Smith, Russell E. A.; (1993) Nitric oxide and the control of coronary vascular tone. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Nitric oxide (NO), synthesised from L-arginine by a constitutive, endothelial enzyme, nitric oxide synthase, plays an important role in the physiological regulation of vascular tone. A second, inducible enzyme may modulate vascular tone in endotoxin shock. Using L-arginine, three inhibitors of nitric oxide synthase; NG-monomethyl-L-arginine (L-NMMA), N-iminoethyl-L-ornithine (L-NIO) and NG-nitro-L-arginine methyl ester (L-NAME), and the endothelium-dependent vasodilator acetylcholine, a dissociated control of basal and agonist- stimulated NO synthesis was demonstrated in the isolated perfused rabbit heart. The inhibitors had different effects on resting tone and only inhibited the duration of the acetylcholine response. Inhibition of nitric oxide synthesis was demonstrated to potentiate the vasodilatation induced by the endothelium- independent vasodilator glyceryl trinitrate. This was due to an increase in the peak effect of glyceryl trinitrate. This may have important implications in situations where endothelial nitric oxide synthesis is impaired. In contrast, the inhibitors had no effect on the vasodilatation induced by adrenaline which was inhibited by propranolol. This disputes a link between the adrenergic nervous system and NO in the coronary circulation. The coronary vascular tone of hearts from rabbits with endotoxin shock was shown to be resistant to vasoconstriction with the thromboxane mimetic U46619. However it was more responsive to L-NMMA and L-NIO and these effects were prevented by prior administration of dexamethasone. This suggests that the vasodilatation and resistance to vasoconstrictors observed in septic shock is due to the induction of nitric oxide synthase and it may explain some of the cardiac changes in sepsis.

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