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Continuous versus intermittent nitroglycerin administration in experimental heart failure: vascular relaxation and
1Department of Pharmaceutics, State University of New York at Buffalo 14260.
Abstract:
Continuous nitroglycerin (NTG) administration causes pharmacologic tolerance in humans and animals, whereas intermittent dosing is capable of avoiding or reducing tolerance development. The mechanism of NTG-induced hemodynamic tolerance may involve specific vascular desensitization 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 micrograms/min) to rats with congestive heart failure (CHF) on radioligand binding from selected tissues. Tension responses in isolated blood vessels, plasma renin activity (PRA), plasma Na+ and K+ concentrations were also determined. The maximal binding values (Bmax) for [3H]glyburide and [3H]PN 200 110 in homogenates of left ventricle, right ventricle, and brain were not significantly different after NTG administration (continuous or intermittent), as compared with control. Intermittent, but not continuous, NTG caused significant increases in beta-adrenoceptor densities in the left ventricle, as judged by [3H]dihydroalprenolol binding (Bmax values: intermittent NTG 34.5 +/- 4.8, continuous NTG 24.4 +/- 2.6, placebo control 20.9 +/- 2.9 fmol/mg protein); Kd values for all ligands were not significantly altered by NTG administration. Both intermittent and continuous NTG increased the vascular contractile response to phenylephrine in isolated rat thoracic aorta. Slight reductions (two- to four-fold shifts in EC50 values) in thoracic aorta relaxant response to NTG were observed in both treatment groups as compared with control. Intermittent and continuous NTG administration caused selective changes in beta-adrenoceptor density and vascular response. These changes may contribute partly to the phenomenon of pharmacologic tolerance after chronic nitrate administration.
Insights
Intermittent nitroglycerin (NTG) dosing in rats with heart failure increased beta-adrenoceptor density, potentially reducing tolerance. Continuous NTG did not show this effect, suggesting dosing schedule impacts tolerance development.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Drug Tolerance Mechanisms
Background:
- Continuous nitroglycerin (NTG) administration can lead to pharmacologic tolerance.
- Intermittent NTG dosing may mitigate or prevent tolerance development.
- Mechanisms of NTG tolerance may involve vascular desensitization and neurohormonal compensation.
Purpose of the Study:
- To compare the effects of continuous versus intermittent NTG administration on tolerance development in rats with congestive heart failure (CHF).
- To investigate the impact of NTG dosing on radioligand binding, vascular responses, and plasma markers.
Main Methods:
- Long-term (10 days) transdermal NTG administration (continuous or intermittent 12h on/12h off) in rats with CHF.
- Assessment of radioligand binding (e.g., [3H]dihydroalprenolol) for beta-adrenoceptors in cardiac and brain tissues.
- Measurement of tension responses in isolated blood vessels and plasma renin activity (PRA).
Main Results:
- Intermittent NTG significantly increased left ventricular beta-adrenoceptor density, unlike continuous NTG.
- Both NTG regimens increased vascular contractile response to phenylephrine in isolated thoracic aorta.
- Both NTG regimens showed slight reductions in thoracic aorta relaxant response to NTG.
Conclusions:
- Intermittent NTG administration selectively altered beta-adrenoceptor density and vascular responses in CHF rats.
- These alterations may contribute to the reduced pharmacologic tolerance observed with intermittent NTG dosing.
- Dosing schedule is a critical factor in managing nitrate tolerance.