Abstract
We previously demonstrated the substantial capacity for angiotensin (ANG) II formation in the interstitium of the dog heart in vivo. The current study tested the hypothesis that interstitial fluid (ISF) bradykinin (BK) is influenced by ANG II formation. Four microdialysis probes were inserted into the left ventricular myocardium of eight open-chest anesthetized dogs. The probe effluent was collected during four stages in each dog. Probes 1 and 3 sequentially delivered: 1) buffer; 2) ANG I (15 μM); 3) ANG II type 1 receptor antagonist (AT1-ant; irbesartan, 50 μM) or AT2-ant (PD123319, 50 μM); and 4) ANG I + AT1-ant or ANG I + AT2-ant. Probes 2 and 4 used the same protocol, substituting ANG II for ANG I in a concentration (0.5 μM) equivalent to that achieved during ANG I infusion. ISF BK levels increased 15-fold during ANG I (p < 0.001) but not during ANG II infusion. Co-infusion of selective AT1- and AT2-ants or nonselective AT-ant did not block the increase in ISF BK. ISF infusions of ANG I also produced a greater than 400-fold rise in ISF ANG-(1-7) over baseline. ISF infusion of ANG-(1-7) (10 μM) produced a 15-fold increase in ISF BK (p < 0.001). The metabolic machinery exists for the formation of BK and ANG-(1-7) in the cardiac ISF space that is not blocked by an AT receptor antagonist. The differential increase in ISF BK during ANG I and ANG-(1-7) but not during ANG II infusions suggests the possibility of decreased catabolism of ISF BK by an angiotensin-converting enzyme due to active site occupation by ANG I and ANG-(1-7).
Footnotes
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This study was supported by the Office of Research and Development, Medical Service, Department of Veterans Affairs (L.J.D.), National Heart, Lung and Blood Institute Grants RO1 HL54816 and HL6707 (L.J.D.), Mechanisms of Hypertension and Cardiovascular Diseases (2T32HL07457-16A1), and Fellowship 9820134V (C.C.W.) from the Southeast affiliate of the American Heart Association.
Abbreviations
- ANG
- angiotensin
- ISF
- interstitial fluid
- BK
- bradykinin
- AT
- ANG type
- AT1-ant
- ANG II type 1 receptor antagonist
- AT2 ant
- ANG II type 2 receptor antagonist
- ACE
- angiotensin-converting enzyme
- RAS
- renin-angiotensin system
- LV
- left ventricular or left ventricle
- bpm
- beats per minute
- Received August 22, 2001.
- Accepted October 10, 2001.
- U.S. Government
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