~ Pergamon 0306-3623(94)E0039-O Gen. Pharmac. Vol. 25, No. 5, pp. 887-891, 1994 Copyright © 1994 ElsevierScienceLtd Printed in Great Britain. All rights reserved 0306-3623/94 $7.00 + 0.00 Role of Nitric Oxide in the Systemic Circulation of Conscious Hyper- and Hypothyroid Rats FELIX VARGAS, l ROSA MONTES, 2 J. MARIO SABIO I and JOAQUIN GARCiA-ESTAiKI 3 IDepartamento de Bioquimica and eDepartamento de Fisiologia, Facultad de Medicina, Granada, Spain [TeL 34-58-243520; Fax 34-58-243518] and 3Departamento de Fisiolgla, Facultad de Medicina, Murcia, Spain (Received 4 January 1994) Abstraet--l. N'°-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO biosynthesis, which blocks basal NO production, caused a similar increase of mean arterial pressure (MAP) in control hyper- and hypothyroid rats at the lowest dose, however, smaller pressor effects were observed with increasing doses in hyper- and hypothyroid rats. An additional dose of L-NAME (30 mg/kg), which produced no further increase in pressure, killed 90% of the hyperthyroid rats, whereas hypothyroid and control rats survived this additional dose. 2. The systemic responses to acetylcholine (ACh), an endothelium-dependent vasodilator that stimu- lates NO production/release, were significantly increased in hypothyroid rats, while hyperthyroid rats showed no significant differences when compared with controls. However, 10 8 M ACh killed hyper- thyroid rats, whereas control and hypothyroid rats survived this dose. 3. The maximal hypotensive response to sodium nitroprusside (SNP), an agonist that generates NO, was similar in intact controls, hyper- and hypothyroid rats. 4. These data indicate that hyper- and hypothyroidism show a reduction in basal NO synthesis/release, this reduced systemic NO tone being essential for life in hyperthyroid rats; whereas the response to ACh is not reduced and the hypotensive response to SNP did not differ between groups, indicating that the responsiveness of the systemic circulation to NO is not altered in either thyroid disorder. Key Words: Nitric oxide, hyperthyroidism, hypothyroidism, acetylcholine, nitroprusside, L-NAME INTRODUCTION Alterations in cardiovascular function are promi- nent manifestations of thyroid dysfunction. Thus, hyperthyroidism is associated with hyperdynamic circulation, characterized by hypertension with increased cardiac output and reduced vascular resistance, whereas hypothyroidism is characterized by arterial hypotension with reduced cardiac output and increased vascular resistance (Bradley et al., 1974). Endothelial cells make important contributions to cardiovascular regulation through the release of vaso- constrictor and vasodilator factors (Furchgott, 1983). The major vasodilator produced by endothelial cells is nitric oxide (NO) (Palmer et al., 1987) which originates from the terminal guanidine nitrogen atom of the amino acid L-arginine (Palmer et aL, 1988). The enzyme involved in this metabolic pathway can be inhibited by the L-arginine analogue N~-nitro-L - arginine methyl ester (L-NAME), and the inhibitory effect of this analogue is abolished by the simul- taneous administration of L-arginine (Moncada et al., 1991). The availability of specific inhibitors of NO syn- thesis from L-arginine has allowed one to evaluate the role of this vasodilator in the regulation of blood pressure in vivo under physiological and patho- physiological conditions. The administration of these inhibitors to rats results in substantial increases in blood pressure (Gardiner et al., 1990; Kiffet al., 1991; Rees et al., 1989) due largely, if not entirely, to an increase in peripheral resistance (Kiff et al., 1991; Pizcueta et al., 1992); the increase is reversed by the i.v. administration of L-arginine, but not by D-arginine (Whittle et al., 1989), suggesting a 887