Sympatho-inhibitory actions of irbesartan in pithed spontaneously hypertensive and Wistar-Kyoto rats.
Angiotensin II (Ang II) can enhance sympathetic neurotransmission by acting on (AT1) receptors that are located on sympathetic nerve terminals. We investigated presynaptic blockade by the selective AT1-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 AT1-receptors on vascular smooth muscle in both strains. To investigate blockade of presynaptic AT1-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 AT1-blockers and alpha-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 vasoconstriction 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 pIC50 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 that both in SHR and in WKY, Ang II exerts a facilitatory effect on sympathetic neurotransmission, which is mediated by prejunctional AT1-receptors in both strains. Irbesartan displays comparable sympatho-inhibitory potency in the normotensive and hypertensive pithed rat preparations. A facilitatory effect via postsynaptically located AT1-receptors on alpha-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 AT1-receptors, respectively.
Balt
Jippe C
JC
Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
Mathy
Marie-Jeanne
MJ
Pfaffendorf
Martin
M
van Zwieten
Pieter A
PA
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D000077405:Irbesartan; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D013045:Species Specificity; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D013565:Sympatholytics / Q000494:pharmacology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013565:Sympatholytics; D013777:Tetrazoles; D000804:Angiotensin II; D000077405:Irbesartan; D009638:Norepinephrine