Aging enhances contraction to thromboxane A2 in aorta from female senescence mice

The time-course for aging-associated effects on vascular reactivity to U46619, a stable analogue of thromboxane A2 (TXA2), was studied in aorta from female senescence-accelerated mice-prone (SAMP8), a murine model of accelerated senescence. SAMP8 and senescence-accelerated mice-resistant (SAMR1) were divided into three groups: 3-, 6- and 10-month-old. Contractile curves to U46619 (10−9 to 10−6 M) were performed in aortic rings in the absence or in the presence of nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10−4 M) and/or cyclooxygenase (COX) inhibitor indomethacin (10−5 M). Protein and gene expression for COX-1 and COX-2 were determined by immunofluorescence and real-time PCR, respectively. Maximal contraction to U46619 was markedly higher in SAMP8 at all ages. In SAMR1, increases were seen at 10 months, while SAMP8 displays augmented contraction at 6 months, which was further increased at 10 months. L-NAME enhanced U46619 contractions in both 6-month-old groups, although the increase was higher on vessels from SAMR1 at this age. Indomethacin equally increased U46619 contractions in both 3-month-old groups, suggesting the production of vasodilator prostaglandin in young animals. In contrast, at 6 and 10 months indomethacin decreased U46619 contractions in both groups, indicating an aging-associated swap to a release of contractile prostanoids in aorta. In conclusion, aging enhances contractile responses to TXA2 in aorta from female mice by a mechanism involving a decrease of NO production and increased action of contractile prostanoids. This process occurs earlier in SAMP8 mice, establishing these mice as good model to study cardiovascular aging in a convenient and standard time-course

Contractile responses of human thyroid arteries to vasopressin

Aims: In the present study we investigated the intervention of nitric oxide and prostacyclin in the responses to vasopressin of isolated thyroid arteries obtained from multi-organ donors. Main methods: Paired artery rings from glandular branches of the superior thyroid artery, one normal and the other deendothelised, were mounted in organ baths for isometric recording of tension. Concentration-response curves to vasopressin were determined in the absence and in the presence of either the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (10−8 M), the nitric oxide synthase inhibitor NG-monomethyl-Larginine (L-NMMA, 10−4 M), or the inhibitor of prostaglandins indomethacin (10−6 M). Key findings: In artery rings under resting tension, vasopressin produced concentration-dependent, endotheliumindependent contractions. The vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (10−8 M) displaced the control curve to vasopressin 19-fold to the right in a parallelmanner. The contractile response to vasopressinwas unaffected by L-NMMA or by indomethacin. Significance: Vasopressin causes constriction of human thyroid arteries by stimulation of V1 vasopressin receptors located on smooth muscle cells. These effects are not linked to the presence of an intact endothelium or to the release of nitric oxide or prostaglandins. The constriction of thyroid arteries may be particularly relevant in certain pathophysiological circumstances in which vasopressin is released in amounts that could interfere with the blood supply to the thyroid gland

Effects of asymmetric dimethylarginine on renal arteries in portal hypertension and cirrhosis

AIM. To evaluate the effects of asymmetric dimethylarginine (ADMA) in renal arteries from portal hypertensive and cirrhotic rats. METHODS. Rat renal arteries from Sham (n = 15), pre-hepatic portal hypertension (PPVL; n = 15) and bile duct ligation and excision-induced cirrhosis (BDL; n = 15) were precontracted with norepinephrine, and additional contractions were induced with ADMA (10-6-10-3 mol/L), an endogenous inhibitor of nitric oxide (NO) synthase. Concentration-response curves to acetylcholine (1 × 10-9-3 × 10-6 mol/L) were determined in precontracted renal artery segments with norepinephrine in the absence and in the presence of ADMA. Kidneys were collected to determine the protein expression and activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes ADMA. RESULTS. In renal arteries precontracted with norepinephrine, ADMA caused endothelium-dependent contractions. The pD2 values to ADMA were similar in the Sham and PPVL groups (4.20 ± 0.08 and 4.11 ± 0.09, P > 0.05, respectively), but were lower than those of the BDL group (4.79 ± 0.16, P < 0.05). Acetylcholine-induced endothelium-dependent relaxation that did not differ, in terms of pD2 and maximal relaxation, among the 3 groups studied. Treatment with ADMA (3 × 10-4 mol/L) inhibited acetylcholine-induced relaxation in the 3 groups, but the inhibition was higher (P < 0.05) in the BDL group compared with that for the Sham and PPVL groups. The mRNA and protein expression of DDAH-1 were similar in kidneys from the three groups. Conversely, DDAH-2 expression was increased (P < 0.05) in PPVL and further enhanced (P < 0.05) in the BDL group. However, renal DDAH activity was significantly decreased in the BDL group. CONCLUSION. Cirrhosis increased the inhibitory effect of ADMA on basal- and induced-release of NO in renal arteries, and decreased DDAH activity in the kidney

