Non‐competitive antagonism of the α‐adrenoceptor‐mediated fast component of contraction of rat aorta, by doxazosin and prazosin

Self Cite

1 The postjunctional x-adrenoceptors mediating contractions in the isolated vascular bed of the perfused rat tail have been investigated, in the presence and absence of an increase in perfusion pressure by arginine vasopressin (AVP). 2 In the absence of AVP, bolus doses of noradrenaline (NA) and phenylephrine produced pressor responses of similar time course, while UK-14,304 was practically inactive. Responses to noradrenaline were inhibited more by 0.05 yM prazosin than by 1 yM rauwolscine, suggesting the presence of ax-adrenoceptors.3 Following a sustained elevation in perfusion pressure by AVP, both UK-14,304 and NA (the latter in the presence of 0.05pM prazosin to inhibit a1-adrenoceptors) elicited dose-dependent pressor responses. The maximum response to UK-14,304 under these conditions was approximately 30% of the maximum response to NA in the absence of prazosin and AVP. Responses to phenylephrine were not affected by the AVP-induced increase in vascular tone. 4 In the presence of AVP, pressor responses to UK-14,304 were resistant to 0.05pM prazosin and susceptible to antagonism by 1 yM rauwolscine (-log Kb 7.65 + 0.15). Similarly, responses to NA in the presence of 0.05 pM prazosin and AVP were inhibited by 1 ,M rauwolscine. This represents the first demonstration of prazosin-resistant, rauwolscine-sensitive a2-adrenoceptor-mediated responses in the vasculature of the rat tail. 5These results suggest that in isolated vascular preparations, functional populations of postjunctional LX2-adrenoceptors may be 'uncovexed' by the presence of AVP.

Section: Resultsmentioning

confidence: 99%

Section: Identification Offunctional Postjunctional A2-adrenoceptors mentioning

confidence: 99%

Evidence for prazosin‐resistant, rauwolscine‐sensitive α‐adrenoceptors mediating contractions in the isolated vascular bed of the rat tail

Templeton

Macmillan

McGrath

et al. 1989

Self Cite

“…A similar action of prazosin has also been reported by Cauvin & Malik (1984). Such effects are apparently unrelated to the action of prazosin as a selective a1-adrenoceptor blocking agent (Downing et al, 1983).…”

Section: Contractions Of the Aortamentioning

confidence: 99%

A comparison of the effects of the calcium entry blockers, verapamil, diltiazem and flunarizine against contractions of the rat isolated aorta and portal vein

Marriott

1988

The actions of the chemically distinct calcium entry blockers, verapamil (Ver), diltiazem (Dlz) and flunarizine (Flu) have been compared in rat isolated aorta and portal vein. KCl‐induced contractions of the rat aorta depend exclusively upon extracellular Ca2+, whereas, those induced by noradrenaline (NA) rely upon Ca2+ from intra‐ and extracellular sources. The NA‐induced contraction was pharmacologically dissected under Ca2+‐free conditions revealing a contraction dependent upon intracellular Ca2+ (EGTA‐resistant response) or a low concentration of prazosin which left a contraction which was mediated by extracellular Ca2+ (prazosin‐resistant response). The portal vein produced spontaneous rhythmic contractions and a sustained contraction to NA and KCl; however, all responses appeared to depend exclusively upon extracellular Ca2+. In the aorta, contractions which might be expected to depend upon Ca2+‐entry through voltage‐operated channels (KCl‐induced contraction) showed similar sensitivities to Ver, Dlz and Flu whereas, marked differences in the sensitivity to these agents was noted against contractions which appear to depend upon Ca2+‐entry through receptor‐operated channels (prazosin‐resistant response). Only Dlz reduced contractions mediated by intracellular Ca2+ (EGTA‐resistant response). In the portal vein, Ver and Dlz caused similar pronounced reductions of spontaneous and NA or KCl‐induced contractions. In contrast, these contractions of the portal vein were unaffected by Flu except at a concentration of 10 μM. However, contractions induced by addition of Ca2+ (0–14 mM) to previously depolarized portal veins could be reduced by Flu (100 nμ‐10 μM). The present study indicates that in the rat aorta, contractions mediated by intracellular Ca2+ and depolarization or receptor‐activated Ca2+ entry can be pharmacologically dissected and that these processes show different sensitivities to calcium entry blockade. Of the agents tested, Ver displays the properties most commonly associated with an ideal calcium entry blocker. Ca2+‐activation mechanisms in the portal vein differ from those in the aorta resulting in a different spectrum of selectivity of the calcium entry blockers studied.

“…(Downing et al, 1983). Pharmacological 'total' autonomic blockade allows the study of mechanisms not involving sympathetic and parasympathetic activity (Korner et al, 1973;West et al, 1975) and in particular a,-adrenoceptorindependent responses.…”

Section: Total Autonomic Blockadementioning

confidence: 99%

“…Like prazosin, it is a relatively selective peripheral postsynaptic xl-adrenoceptor antagonist in animals (Karamat Ali et al, 1980;Timmermans et al, 1980;Cambridge & Davey, 1980;Wilson et al, 1981;Vincent et al, 1983a;Downing et al, 1983); in human vascular preparations in vitro (Stevens & Moulds, 1981); and in man in vivo (Singleton et al, 1980;1982;Elliott et al, 1982;Vincent et al, 1983b). This paper describes further in vitro and in vivo studies in the rabbit using doxazosin and prazosin.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic studies with two α‐adrenoceptor antagonists, doxazosin and prazosin in the rabbit

Hamilton

Reid

Vincent

1985

1 The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. 2 Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]-prazosin from specific binding sites. However, the lower pA2 value for doxazosin at a,-adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin. 3 The dose-related pressor effects of intravenous phenylephrine were used to assess vascular a,-adrenoceptor antagonism in vivo. There was a close agreement between oE,-adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The ac,-adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin. 4 Studies using either radioligand binding or pressor responses to B-HT 920 showed that doxazosin did not show any significant affinity for the a2-adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium. 5 Doxazosin has a longer terminal elimination half-life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined. 6 Following pharmacological 'autonomic blockade' and treatment with prazosin, doxazosin did not cause any further fall in blood pressure. 7 These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through a,-adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained a,-adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has x,-adrenoceptor blocking properties.