Paradoxical Effects of Isothiocyanate Analog of Tolazoline on Rat Aorta and Human Platelets

Abstract

The isothiocyanate analog (IBI) of tolazoline produced contraction of the rat aortic strip, with an ED₅₀ value of 1.63 × 10^–5 M. The maximum contraction of the analog was nearly equal to that of tolazoline or phenylephrine. At 27 °C the tissue reactivity of phenylephrine and IBI was similar. When compared at equiactive concentrations, the total duration of contraction of IBI was three times longer than that of tolazoline. Thus, the longer duration of action of IBI may be attributed to the S=C=N group substitution of the molecule. IBI at 10^-6 M shifted the dose-response curve of phenylephrine to the right with reduction in maxima. Phentolamine and other α₁or α₂ adrenoceptor blockers failed to block the responses of IBI in aorta, whereas verapamil or nifedipine blocked the response significantly. It appears that IBI is acting through calcium-channel-sensitive or calcium-receptor-related mechanism(s). In aspirin-treated platelets from human plasma, a distinct phase of aggregation induced by epinephrine can be blocked by IBI with KB of 2 × 10^–5 M. This indicates a small but selective α₂ related action of IBI. The aggregation induced by ADP or second component of aggregation induced by epinephrine were also blocked by IBI at concentrations comparable to that of the 012-adrenoceptor-mediated response. This indicates a lack of specificity of IBI in differentiating various phases of aggregation. Therefore, as compared to tolazoline, IBI presents an interesting paradox in its interaction with various receptors or mechanisms in the vascular tissue and platelets.

Irreversible agonist and antagonist properties of isothiocyanatobenzyl imidazoline in albino rabbit iris muscles

“…Qualitatively the characteristics of the sphincter responses to IBI were similar to those on rat aorta (Venkataraman et al 1989). Repeated administration of the agonist caused desensitization.…”

“…It is reported that the contractile response of the rabbit iris sphincter to K ÷ and acetylcholine were inhibited by papaverine, which is known to prevent both Ca ++ influx and Ca ++ release from intracellular stores (Takayanagi et al 1983). Although, the response to IBI does not depend on the external source of Ca ++ in the rat aorta (Venkataraman et al 1989), the response to IBI in the rabbit iris sphincter was abolished by Ca ++ removal from the organ bath, suggesting that the contractile response to IBI was due to Ca ++ influx.…”

“…Although chemically different types of irreversible blockers of neurotransmitter-receptors are recognized for a long time (Nickerson 1949;Patil et al 1970;Lippert and Belleau 1973;Brasili et al 1981) reports on irreversible agonists are few in number (Leclerc et al 1980;Decker et al 1983;Venkataraman et al 1989;Patti et al 1991).…”

“…Phentolamine-resistant, long lasting vascular responses to isothiocyanatobenzyl imidazoline (IBI), which can be considered an analog of tolazoline, has been described recently (Venkataraman et al 1989). But due to the high liposolubility of the imidazoline analogue and its resistance to metabolic degradation, the nature of the irreversible pharmacologic action was in dispute.…”

Depolarization of membrane potential and the smooth muscle contraction by isothiocyanatobenzyl imidazoline in guinea-pig stomach circular muscle

“…The imidazoline class of drugs interacts with α-adrenoceptors as well as with other non-α-adrenoceptors (Sanders et al 1975;Venkataraman et al 1989;Reis et al 1995). The list for the latter types of receptors includes specific imidazoline binding sites, monoamine oxidase, ATP-sensitive potassium channels and calcium channels.…”