Interaction between nitric oxide and endogenous vasoconstrictors in control of renal blood flow.
The level of renal blood flow (RBF) is controlled by opposing vasoconstrictor and vasodilator influences. In a recent investigation in normotensive dogs, we found that combined blockade of endothelin type A (ET(A)) receptors and angiotensin II formation induces marked increases in RBF that were much larger than the effects of blocking either system alone. The aim of the present study was to determine the contribution of nitric oxide (NO) to this vasodilator response. Experiments were made in 6 conscious, chronically instrumented dogs subjected to 5 different experimental treatments on separate days. Blockade of ET(A) receptors alone by the selective antagonist LU 135252 had only minor effects on RBF compared with time-control experiments. Additional blockade of angiotensin II formation by angiotensin-converting enzyme inhibition with trandolaprilat caused a substantial increase of RBF by approximately 50%. This vasodilation was entirely suppressed when NO formation was prevented by inhibition of NO synthase with N(G)-nitro-L-arginine methyl ester HCl. However, when during NO synthase inhibition renal vascular NO concentrations were clamped at control levels by infusing the NO donor S-nitroso-N-acetyl-D, L-penicillamine, the vasodilator response to combined blockade of ET(A) receptors and angiotensin II formation was completely restored (DeltaRBF approximately 60%). These results indicate that the vasodilation after combined ET(A) receptor blockade and angiotensin-converting enzyme inhibition is not mediated by an increase in NO release but results from the unmasking of the tonic influence that is normally exerted by constitutively released NO. Accordingly, the tonic activity of endothelial NO synthase appears to be of major importance in the physiological regulation of renal vascular resistance by determining the vasomotor responses to endothelin and angiotensin II.
Berthold
H
H
I. Physiologisches Institut der Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.
Just
A
A
Kirchheim
H R
HR
Ehmke
H
H
D000804:Angiotensin II / Q000096:biosynthesis*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D044022:Receptor, Endothelin A; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C110881:S-nitro-N-acetylpenicillamine; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; C107831:darusentan; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester