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 μM) 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 μM) 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 μM) 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.
Maturation is accompanied by a variety of alterations in cardiovascular function, as evidenced by clinical and experimental studies. 1 Maturation can be described as the complex of physiological changes occurring from birth to adulthood and hence it should be noted that this term does not include the natural process of ageing or senescence, which covers the changes occurring between adulthood and old age. As evidenced repeatedly, the renin angiotensin aldosterone system (RAAS) and predominantly its effector hormone angiotensin II appear to play a major role in cardiovascular homeostasis and adequate tissue perfusion. Angiotensin II is known to mediate vasoconstriction of vascular smooth muscle, to increase aldosterone from the adrenal gland, to regulate the fluid electrolyte balance, and to enhance sympathetic neurotransmission. 2–5 However, during the natural process of maturation little is known about the neuronal and vascular reactivity to this peptide.
At the level of the vasculature conflicting data exist regarding the receptor-mediated responsiveness to angiotensin II and several other vasoactive agents, such as noradrenaline and serotonin during maturation. 1 In the rat isolated coronary artery the contractile responses to angiotensin II remained unchanged, whereas the responses to endothelin-1 and serotonin were reported to increase with age. 6 In the rabbit isolated basilar artery the responses to angiotensin II, serotonin, and noradrenaline increased with age. 7 The contractile responses to angiotensin II were reported to decrease in the isolated rat mesenteric vascular bed as was reported for the isolated rat aorta. 8,9 Accordingly, important discrepancies exist. These can be explained, at least in part by differences in experimental design, such as the use of different species, vascular beds, and animal models. Moreover, the exact mechanism(s) responsible for the differences concerning vascular sensitivity and reactivity during maturation remain to be elucidated in detail. However, it can be well imagined that the endothelial function/integrity as well as the receptor number and G-protein–dependent signaling play pivotal roles.
The effect of maturation regarding sympathetic neurotransmission and the subsequent influence of angiotensin II on sympathetic nerve traffic is even more confusing and still largely unsolved. Nonetheless, there exists data concerning the sympathetic nervous system and the immediate postnatal period that points toward alterations in the autonomic innervation of various organs. The proliferation of nerve fibers as well as an increase in neuronal noradrenaline content and reuptake of the catecholamine has been proposed as relevant factors. 10–12
Accordingly it is not surprising that the influence of maturation concerning the neuronal and vascular responses to angiotensin II is subject to discussion. Therefore the aim of the present study was to investigate the influence of maturation 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). To study the effects of angiotensin II at the neuronal AT1-receptor we investigated its influence on electrical field stimulation (EFS)-evoked sympathetic neurotransmission in the isolated rabbit thoracic aorta, in a noradrenaline spillover model. To study angiotensin II at the level of the vasculature concentration-response curves for angiotensin II were constructed. Additionally, we investigated the inhibitory effect of the selective AT1-receptor antagonist eprosartan on angiotensin II-mediated responses at both pre- and postjunctional sites.
From the Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
Received for publication July 16, 2003; accepted December 8, 2003.
Reprints: Alexander Nap, Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands (e-mail: firstname.lastname@example.org).