Beta-adrenoceptor blockade and sympathetic neurotransmission in the pithed rat

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Abstract
The effects of the .beta.1-adrenoceptor blocking drug atenolol and the .beta.2-adrenoceptor blocking drug ICI 118551 (ICI, Melbourne, Australia) on noradrenaline release and blood pressure were investigated using the pithed rat, which was subjected to continuous electrical stimulation of the spinal sympathetic outflow (pulses at 3 Hz). This stimulation increased blood pressure but not heart rate. The noradrenaline release rate was calculated by infusing [3H] noradrenaline and measuring the steady-state concentrations of both endogenous and infused noradrenaline. Atenolol (0.2 mg/kg bolus plus 0.1 mg/kg per h, intra-arterially) had to effect on the noradrenalin release rate or heart rate, but significantly decreased blood pressure. On the other hand, ICI 118551 (0.2 mg/kg bolus plus 0.1 mg/kg per h, intra-arterially) had no significant effect on blood pressure or heart rate, but did inhibit the noradrenaline release rate. The sympathoinhibitory effect of ICI 118551 was not observed in animals which had been adrenal medullectomized, suggesting that its effect on noradrenaline release was due to blockade of activation of facilitatory prejunctional .beta.2-adrenoceptors by adrenaline. The reduced noradrenaline release in the presence of ICI 118551 was not accompanied by a reduction in blood pressure. This may be because ICI 118551 also blocked vasodilatory .beta.2-adrenoceptors on vascular smooth muscle. Indeed, in unstimulated pithed rats, infusions of adrenaline which were non-pressor were found to be pressor after ICI 118551 was administered. Together, these results suggest that .beta.2-adrenoceptor blockade may be ineffective in reducing blood pressure, since the effect of reduced noradrenaline release through blockade of prejunctional .beta.2-adrenoceptors may be counteracted by reduced vasodilation through postjunctional .beta.2-adrenoceptors.