title: Prazosin potentiates the acute hypotensive effects of nitroglycerin but does not attenuate nitrate tolerance in normal conscious rats.
abstract: Sympathetic activation has been suggested as a mechanism of acute nitrate tolerance, but the available literature is not definitive. We investigated the effects of prazosin, an alpha1-adrenoceptor antagonist, on acute nitroglycerin (NTG) hemodynamics and tolerance development in normal conscious rats. The effect of prazosin bolus injection (300 microg/kg) on NTG hemodynamics was first determined after acute dosing. The extent of maximal mean arterial pressure (MAP) response and the duration of drug-induced hypotension to NTG bolus doses (5, 15, and 30 microg) were measured before and after prazosin. In separate studies, the effects of prazosin on NTG tolerance development were examined. Rats received either 10 microg/min NTG or vehicle infusion for 5 hours after predosing with prazosin (300 microg/kg). Maximal MAP response to the hourly 30-microg NTG i.v. bolus challenge dose (CD) was determined before and after prazosin, and during NTG or vehicle infusion. Our results showed that bolus doses of NTG (at 5, 15, and 30 microg) dose-dependently decreased maximal MAP by 20.8 +/- 5.8, 26.1 +/- 5.0, and 30.6 +/- 5.7 mm Hg, respectively. Prazosin caused an average of 16 mm Hg depression in MAP, and it only slightly potentiated the hypotensive effects of bolus doses of NTG both after acute dosing and during continuous infusion. Prazosin treatment prolonged the duration of NTG-induced MAP response by about 4-fold for all NTG doses examined (P < 0.01 versus corresponding dose before prazosin, ANOVA). In both prazosin-treated and untreated groups, NTG infusion significantly attenuated the MAP response of the NTG CD starting from 1 hour of infusion (P < 0.001 versus 0 hour response, ANOVA), confirming tolerance development. In the presence of NTG tolerance development, prazosin no longer enhanced the apparent duration of NTG action. The hypotensive effect produced by the 30-microg NTG CD lasted for 7 +/- 2 and 10 +/- 2 seconds for prazosin-treated and untreated groups, respectively (P > 0.05, ANOVA). Our results showed that, in both NTG-tolerant and control animals, prazosin only slightly potentiated the maximum hypotensive effects of a challenge NTG dose, but did not significantly alter the pharmacodynamics of NTG-induced hemodynamic tolerance. Thus, in our animal model, sympathetic blockade by prazosin neither prevented nor attenuated in vivo tolerance induced by NTG.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260-1200, USA. hlfung@buffalo.edu
authors.forename: Ellen Q
authors.initials: EQ
authors.lastname: Wang
authors.forename: Ho-Leung
authors.initials: HL
authors.lastname: Fung
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004357:Drug Synergism; D004361:Drug Tolerance; D007022:Hypotension / Q000139:chemically induced; D007275:Injections, Intravenous; D008297:Male; D009566:Nitrates / Q000494:pharmacology; D005996:Nitroglycerin / Q000009:adverse effects / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D009566:Nitrates; D014665:Vasodilator Agents; D005996:Nitroglycerin; D011224:Prazosin