Angiotensin II attenuates the vasodilating effect of a nitric oxide donor, glyceryl trinitrate: roles of superoxide and angiotensin II type 1 receptors.
OBJECTIVE
The development of tolerance to organic nitrates limits their usefulness in the treatment of heart disease. Activation of the renin-angiotensin system by heart failure itself and by nitrate therapy may be one possible mechanism underlying nitrate tolerance. We investigated the effect of subpressor doses of angiotensin II on the vasodilating effect of glyceryl trinitrate in human forearm resistance vessels of healthy male subjects by using venous occlusion strain-gauge plethysmography.


METHODS
Glyceryl trinitrate was infused intra-arterially with angiotensin II or vehicle. The effect of blockade of angiotensin II type 1 receptors by candesartan or an antioxidant, vitamin C, on the interaction between angiotensin II and glyceryl trinitrate was also investigated.


RESULTS
Angiotensin II infused at 5 pmol/min significantly attenuated the vasodilating effect of glyceryl trinitrate (mean +/- standard deviation [SD] of percentage change in forearm blood flow [FBF]: 28% +/- 20%, 79% +/- 59%, and 208% +/- 72% at 100, 250, and 1000 ng/min of glyceryl trinitrate with placebo; 8% +/- 18%, 47% +/- 41%, and 173% +/- 98% with angiotensin II at 1 pmol/min; and 2% +/- 27%, 39% +/- 40%, and 132% +/- 74% with angiotension II at 5 pmo;/min; P =.0259). Either a single dose of candesartan or coinfusion with vitamin C abolished the angiotensin II-induced attenuation of vasodilation of glyceryl trinitrate.


CONCLUSIONS
Our results suggest that angiotensin II may attenuate the arterial vasodilating effect of glyceryl trinitrate through angiotensin type 1 receptors and presumably through receptor-mediated superoxide production, which may be relevant to the development of nitrate tolerance.
Wada
Atsushi
A
Human Vascular Pharmacology Lab, Department of Medicine II, Yokohama City University School of Medicine, Japan.
Ueda
Shinichiro
S
Masumori-Maemoto
Satoko
S
Kuji
Naomitsu
N
Sugimoto
Koh-ichi
K
Umemura
Satoshi
S
D000328:Adult; D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins / Q000502:physiology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012016:Reference Values; D012107:Research Design; D013481:Superoxides / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins; D000959:Antihypertensive Agents; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D020030:Nitric Oxide Donors; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014665:Vasodilator Agents; D013481:Superoxides; D005996:Nitroglycerin; D001205:Ascorbic Acid; C081643:candesartan