The role of nitric oxide in the regional vasodilator effects of endothelin-1 in the rat.
1. The role of nitic oxide (NO) derived from L-arginine in the regional vasodilator effects of endothelin-1 has been investigated in anaesthetized, spontaneously hypertensive (SH) rats in which autonomic reflexes were abolished by ganglion blockade. The experimental design incorporated animals infused with phenylephrine to mimic the peripheral vasconstrictor effects of the NO biosynthesis inhibitors and a single dose per animal paradigm to obviate problems of tachyphylaxis to the vasodilator effects of endothelin-1. 2. Infusion of the inhibitor of NO synthase, N-monomethyl-L-arginine (L-NMMA) at a dose (5 mg kg-1 min-1) which maximally raised blood pressure did not influence either the fall in blood pressure or the vasodilator responses induced in the hindquarters and carotid vascular beds by endothelin-1 (1 nmol kg-1, i.v.) The duration (but not the initial magnitude) of the vasodepressor response to endothelin-1 was however significantly attenuated (by 49%) during infusion of the more potent inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), 2 mg kg-1 min-1. 3. Increasing the dose of L-NAME to 10 and 25 mg kg-1min-1 significantly attenuated, but did not abolish, the falls in blood pressure and hindquarters vasodilator responses to acetylcholine, 1 microgram kg-1, and endothelin-1, 1 nmol kg-1 min-1. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-10 micrograms kg-1 min-1, were unaltered. The effects were selective in that vasodepressor responses to the endothelium-independent vasodilator, sodium nitroprusside, 1-l0mg kg min , were unaltered.4. The data indicate that NO generated de novo from L-arginine mediates a significant component of the vasodilator effect of endothelin-1 in the anaesthetized, ganglion-blocked SH rat. However, a major component of the vasodepressor effects of both endothelin-1 and acetylcholine may occur independently of this mechanism.
Fozard
J R
JR
Preclinical Research, Sandoz Pharma AG, Basel, Switzerland.
Part
M L
ML
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D013618:Tachyphylaxis / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine
D016232:Endothelins; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester