Different prejunctional and postjunctional responses to angiotensin II and AT1-receptor inhibition: influence of maturation.
The present study was designed to investigate the influence of maturation (young versus adult) on the angiotensin II-mediated facilitation of sympathetic nerve traffic (prejunctional AT1-receptor) as well as on the angiotensin II-mediated vasoconstriction (postjunctional AT1-receptor). Additionally, we investigated the inhibitory effect of the selective AT1-receptor antagonist eprosartan on angiotensin II-mediated responses at both sites during maturation. Male New Zealand White rabbits, aged 12 to 14 and 35 to 38 weeks (young versus adult, respectively), were used. To study angiotensin II at the neuronal AT1-receptor we investigated its influence on electrical field stimulation (EFS)-evoked sympathetic neurotransmission in the isolated thoracic aorta in a noradrenaline spillover model. To study the effects of angiotensin II at the level of the vasculature concentration-response curves for angiotensin II were constructed. In both models the influence of eprosartan on angiotensin II-mediated responses was studied. Angiotensin II (0.01 nM-0.1 microM) concentration-dependently enhanced the EFS-evoked noradrenaline release in both groups. No differences concerning the relative (approximately 100%, P > 0.05) and absolute facilitation were observed between groups, although concentrations required in adult rabbits exceeded those in young animals by 1 unity log M increment. Eprosartan concentration-dependently attenuated the angiotensin II-enhanced (10 nM) sympathetic outflow. The inhibitory potency differed approximately by a factor ten between both groups (young; pIC50 7.91 +/- 0.12 and adult; pIC50 8.81 +/- 0.31, respectively, P < 0.05). Angiotensin II (1 nM-0.3 microM) caused a concentration-dependent increase in contractile force (young rabbits; Emax 20.62 +/- 2.24 mN, pD2 8.16 +/- 0.04, n = 10 and adult rabbits; Emax 21.64 +/- 3.86 mN, pD2 7.63 +/- 0.02, n = 7). We observed approximately a 0.5 unity log M increment difference in potency, although the maximal absolute contraction was similar in both groups. Eprosartan (0.1 nM-0.1 microM) inhibited the angiotensin II-mediated contractions in a competitive manner in preparations from young rabbits (pA2 8.90 +/- 0.11, n = 24), whereas a mixed form of antagonism, in the same concentration range, was observed in tissues from adult rabbits. One possible explanation concerning these experiments is that maturation influences the AT1-receptor density negatively, although further studies are necessary to test this question. In addition, the decreased AT1-receptor density offers a potential explanation for the discrepancy in the profile of antagonism displayed by eprosartan in young compared with adult rabbits.
Nap
Alexander
A
Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands. a.nap@amc.uva.nl
Mathy
Marie-Jeanne
MJ
Pfaffendorf
Martin
M
van Zwieten
Pieter A
PA
D000179:Acrylates / Q000494:pharmacology*; D000375:Aging / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004594:Electrophysiology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D013876:Thiophenes; D014661:Vasoconstriction / Q000187:drug effects
D000179:Acrylates; D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013876:Thiophenes; C068373:eprosartan; D013779:Tetrodotoxin; D003891:Desipramine; D009638:Norepinephrine