Re-assessment of the Pharmacological Characteristics of the Response of the Porcine Isolated Splenic Artery to Noradrenaline

Hamza Denfria, Vincent Wilson, Ravi Mahajan. University of Nottingham, Nottingham, UK

Introduction: Pharmacological examination of contractions of conduit arteries to noradrenaline is generally attributed to activation of α1-adrenoceptors, based on the rank order of potency of antagonists and their ability to causes a parallel rightward displacement of the concentration response curve. In the case of the porcine isolated splenic artery, despite evidence for the presence of both α1- and α2-adrenoceptors, responses to noradrenaline appears to involve only the former subtype (Wright et al., 1995), even though pharmacological manipulation can uncover responses via α2-adrenoceptors when activated by briminodine (Roberts et al., 1999). We have re-examined the response of the porcine splenic artery to noradrenaline and the effect of a non-selective α-adrenoceptor antagonist (phentolamine), a selective α1-adrenoceptor antagonist (prazosin) and a selective α2-adrenoceptor antagonist (RX-811059) using a 1000-fold concentration range.

Methods: Ring segments of porcine isolated splenic artery were prepared for isometric tension recording in isolated organ baths containing Krebs-Henseleit solution with 10 µM cocaine, 30 µM corticosterone and 1 µM propranolol, gassed with 95%O2/5% CO2, and maintained at 37°C. Segments were exposed to cumulative concentrations of noradrenaline in presence of different concentrations of either prazosin (0.001 to 1 µM), phentolamine (0.03 to 30µM) or RX-811059 (0.001 to 1µM). In addition, the effect of phentolamine against phenylephrine-induced contractions was also examined and PA2 or pKB values determined.

Results: Phentolamine and prazosin caused a rightward, concentration-dependent, displacement of responses to noradrenaline and phenylephrine in the splenic artery, with no change in the maximum response. However, Table 1 shows that the slope of the Schild plot for both antagonists against noradrenaline was significantly less than unity, while phentolamine behaved as a competitive antagonist against phenylephrine contractions, RX-811059 (1nM to 0.1µM) did not affect noradrenaline-induced contractions, but the highest concentration caused a 10-fold rightward shift (Table 1).

Table 1. Schild analysis of competitive antagonist against contractions in the splenic artery

Discussion & Conclusion. The relative potency of the antagonists is consistent with a principal role for α1-adrenoceptors in responses to noradrenaline (Wright et al., 1995). However, the non-competitive antagonism (Slope < 1) produced by a 300-fold concentration range for prazosin against noradrenaline also suggests a minor role for α2-adrenoceptor; possibility involving simulataneous activition of α1-adrenoceptors. The non-selective α-adrenoceptor antagonist phentolamine behaved as a competitive antagonist against phenylephrine contractions but not against responses to noradrenaline. The latter finding implicates a factor(s) other than α-adrenoceptor subtype in the agonist/antagonist interaction for phentolamine and noradrenaline. and raises the question of examining the interaction between phentolamine and the other endogenous catecholamine, adrenaline.

Roberts RE, Kendall DA, Wilson VG (1999). Brit. J. Pharmacol 128 1705-1712

Wright IK, Blaylock NA, Kendall DA, Wilson VG (1995). Br. J. Pharmacol. 114, 678-688.