BQ 788 sodium salt

Experiments have been conducted to investigate the actions of endothelins on the guinea-pig prostate gland. Saturation experiments with [125I]-endothelin-1 (2-800 pM) in guinea-pig prostatic homogenates indicated the presence of high affinity binding sites with an equilibrium dissociation constant (KD) of 230+/-50 pM, a maximum number of binding sites (Bmax) of 52+/-16 fmol mg(-1) protein or 269+/-61 fmol g(-1) tissue and a Hill coefficient (nH) of 1.01+/-0.03 (n = 3). Competition experiments revealed that binding of [125I]-endothelin-1 (20 pM) was inhibited with the following order of potency: endothelin-1 >>BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl-Leu-D-Trp[1-+ ++CO2CH3-D-Nle-ONa])> BQ-123 (cyclo-D-Asp-L-Pro-D-Val-Leu-D-Trp) > or = sarafotoxin S6c. At concentrations with negligible influence on smooth muscle tone, endothelin-1, endothelin-2 and sarafotoxin S6b (1 nM-0.1 microM) produced concentration-dependent potentiation of the contractions evoked by electrical field stimulation with trains of 20 pulses at 10 Hz every 50 s, 0.5 ms pulse width and a dial setting of 60 V. In contrast, the endothelin ET(B) receptor-preferring agonist endothelin-3 (1 nM- 1 microM) was much less potent, and the endothelin ET(B) receptor-selective agonists sarafotoxin S6c and BQ-3020 (Ac-[Ala11,15]-endothelin-1 (6-21)), up to 1 microM, were without effect.

Exercise-induced adaptations of the modulating mechanisms that influence the angiotensin (Ang II) responses assume different features depending on the venous bed. In femoral veins, exercise mobilizes vasodilator prostanoids to cooperate with NO in order to maintain reduced Ang II responses. On the other hand, exercise's influence on the Ang II responses in veins that drain blood from the mesenteric region has been poorly described. Therefore, the present study aimed to identify the effects of a single bout of exercise, as well as exercise training, on the Ang II responses in mesenteric veins. The present study also aimed to investigate the involvement of prostanoids, NO and ET-1 in eventual exercise-induced modifications in these veins. To this end, mesenteric veins taken from resting-sedentary, exercised-sedentary, resting-trained and exercised-trained animals were studied in organ baths. In addition, the mRNA expression of prepro-endothelin-1 (ppET-1), as well as that of the ET;A; and ET;B; receptors, were quantified by real-time PCR in these veins. The results show that, either in absence or in presence of L-NAME, the Ang II responses were not different between groups. In the presence of indomethacin, higher Ang II responses were observed in the resting-trained animals than in the resting-sedentary animals.

We characterized vascular reactivity to endothelin-1 (ET-1) in mesenteric vessels from DOCA-salt hypertensive and SHAM control mice and assessed the effect that endothelial-derived vasodilators have on ET-1-induced vasoconstriction. Changes in the diameter of unpressurized small mesenteric arteries and veins (100- to 300-microm outside diameter) were measured in vitro using computer-assisted video microscopy. Veins were more sensitive than arteries to the contractile effects of ET-1. There was a decrease in arterial maximal responses (E(max)) compared to veins, this effect was larger in DOCA-salt arteries. The selective ET(B) receptor agonist, sarafotoxin 6c (S6c), contracted DOCA-salt and SHAM veins but did not contract arteries. The ET(B) receptor antagonist, BQ-788 (100 nM), but not the ET(A) receptor antagonist, BQ-610 (100 nM), blocked S6c responses. BQ-610 partially inhibited responses to ET-1 in mesenteric veins from DOCA-salt and SHAM mice while BQ-788 did not affect responses to ET-1. Co-administration of both antagonists inhibited responses to ET-1 to a greater extent than BQ-610 alone suggesting a possible functional interaction between ET(A) and ET(B) receptors. Responses to ET-1 in mesenteric arteries were completely inhibited by BQ-610 while BQ-788 did not affect arterial responses.