CONTINUOUS VERSUS INTERMITTENT NITROGLYCERIN ADMINISTRATION IN EXPERIMENTAL HEART-FAILURE - VASCULAR RELAXATION AND RADIOLIGAND BINDING TO ADRENOCEPTORS AND ION CHANNELS

Continuous nitroglycerin (NTG) administration causes pharmacologic tol erance in humans and animals, whereas intermittent dosing is capable o f avoiding or reducing tolerance development. The mechanism of NTG-ind uced hemodynamic tolerance may involve specific vascular desensitizati on and/or neurohormonal compensation. We compared effects of long-term (10 days) NTG administration (continuous or intermittent 12 h on/12 h off transdermal dosing, 10 mug/min) to rats with congestive heart fai lure (CHF) on radioligand binding from selected tissues. Tension respo nses in isolated blood vessels, plasma renin activity (PRA), plasma Na + and K+ concentrations were also determined. The maximal binding valu es (B(max)) for [H-3]glyburide and [H-3]PN 200 110 in homogenates of l eft ventricle, right ventricle, and brain were not significantly diffe rent after NTG administration (continuous or intermittent), as compare d with control. Intermittent, but not continuous, NTG caused significa nt increases in beta-adrenoceptor densities in the left ventricle, as judged by [H-3]dihydroalprenolol binding (B(max) values: intermittent NTG 34.5 +/- 4.8, continuous NTG 24.4 +/- 2.6, placebo control 20.9 +/ - 2.9 fmol/mg protein); K(d) values for all ligands were not significa ntly altered by NTG administration. Both intermittent and continuous N TG increased the vascular contractile response to phenylephrine in iso lated rat thoracic aorta. Slight reductions (two- to four-fold shifts in EC50 values) in thoracic aorta relaxant response to NTG were observ ed in both treatment groups as compared with control. Intermittent and continuous NTG administration caused selective changes in beta-adreno ceptor density and vascular response. These changes may contribute par tly to the phenomenon of pharmacologic tolerance after chronic nitrate administration.