Role of nitric oxide synthesis in the regulation of coronary vascular tone in the isolated perfused rabbit heart.
OBJECTIVE
The aim was to study the effects on coronary vascular tone of three inhibitors of nitric oxide (NO) synthesis.


METHODS
Studies were performed on isolated perfused hearts of 74 male New Zealand White rabbits fed normal laboratory diet. Resting coronary perfusion pressure was increased to 40-60 mm Hg with the thromboxane mimetic 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F2 alpha (U46619). The effects of NG-monomethyl-L-arginine (L-NMMA), N-iminoethyl-L-ornithine (L-NIO), and NG-nitro-L-arginine methyl ester (L-NAME) (0.3-300 microM) on resting coronary perfusion pressure were determined. The effects of these compounds, at concentrations that increased the resting perfusion pressure to a similar extent, on the fall in perfusion pressure induced by acetylcholine (0.1 microM) and glyceryl trinitrate (1 microM) were also investigated. In these studies the resting perfusion pressure was maintained at 40-60 mm Hg by reducing the concentration of U46619.


RESULTS
L-NMMA, L-NIO, and L-NAME induced concentration dependent increases in resting coronary perfusion pressure (n = 3-9, p < 0.05). L-NAME had the greatest potency and efficacy, increasing the resting pressure by 48.0(SEM 9.6) mm Hg at 30 microM. L-NIO and L-NMMA increased perfusion pressure by 27.3(3.0) and 19.5(5.8) mm Hg respectively at the maximum concentration studied (300 microM). However, at concentrations that were equieffective on resting perfusion pressure (15 mm Hg increase), L-NMMA (100 microM), but not L-NIO (25 microM) or L-NAME (4 microM), significantly inhibited the fall in pressure induced by acetylcholine by 57.2(5.0)%, n = 6, p < 0.05. This effect of L-NMMA++ was attributed to a shorter duration of fall and was reversed by L-arginine (300 microM). L-NMMA (100 microM) and L-NIO (25 microM) potentiated the effect of glyceryl trinitrate by increasing the peak fall in perfusion pressure by 75.6(11.0)% and 68.8(24.1)% respectively (n = 6 for each, p < 0.05).


CONCLUSIONS
The differential effects of the three inhibitors on resting coronary perfusion pressure and the acetylcholine induced fall in coronary perfusion pressure suggest that basal and stimulated NO synthesis may be differentially regulated. Reduction in the synthesis of endogenous NO by these compounds potentiates the glyceryl trinitrate induced fall in perfusion pressure, which may have important clinical implications.
Smith
R E
RE
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Palmer
R M
RM
Bucknall
C A
CA
Moncada
S
S
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D009952:Ornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D010477:Perfusion; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011817:Rabbits; D014661:Vasoconstriction / Q000187:drug effects; D014690:Venous Pressure / Q000187:drug effects; D019323:omega-N-Methylarginine
D011450:Prostaglandin Endoperoxides, Synthetic; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C065027:N(G)-iminoethylornithine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001120:Arginine; D009952:Ornithine; D005996:Nitroglycerin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester