Cardiovascular manifestations are frequent findings in patients with thyroid hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial-mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme inhibited by endogenous compounds, mainly asymmetric dimethylarginine [asymmetric N(G),N(G)-dimethyl-L-arginine (ADMA)]. The aim of our work was to investigate whether plasma L-arginine and dimethylarginine concentrations and NO production are altered in hypo- and hyperthyroid patients, compared with control subjects. L-arginine, ADMA and symmetric dimethylarginine were analyzed by HPLC. NO was measured as plasma nitrite plus nitrate (NO(x)) concentration by a colorimetric method based on Griess reagent. L-arginine, ADMA, and symmetric dimethylarginine plasma levels in the hypothyroid group were similar to those of the control group; whereas in hyperthyroidism, these values were significantly increased. However, the L-arginine/ADMA ratio was decreased in hyperthyroid patients, resulting in diminished NO(x) production. When all subjects were analyzed together, free T(4) levels were directly correlated with ADMA and inversely correlated with NO(x).

Sildena®l (0.1 ± 30 mM), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1 ± 100 mM), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1 ± 100 mM) had no e ect on neurogenic contractions. The inhibition induced by sildena®l was not modi®ed by the inhibitor of guanylate cyclase 1H-[1,2,4]oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) (1 ± 30 mM) but it was abolished by the K + channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 mM) and charybdotoxin (0.1 mM). Sildena®l, zaprinast and SNP did not a ect the contractions induced by noradrenaline. SNP (10 mM) caused elevation of cyclic GMP levels that was potentiated by sildena®l (10 mM) and zaprinast (100 mM). ODQ (10 mM) inhibited the increase in cyclic GMP. Sildena®l inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large-conductance Ca 2+ -activated K + channels.

1 The aim of the present study was to investigate in rat mesenteric artery rings whether low concentrations of vasopressin could modify the contractile responses to noradrenaline and electrical stimulation of perivascular nerves. 2 Vasopressin (10 710 ± 10 77 M) caused concentration-dependent contractions (pD 2 =8.36+0.09). The V 1 -receptor antagonist d(CH 2 ) 5 Tyr(Me)AVP (10 79 ± 10 78 M) produced parallel rightward shifts of the control curve for vasopressin. Schild analysis yielded a pA 2 value of 9.83 with a slope of 1.10+0.14. The results demonstrate that low concentrations of vasopressin strongly potentiate the contractions to adrenergic stimulation and KCl depolarization. This e ect appears to be mediated by V 1 receptor stimulation which brings about an increase in calcium entry through dihydropyridine-sensitive calcium channels.

1 The effects of vasopressin and deamino-8-D-arginine vasopressin (DDAVP, desmopressin) were studied in artery rings (0.8-1 mm in external diameter) obtained from portions of human omentum during the course of abdominal operations (27 patients). 2 In arterial rings under resting tension, vasopressin produced concentration-dependent, endotheliumindependent contractions with an EC% of 0.59 ± 0.12 nM. The V, antagonist d(CH2)5Tyr(Me)AVP (1 f1M) and the mixed V1-V2 antagonist desGly-d(CH2)5D-Tyr(Et)ValAVP (0.01 JAM) displaced the control curve to vasopressin to the right in a parallel manner without differences in the maximal responses. In the presence of indomethacin (1 AM) the contractile response to vasopressin was significantly increased (P <0.01). 4 The selective V2 receptor agonist, DDAVP, caused endothelium-independent, concentration-dependent relaxations in precontracted arterial rings that were inhibited by the mixed V1-V2 receptor antagonist, but not by the VI receptor antagonist or by pretreatment with indomethacin or L-NAME.5 Results from this study suggest that vasopressin is primarily a constrictor of human mesenteric arteries by VI receptor stimulation; vasopressin causes dilatation only during VI receptor blockade. The relaxation appears to be mediated by the release of vasodilator prostaglandins from the endothelial cell layer and is independent of V2 receptor stimulation or release of nitric oxide. In contrast, the relaxation induced by DDAVP is largely dependent on stimulation of V2 receptors.

Background and Purpose-Accumulation of endogenous guanidino-substituted analogues of L-arginine in chronic renal failure might contribute to some of the vascular and neurological disorders of this pathology. We tested the hypothesis that in human cerebral arteries, some guanidino compounds may increase vascular tone, through nitric oxide (NO) synthase inhibition, and impair endothelium-dependent relaxation. Methods-Rings of human middle cerebral artery were obtained during autopsy of 26 patients who had died 3 to 12 hours before. The rings were suspended in organ baths for isometric recording of tension. We then studied the responses to N G -monomethyl-L-arginine (L-NMMA), N G ,N G -dimethyl-L-arginine (asymmetrical dimethylarginine; ADMA), aminoguanidine (AG), and methylguanidine (MG). Results-L-NMMA (10Ϫ6 to 3ϫ10 Ϫ4 mol/L) and ADMA (10 Ϫ6 to 3ϫ10 Ϫ4 mol/L) caused concentration-and endothelium-dependent contractions (median effective concentrations [EC 50 ]ϭ1.1ϫ10Ϫ5 and 1.6ϫ10 Ϫ5 mol/L, respectively; E max ϭ35.5Ϯ7.9% and 43.9Ϯ5.9% of the response to 100 mmol/L KCl). AG (10 Ϫ5 to 3ϫ10 Ϫ3 mol/L) and MG (10 Ϫ5 to 3ϫ10 Ϫ3 mol/L) produced endothelium-independent contractions (E max ϭ44.3Ϯ8.8% and 45.7Ϯ5.8% of the response to 100 mmol/L KCl, respectively). L-Arginine (10 Ϫ3 mol/L) prevented the contractions by L-NMMA and ADMA but did not change contractions induced by AG and MG. L-NMMA and ADMA inhibited endothelium-dependent relaxation induced by acetylcholine in a concentration-dependent manner; AG and MG were without effect. Conclusions-The results suggest that the contractions induced by L-NMMA and ADMA are due to inhibition of endothelial NO synthase activity, whereas AG and MG do not affect the synthesis of NO. An increase in the plasma concentration of L-NMMA and ADMA associated with uremia is likely to represent a diminished release or effect of NO, and consequently, an increased cerebrovascular tone in uremic patients is highly conceivable. (Stroke. 1999;30:2206-2211.)Key Words: cerebral arteries Ⅲ endothelium Ⅲ nitric oxide N itric oxide (NO) synthesized from L-arginine accounts for the powerful vasodilator effects of endotheliumderived relaxing factor 1,2 and consequently plays a decisive role in determining vasomotor tone in several vascular beds, including the cerebral circulation. [3][4][5][6][7] The synthesis of NO can be specifically and competitively antagonized by arginine analogues such as N G -monomethyl-L-arginine (L-NMMA). 4,8 Histochemical studies have demonstrated the presence of NO synthase immunoreactivity in the adventitia of rat and human cerebral arteries. 9,10 Consistent with these observations, several reports have shown that NO from perivascular nerve endings mediates dilatation in the cerebral arteries through a nonadrenergic, noncholinergic mechanism, 11-13 whereas NO of endothelial origin can modulate contractile responses of isolated human cerebral arteries to sympathetic stimulation. 6 Uremia is an established risk factor for cardiovascular disease and cerebrovascular acciden...