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Sympatho‐inhibitory actions of irbesartan in pithed spontaneously hypertensive and Wistar–Kyoto rats
Author(s) -
Balt Jippe C.,
Mathy MarieJeanne,
Pfaffendorf Martin,
Zwieten Pieter A.
Publication year - 2003
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1046/j.1472-8206.2003.00147.x
Subject(s) - irbesartan , medicine , endocrinology , angiotensin ii , angiotensin ii receptor type 1 , stimulation , inhibitory postsynaptic potential , chemistry , vasoconstriction , receptor , blood pressure
Angiotensin II (Ang II) can enhance sympathetic neurotransmission by acting on (AT 1 ) receptors that are located on sympathetic nerve terminals. We investigated presynaptic blockade by the selective AT 1 ‐receptor antagonist irbesartan in pithed spontaneously hypertensive rats and normotensive Wistar–Kyoto rats (WKY). We compared the presynaptic inhibitory dose with that required for the blockade of AT 1 ‐receptors on vascular smooth muscle in both strains. To investigate blockade of presynaptic AT 1 ‐receptors, we studied the effect of irbesartan on the sequelae of electric stimulation of the thoraco‐lumbar sympathetic outflow (0.25–8 Hz). To study the interaction between postsynaptic AT 1 ‐blockers and α‐adrenoceptors, the effects of irbesartan on pressor responses to exogenous noradrenaline (NA) were established. Additionally, we studied the effect of irbesartan on dose–response curves for the vasocontriction induced by exogenous Ang II. Pressor responses to electrical stimulation of thoracolumbar sympathetic neurones, to exogenous Ang II, as well as to (NA) were enhanced in spontaneously hypertensive rats (SHR) compared with WKY. The stimulation‐induced rise in DBP could be dose‐dependently reduced by irbesartan (0.3–10 mg/kg) in both SHR and WKY. The pIC 50 values (doses which suppress the rise in DBP by 50% compared with control) were 5.60 ± 0.09 and 5.72 ± 0.08 for SHR and WKY, respectively ( P > 0.05). In SHR, no effect of irbesartan (3 mg/kg) on pressor responses to exogenous NA was observed. In contrast, in WKY, irbesartan (3 mg/kg) caused a rightward shift of the dose–response curve to exogenous NA. Irbesartan (0.3–3 mg/kg) caused a depression of E max values and a rightward shift of the dose–response curves to exogenous Ang II in a similar fashion in both SHR and WKY. From these results we conclude thatboth in SHR and in WKY, Ang II exerts a facilitatory effect on sympathetic neurotransmission, which is mediated by prejunctional AT 1 ‐receptors in both strains. Irbesartan displays comparable sympatho‐inhibitory potency in the normotensive and hypertensive pithed rat preparations. A facilitatory effect via postsynaptically located AT 1 ‐receptors on α‐adrenoceptor‐mediated responses exists in WKY, but not in SHR. In both strains the required dose to inhibit presynaptic effects is somewhat higher than the dose required to inhibit postsynaptic effects. No differences, therefore, seem to exist between the two strains regarding the affinity of irbesartan for pre‐ and postjunctional AT 1 ‐receptors, respectively.