Cell-penetrating peptides (CPP) are a family of peptides able to penetrate the cell membrane. This group of compounds has attracted consideration as potential therapeutic tools for the delivery of various substances into cells. Here, we investigated possible interactions between several CPP synthesized in our laboratory and the vascular action of phenylephrine. We used isolated rat tail artery and examined the influence of pretreatment by seven different CPP on the concentration-response curve induced by the α1 receptor agonist phenylephrine. Peptides were synthesized by solid-phase peptide synthesis (SPPS) using the 9-fluorenylmethoxycarbonyl (Fmoc) method. Among the seven different polypeptides, i.e., TP10 (transportan-10), [Lys(AAc)13]TP, [Lys(CAc)13]TP, [Lys(GAc)13]TP, [Lys(TAc)13]TP, [Lys(UAc)13]TP and [Lys(Ac)13]TP, only TP10 and [Lys(AAc)13]TP, both at a concentration of 1 μM (the lowest concentration inducing a significant change in the contraction of isolated rat stomach in our pilot study), rendered rat tail artery more sensitive to phenylephrine; the relative potency increased significantly. Conversely, [Lys(Ac)13]TP strongly decreased the efficacy of phenylephrine.
Extensive research has shown that manipulations that augment activity in the renin-angiotensin system can reduce alcohol intake. Inhibition of aminopeptidase B and M can prolong the action of angiotensin (ANG) II and ANG III by preventing their degradation. This study assessed the ability of bestatin, an aminopeptidase B and M inhibitor, to decrease alcohol intake. Bestatin produced a dose-dependent reduction in alcohol intake without altering water intake. The angiotensin antagonist Sar1Thr3-ANG II, however, did not attenuate the effect of bestatin, suggesting that the reduction in alcohol intake was mediated by a system other than the renin-angiotensin system. Bestatin (Ubenimex) is used extensively in Japan as an anticancer agent. It has a low toxicity and is readily absorbed after oral administration. Although further research is needed to uncover the mechanism of its effect, the potential of this drug as an adjunct for the treatment of alcohol abuse should be evaluated.
The mechanism of relaxation in the rat tail artery induced by the adenosine A(1) receptor-selective agonist N(6)-cyclohexyladenosine (CHA, 10 nM-300 microM) and the adenosine A1/A(2a) receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA, 10 nM-300 microM) has been characterized. To do this, we used alpha(1)-receptor agonist phenylephrine to evoke contraction (10 microM), and inhibitors of nitric oxide synthase (L-NAME, 10 microM), ATP-sensitive K(+) channels (glibenclamide, 10 microM) and prostaglandin synthesis (indomethacin, 10 microM). CHA and NECA induced relaxation of rat-tail artery by 80% and 70% in a concentration-dependent manner, respectively. The relaxation effect of NECA was completely abolished in the presence of L-NAME, while glibenclamide and indomethacin prevented CHA-induced relaxation of the rat tail artery by approximately 25% and 40%, respectively. Our results indicate that nonspecific effects such nitric oxide and prostaglandins release or the activation of potassium channels significantly contributed to the effects of CHA and NECA.
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