Accumulation of symetric dimethylarginine in hepatorenal syndrome.

In patients with cirrhosis, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and possibly symmetric dimethylarginine (SDMA) have been linked to the severity of the disease. We investigated whether plasma levels of dimethylarginines and NO are elevated in patients with hepatorenal syndrome (HRS), compared with patients with cirrhosis without renal failure (no- HRS). Plasma levels of NO, ADMA, SDMA, and L-arginine were measured in 11 patients with HRS, seven patients with no-HRS, and six healthy volunteers. SDMA concentration in HRS was higher than in no-HRS and healthy subjects (1.47 6 0.25 vs. 0.38 6 0.06 and 0.29 6 0.04 lM, respectively; P , 0.05). ADMA and NOx concentrations were higher in HRS and no-HRS patients than in healthy subjects (ADMA, 1.20 6 0.26, 1.11 6 0.1, and 0.53 6 0.06 lM, respectively; P , 0.05; NOx, 94 6 9.1, 95.5 6 9.54, and 37.67 6 4.62 lM, respectively; P , 0.05). In patients with HRS there was a positive correlation between serum creatinine and plasma SDMA (r2¼0.765, P , 0.001) but not between serum creatinine and ADMA or NOx. The results suggest that renal dysfunction is a main determinant of elevated SDMA concentration in HRS. Accumulation of ADMA as a result of impaired hepatic removal may be the causative factor initiating renal vasoconstriction and SDMA retention in the kidney. Exp Biol Med 231:7075, 200

Nitric oxide mediates abnormal responsiveness of thyroid arteries in methimazole-treated patients

Objective: We studied the intervention of nitric oxide (NO), prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor (EDHF) in mediating responses to acetylcholine in thyroid arteries from euthyroid (E) and methimazole-treated (MT) patients. Design and methods: Branches of the superior thyroid artery were obtained from 19 E patients and 17 MT patients (euthyroid at the time of surgery) undergoing total thyroidectomy or hemithyroidectomy. Artery rings were suspended in organ baths for isometric recording of tension. Results and conclusions: Acetylcholine caused endothelium-dependent relaxation of greater magnitude in arteries from MT patients (pD2 7.68±0.19 in E and 8.17±0.26 in MT, P<0.05). The relaxation was unaffected by indomethacin and partially reduced by the NO synthase inhibitor L-NMMA. This reduction was higher in arteries from MT patients (50±6 %) as compared to E patients (36±6 %) (P<0.05). Inhibition of K+ channels using apamin combined with charybdotoxin or high K+ solution abolished the relaxation resistant to L-NMMA and indomethacin. The maximal contractions to noradrenaline (in percentage of the response to 100 mM KCl) were lower in MT than in E patients (57±10 and 96±8, respectively, P<0.05). The hyporesponsiveness to noradrenaline in arteries from MT patients was corrected by L-NMMA. The results indicate: (1) thyroid arteries from MT patients show increased relaxation to acethylcholine and decreased contraction to noradrenaline due to overproduction of NO; (2) EDHF plays a prominent role in acetylcholine-induced relaxation through activation of Ca2+-activated K+ channels; (3) the abnormal endothelium-dependent responses in arteries from MT patients are not corrected by medical treatment

Modulation of adrenergic responses of human vas deferens by K+ channel inhibitors

The results suggest that charybdotoxin-sensitive, but iberiotoxin-insensitive, K+ channels are activated by stimulation with norepinephrine and electrical field stimulation to counteract the adrenergic-induced contractions of human vas deferens. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca2+ entry through L-type voltage-dependent Ca2+ channels