Experimental Pharmacology of Nisoldipine: Perspectives from Long-Term Studies
Nisoldipine is a 1,4-dihydropyridine derivative with an outstanding vascular selectivity. As a specific calcium antagonist, it shortens the action potential and causes electromechanical uncoupling in ventricular myocardium. However, this effect, resulting in a negative inotropic action, appears at 100–1000 times higher concentrations of nisoldipine in comparison with its inhibition of calcium-dependent vascular contractions. Detailed analyses of pharmacological effects revealed additional properties such as enhancement of sodium excretion, an interaction with the reninangiotensin-aldosterone system and a protective effect against acute renal ischaemia, that may contribute to its therapeutic efficacy.
In chronic experiments nisoldipine prevented mortality, reduced cardiac hypertrophy and limited vascular lesions, normalising blood pressure in prophylactic administration to spontaneously hypertensive rats as well as in therapeutic administration to Dahl rats with already existing malignant hypertension. It is evident that such effects cannot be achieved by a simple peripheral vasodilation.
In fact, minoxidil only temporarily decreased blood pressure in Dahl rats with malignant hypertension; the degree of cardiac hypertrophy was even aggravated by minoxidil. Some additional effect of nisoldipine normalising water and electrolyte balance by an improvement of the impaired kidney function, is postulated. In addition, nisoldipine induced a regression of cardiac hypertrophy and improved survival rate when given therapeutically to old, spontaneously hypertensive rats with evident heart failure. Simultaneously, this drug induced a decrease of high plasma levels of atrial natriuretic peptides (ANP) in these rats. The mechanism of the therapeutic effect of nisoldipine is complex. It involves a decrease of the total peripheral vascular resistance (reduction of afterload) and an increase in coronary blood flow. Moreover, nisoldipine obviously normalises the impaired volume homoeostasis by improving renal function and thus reduces the need for activation of the ANP system.
In the advanced stages of hypertension, nisoldipine prevents deleterious calcium overload and the resulting tissue damage.
KeywordsCardiac Hypertrophy Atrial Natriuretic Peptldes Total Peripheral Vascular Resistance Negative Inotropic Action Cardiac Purkinje Fiber
Unable to display preview. Download preview PDF.
- 1.Wehinger E, Bossert F, Heise A, Kazda S, Stoepel K, Vater W (1977) Chern Abstr 87: 8431dGoogle Scholar
- 2.Kass RS (1982) A new, more selective calcium current blocker in cardiac Purkinje fibers. J Pharmacal Exp Ther 233: 446–456Google Scholar
- 5.Tung L, Morad M (1983) Electrophysiological studies with Ca2+ entry blockers. In: Merril GF, Weiss HR (ed’s) Ca2+ entry blockers, Adenosine and Neurohumors, Urban and Schwarzenberg, Baltimore Munich, p 19Google Scholar
- 6.Kazda S, Garthoff B, Meyer H, Schloßmann K, Stoepel K, Towart R, Vater W, Wehinger E (1980) Pharmacology of a new calcium antagonistic compound, isobutyl methyl 1,4 dihydro-2,6- dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate (nisoldipine, BAY K 5552). Arzneim Forsch (Drug Res) 30: 2144–2162Google Scholar
- 7.Kazda S, Towart R (1982) The duration of action of calcium antagonists in vitro: a comparison of nifedipine and nisoldipine (BAY K 5552). Br J Pharmacol 76: 255 PGoogle Scholar
- 8.Kazda S, Garthoff B, Rämsch KD, Schlüter G (1983) Nisoldipine. In: Scriabine A (ed) New Drugs Annual: Cardiovascular Drugs, Raven Press New York, p 243Google Scholar
- 9.Pan M, Janis RA, Triggle DJ (1983) Comparison of the equilibrium and kinetic binding characteristics of tritiated Ca2+ channel inhibitors, nisoldipine, nimodipine, nitrendipine and nifedipine. Pharmacologist 25: 202, Abstr 257Google Scholar
- 10.Janis RA et al. (1987) Review of nisoldipine binding studies. Hugenholtz PG, Meyer J (eds.) Nisoldipine 1987. Springer, Berlin Heidelberg New York pp 27–35Google Scholar
- 11.Garthoff B, Hirth C, Federmann A, Kazda S, Stasch JP (1987) Renal effects of 1 ,4-dihydropyridines in animal models of hypertension and renal failure. J Cardiovasc Pharmacol 9 (Suppl 1)Google Scholar
- 15.Bertie L, Garthoff B, Chur C, Funke PJ, Kazda S (1984) Protective effects of Ca2+-channel blocker nisoldipine in post-ischemic acute renal failure in the rats. J Urol 131: 256 AGoogle Scholar
- 16.Hirth C, Federmann A, Garthoff B, Bertie L, Kazda S, Stasch JP (1987) The effect of nisoldipine in experimentally induced renal failure. Hugenholtz PG, Meyer J (eds.) Nisoldipine 1987. Springer, Berlin Heidelberg New York, pp 144–150Google Scholar
- 18.Strauer BE, Motz W, Ringsgwandel G, Motz U, Bayer F (1985) Herzhypertrophie und Ventrikelfunktion unter chronischer Nifedipin-Behandlung. In: Distler A, Philipp T (ed’s) Neue Entwicklungen in der Hochdrucktherapie, F. K. Schattauer Verlag, Stuttgart- New York p 129Google Scholar
- 19.Stasch JP, Kazda S, Hirth C, Morich F (1987) Role of nisoldipine on blood pressure, cardiac hypertrophy and atrial peptides in spontaneously hypertensive rats. Hypertension, in pressGoogle Scholar
- 26.Stasch JP, Kazda S, Hirth C (1987) The different effect of a calcium antagonist and a sodium retaining vasodilatator on blood pressure, cardiac hypertrophy and atrial natriuretic peptides in adult SHR. J Hypertens (suppl) in pressGoogle Scholar
- 27.Knorr A, Laguna C, Stasch JP (1987) Nifedipine on ANP, membrane Na+ transient and plasma volume in rats with (1-k, 1-c) renal hypertension. Eur J Pharmacol, in pressGoogle Scholar