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  • Title: Differential inhibition of 5-hydroxytryptamine (5-HT) mediated contraction of rat thoracic aortae by phentolamine and tolazoline: correlation with inhibition of 5-HT binding and calcium ion.
    Author: Curro FA, Greenberg S.
    Journal: Methods Find Exp Clin Pharmacol; 1983; 5(2):107-20. PubMed ID: 6876942.
    Abstract:
    The contribution of alpha receptor stimulation to the contractile responses of vascular smooth muscle to 5-HT was evaluated, in vitro utilizing helical strips of rat thoracic aortae (RTA). The contractile responses of RTA to 5-HT and norepinephrine (NE) were inhibited by the alpha receptor blocking agent phentolamine. The inhibition persisted in RTA obtained from rats treated with reserpine (1.5 mg/kg/day for 6 days). Analysis of the interaction of phentolamine with 5-HT and NE demonstrated that: 1) phentolamine is a competitive inhibitor of the responses to 5-HT; and 2) the pA2 values for the interaction of phentolamine with 5-HT and NE differed. When the concentration of calcium ion in the physiologic saline solution (PSS) was increased from 1.6 mM to 2.5 mM, phentolamine was approximately 100 times more potent an inhibitor of the response to NE than 5-HT. Phentolamine decreased the binding of 14C-5-HT to rat thoracic aortae in control PSS, but not when the calcium concentration was increased to 2.5 mM. Tolazoline inhibited the contractile responses of RTA to NE but not 5-HT. The data support the conclusion that the contractile responses of RTA to 5-HT are mediated by receptors similar to the alpha receptor. The ability of phentolamine to inhibit 5-HT induced contraction may be dependent on the ability of phentolamine to bind to anionic sites of the 5-HT receptor. The inhibitory effect of calcium ion may result from its ability to combine with, and neutralize, these negatively charged moieties on the smooth muscle membrane. The lack of effect of tolazoline may result from the absence of the third ring structure present in the phentolamine molecule, and therefore an inability to bind to these postulated anionic sites. Alternatively, the absence of an imino-nitrogen in the chain separating the phenyl and imidazole groups of tolazoline may prevent tolazoline from interacting with the 5-HT receptor. The different pA2 values for phentolamine mediated inhibition of the responses to 5-HT and NE, and the ability of NE to poorly displace 5-HT from the RTA, despite blockade of alpha receptors with tolazoline, support the possibility that the 5-HT receptor of RTA differs from the alpha receptor and that phentolamine has affinity for both 5-HT and adrenergic receptors.
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