title: Direct interaction between the sympathetic and renin-angiotensin system in myocardial tissue: a microdialysis study in anaesthetised rats.
abstract: It has been suggested that local activation of the renin-angiotensin system is involved in early stages of myocardial pathophysiology. To date, there is increasing evidence for interactions between the renin-angiotensin system and the sympathetic nervous system; consequently, local sympathetic activation may also be involved in this. Microdialysis has great potential in the direct investigation of neurohormonal interactions. Therefore, the present study employs microdialysis to study the local effects of exogenous angiotensin II on the interstitial norepinephrine concentration of the normally innervated left ventricle of the anaesthetised rat. The present study investigates the effect of increasing dosages of exogenous angiotensin II on local interstitial norepinephrine. Furthermore, a single dose of losartan was infused on top of the highest dose of angiotensin II, in order to study possible involvement of angiotensin II type 1 (AT1) receptors. Both infusion and sampling were carried out locally, via the microdialysis probes. Concomitantly, circulating norepinephrine levels, heart rate and respiratory rate were monitored to evaluate physiologic stability of the preparation throughout the experiment. Time controls consisted of rats that were perfused with only a Ringer's solution. Angiotensin II induced a dose dependent increase in norepinephrine that was significantly reduced by losartan. Norepinephrine levels in both plasma (infusion experiment and time controls) and the left ventricular wall (time controls) remained stable throughout the experiment, just as heart rate and respiratory rate did. This study for the first time employs microdialysis to demonstrate direct interaction between the sympathetic nervous system and the renin-angiotensin system in the rat left ventricle. The data strongly suggest that AT1 receptors are involved in this interaction, since selective AT1 receptor blockade with losartan significantly reduced the angiotensin II induced norepinephrine concentration.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, The Netherlands. cliphar@med.rug.nl
authors.forename: A C
authors.initials: AC
authors.lastname: Teisman
authors.forename: B H
authors.initials: BH
authors.lastname: Westerink
authors.forename: D J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: E
authors.initials: E
authors.lastname: Scholtens
authors.forename: D
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: W H
authors.initials: WH
authors.lastname: van Gilst
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000294:innervation* / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019808:Losartan; D009638:Norepinephrine