title: Decreased facilitation by angiotensin II of noradrenergic neurotransmission in isolated mesenteric artery of rabbits with chronic heart failure.
abstract: Both in human and in experimental heart failure (HF), the renin-angiotensin system and the sympathetic nervous system are activated. In a previous study a facilitatory action of angiotensin II (Ang II) was shown in the rabbit mesenteric artery, which was mediated via prejunctionally located Ang II type 1 (AT ) receptors. Very little is known about the effects of Ang II on sympathetic neurotransmission at the peripheral level in congestive heart failure (CFH). Accordingly, in the isolated mesenteric arteries obtained from rabbits with experimentally induced CHF, as well as in age-matched control rabbits, the effect of Ang II on contractions provoked by electrical field stimulation was investigated in the presence and absence of the AT receptor antagonist eprosartan. Additionally, to investigate a possible postjunctional facilitation, the effects of Ang II on alpha-adrenoceptor-mediated responses were studied using noradrenaline (NA). Lastly, the vasoconstrictor effects of Ang II were compared between HF rabbits and controls, by constructing concentration-response curves to Ang II. In control rabbits, Ang II 0.5 n caused an enhancement of stimulation-induced responses by a factor 3.2 +/- 0.5, 2.4 +/- 0.3, and 1.5 +/- 0.08, at 1, 2, and 4 Hz, respectively ( < 0.05 at all frequencies compared with vehicle). In rabbits with HF, the enhancement by Ang II (0.5 n ) amounted to a factor 2.1 +/- 0.2, 1.7 +/- 0.1, and 1.2 +/- 0.04, at 1, 2, and 4 Hz, respectively ( < 0.05 compared with vehicle at all frequencies). Accordingly, the enhancing effect of Ang II was more pronounced in the control group compared with rabbits with HF ( < 0.05 at each frequency). Eprosartan (1 nM -0.1 microM) could inhibit the facilitatory effects of Ang II in arteries from HF as well as from control rabbits. Contractile responses to exogenous NA (3 n -0.1 m ) were the same in HF rabbits and controls, and they were unaltered in the presence of Ang II 0.5 n Ang II (0.1 nM -1 microM) caused a concentration-dependent increase in contractile force, which was the same in HF rabbits and controls. From these findings it can be concluded that in rabbits with CHF as well as in control animals, Ang II facilitates the stimulation-induced vasoconstrictor responses via prejunctionally located AT receptors. The facilitating effect was decreased in vessels obtained from rabbits with CHF, whereas responses to exogenous Ang II were unchanged. These findings may be explained by downregulation or uncoupling of the prejunctional AT receptor.
authors.affiliation: Department of Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands. jcbalt@hotmail.com
authors.forename: Jippe C
authors.initials: JC
authors.lastname: Balt
authors.forename: Charly N W
authors.initials: CN
authors.lastname: Belterman
authors.forename: Marie-Jeanne
authors.initials: MJ
authors.lastname: Mathy
authors.forename: Alexander
authors.initials: A
authors.lastname: Nap
authors.forename: Anton
authors.initials: A
authors.lastname: Baartscheer
authors.forename: Martin
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Van Zwieten
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D002908:Chronic Disease; D004558:Electric Stimulation / Q000379:methods; D006333:Heart Failure / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology*; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000819:agonists / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D009638:Norepinephrine