the phosphodiesterase inhibitor enoximone was observed in patients with proven significant coronary heart disease. With respect to the hemodynamic parameters, the most striking findings were the decreases in left ventricular enddiastolic pressure and systemic vascular resistance. Furthermore, when left ventricular stroke work index was plotted as a function of the left ventricular enddiastolic pressure, enoximone shifted the left ventricular function curve to the left. Therefore, the anti-ischemic effect of enoximone may not only be due to a reduction in preload and afterload but may rather reflect an effect on diastolic compliance. Studies with intracoronary injections of enoximone and animal experiments support this hypothesis.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Kariya T, Wille LJ, Dage RC (1982) Biochemical studies of mechanism of cardiotonic activity of MDL 17,043. J Cardiovasc Pharmacol 4:509
Endoh M, Yamashita S, Taira N (1981) Positive inotropic effect of amrinone in relation to cyclic nucleotide metabolism in the canine ventricular muscle. J Pharm Exp Ther 216:220–224
Honerjager P, Schafer-Korting M, Reiter M (1981) Involvement of cyclic AMP in the direct inotropic action of amrinone: biochemical and functional evidence. Naunyn Schmiedeberg’s Arch Pharmacol 318:112–120
Kramer W, Thormann J, Schlepper M (1981) Effects of the new cardiotonic agent AR-L115 in normal hearts and loss of its effectivity by the Ca++ antagonist verapamil. Eur Heart J 2 (Suppl A):56
Kramer W, Thormann J, Schlepper M, Bittner C, Zrenner E (1981) Aktivitätsprofil von AR-L 115 BS bei therapierefraktärer kongestiver Kardiomyopathie (CC) und Herzgesunden (HG): Wirkungsverlust durch Ca2+-Antagonisten. Verh Dtsch Ges Inn Med 87:446–450
Bristow MR, Strosberg AM, Ginsburg R (1983) Forskolin activation of human myocardial adenylate cyclase. Circulation 69 (Suppl III):60
Ginsburg R, Strosberg AM, Bristow MR, Montgomery W (1983) Inotropic potential of forskolin in failing human hearts. Circulation 69 (Suppl III):373
Linderer E, Metzger H (1985) The positive inotropic and smooth muscle relaxing effects of forskolin by direct activation of adenylate cyclase. In: Rupp RH, de Souza NJ, Dohadwalla AN (eds) Proceedings of the International Symposium on Forskolin: Its chemical biological and medical potential. Bombay, January, pp 83–101
Lele RD, Kamdar NB, Popat N, Nair KG (1985) Study of forskolin with the nuclear stethoscope. In: Rupp RH, de Souza NJ, Dohadwalla AN (eds) Proceedings of the International Symposium on Forskolin: Its chemical biological and medical potential. Bombay, January, pp 115–127
Linderer T, Biamino G (1985) Hemodynamic and cardiac metabolic effects of forskolin. In: Rupp RH, de Souza NJ, Dohadwalla AN (eds) Proceedings of the International Symposium on Forskolin: Its chemical biological and medical potential. Bombay, January, pp 103–115
Kramer W, Thormann J, Kindler M, Schlepper M (1987) Forskolin’s effects on left ventricular function in dilated cardiomyopathy. Arzneim-Forschg/Drug Res 37 (I)/3:364–367
Bretschneider HJ, Cott La, Hellige G, Hensel I, Kettler D, Martl J (1971) A new hemodynamic parameter consisting of 5 additive determinants of estimation of the O2-consumption of the left ventricle. Proceedings of the International Congress of Physiological Sciences, pp 98–111
Baller D, Bretschneider HJ, Hellige G (1981) A critical look at currently used indirect indices of myocardial oxygen consumption. Basic Res Cardiol 76:163–181
Gaasch WH, Batlle WE, Oboler AA, Banas JS, Levine HJ (1972) Left ventricular stress and compliance in man. Circulation 45:746–751
Amin DK, Shah PK, Hulse S, Shellock FG, Swan HJC (1984) Myocardial metabolic and haemodynamic effects of intravenous MDL 17,043, a new cardiotonic drug, in patients with chronic severe heart failure. Am Heart J 108:1285
Arbogast R, Brandt C, Haegele KD, Fincker JL, Schechter PJ (1983) Haemodynamic effects of MDL 17,043, a new cardiotonic agent in patients with congestive heart failure: comparison with sodium nitroprusside. J Cardiovasc Pharmacol 5:998
Benotti J, Grossman W, Braunwald E et al. (1980) Effects of amrinone on myocardial energy metabolism and hemodynamics in patients with severe congestive heart failure due to coronary artery disease. Circulation 62:28
Grosse R, Strain M, Greenberg M et al. (1986) Systemic and coronary effects of intravenous milrinone and dobutamine in congestive heart failure. J Am Coll Cardiol 7:1107
Jentzer J, LeJemtel T, Sonnenblick E, Kirk E (1981) Beneficial effect of amrinone on myocardial oxygen consumption during acute left ventricular failure in dogs. Am J Cardiol 48:75–83
Likoff MJ, Martin JL, Andrews V, Weber KT (1983) Long-term therapy with the cardiotonic agent MDL 17,043, in chronic cardiac failure. Circulation 68 (Suppl III):III-373
Neuzner J, Mitrovic V, Kornecki P, Schlepper M (1987) Enoximone (MDL 17,043): Hämodynamische Effekte bei dilatativer Cardiomyopathie (DCM). Z Kardiol 76 (Suppl):69
Uretsky BF, Generalovich T, Reddy RS, Spangenberg RB, Follansbee WP (1983) The acute haemodynamic effects of a new agent, MDL 17,043, in the treatment of congestive heart failure. Circulation 67:823
Weber KT, Jain MC, Janicki JS (1985) Enoximone (MDL 17,043) in the long-term treatment of chronic cardiac failure of mild to moderate severity. Circulation 72 (Suppl III):III-202
Cardenas LM, Vidaurri DA (1979) Estudio de los efectos hemodynamicos de differentes dosis de un nuevo intropico: la amrinona. Arch Inst Cardiol Mex 49:961–968
Firth BG, Ratner AV, Grassman ED, Winniford MD, Nocod P, Hillis LD (1984) Assessment of the inotropic and vasodilator effects of amrinone versus isoproterenol. Am J Cardiol 54:1331–1336
Hermiller JB, Leithe ME, Magorien RD, Unverferth DV, Leier CV (1984) Amrinone in severe congestive heart failure: another look at an intriguing new cardiotonic drug. J Pharmac Exp Ther 228:319–326
Wilmshurst PT, Thompson DS, Jenkins BS, Coltart DJ, Webb-Peploe MM (1983) Hemodynamic effects of intravenous amrinone in patients with impaired left ventricular function. Br Heart J 49:77–82
Wilmshurst PT, Thompson DS, Juul SM, Jenkins BS, Coltart DJ, Webb-Peploe MM (1984) Comparison of the effect of amrinone and sodium nitroprusside on hemodynamics, contractility and myocardial metabolism in patients with cardiac failure due to coronary artery disease and dilated cardiomyopathy. Br Heart J 52:38–48
Thormann J, Kramer W, Kindler M, Kremer P, Schlepper M (1987) Bestimmung der Wirkkomponenten von Amrinon durch kontinuierliche Analyse der Druck/Volumen-Beziehungen; Anwendung der Conductance (Volumen-) Katheter-Technik und der schnellen Laständerung durch Ballon-Okklusion der Vena cava inferior. Z Kardiol 76:530–540
Baan J, Van der Velde ET, De Bruin HG, Smeenk GJ, Koops J, Van Duk AD, Temmerman D, Senden J, Buis B (1984) Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 70:812–823
Mitrovic V, Neuzner J, Dieterich HA, Schlepper M (1988) Hemodynamic effects of an i.v.- and p.o. single dose of enoximone in patients with impaired LV-function. Eur Heart J 9 (Suppl 1)
Schliep HJ, Harting I (1986) Effect of ismazole and reference compounds on hemodynamic parameters in anesthetized dogs. Naunyn-Schmiedeberg’s Arch Pharmacol [Suppl] 334:R36
Herrmann HC, Ruddy TD, Dec W, Strauss HW, Boucher CA, Fifer MA (1987) Inotropic effect of enoximone in patients with severe heart failure: demonstration by left ventricular end-systolic pressure-volume analyis. J Am Coll Cardiol 9:1117–1123
Thormann J, Kramer W, Schlepper M (1982) Hemodynamic and myocardial energetic changes induced by the new cardiotonic agent, AR-L 115, in patients with coronary artery disease. Am Heart J 104:1294–1302
Thormann J, Schlepper M, Kramer W, Gottwik M, Kindler M (1983) Effects of AR-L 115 BS (Sulmazol), a new cardiotonic agent, in coronary artery disease: improved ventricular wall motion, increased pump function and abolition of pacing-induced ischemia. J Am Coll Cardiol 2:332–337
Rooke GA, Feigl EO (1982) Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting. Circul Res 50:273
Mitrovic V, Schlepper M, Neuzner J, Bahavar H, Volz M, Dieterich HA (1988) Hämodynamische, antiischämische, metabolische und neurohumorale Effekte von Enoximon (MDL 17,043) bei Patienten mit koronarer Herzkrankheit. Z Kardiol 77:660–667
Mitrovic V, Bahaver H, Neuzner J, Dieterich HA, Schlepper M (1989) Antiischämische Wirksamkeit nach Einzelgabe von 150 mg Enoximon bei Patienten mit koronarer Herzkrankheit. Z Kardiol (in press)
Thormann J, Kremer P, Mitrovic V, Neuzner J, Bahavar H, Schlepper M (1989) Effects of enoximone in coronary artery disease: increased pump function, improved ventricular wall motion, and abolition of pacing-induced myocardial ischemia. J Appl Cardiol 4:152–167
Berwing K, Schlepper M, Kremer P, Bahavar H (1986) Assessment of myocardial perfusion abnormalities in patients with coronary heart disease by intracoronary injection of a new echo contrast agent. Circulation 74:(Suppl II)475
Berwing K, Schlepper M, Kremer P, Bahavar H (1989) Beurteilung myokardialer Perfusionsstörungen bei Patienten mit koronarer Herzkrankheit mittels intrakoronarer Injektion eines neuen Echo-Kontrastmittels. In: Grube E (Hrsg) Farb-Doppler- und Kontrast-Echokardiographie. Thieme, Stuttgart New York, S 323–335
Taira N (1983) Amrinone. Nippon Rinsho 41:15
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schlepper, M., Thormann, J. & Mitrovic, V. Cardiovascular effects of forskolin and phosphodiesterase-III inhibitors. Basic Res Cardiol 84, 197–212 (1989). https://doi.org/10.1007/BF02650360
Issue Date:
DOI: https://doi.org/10.1007/BF02650360