Multiple sites for the cardiovascular actions of fentanyl in rats

We studied the cardiovascular effects of intravenously administered fentanyl in normotensive rats anesthetized with pentobarbital and artificially ventilated. Fentanyl induced an immediate and short-lasting fall in blood pressure and heart rate by an action on opiate receptors localized at vagal nerve endings. Bilateral vagotomy suppressed these effects. The bradycardia, suppressed by bilateral vagotomy and reduced by previous administration of atropine, seemed to be due to a vagovagal reflex. Inhibition of the sympathetic outflow may also occur, because in pithed rats fentanyl failed to lower blood pressure. This masks a direct central stimulation of sympathetic outflow, because in bilaterally vagotomized rats fentanyl induced an alpha-adrenoceptor-blocking drug-sensitive hypertension which was insensitive to adrenalectomy. In addition, stimulation of cardiac opiate receptors by high doses of fentanyl lead to bradycardia in pithed rats. We conclude that in the rat, fentanyl administered intravenously can act at three different levels on cardiovascular regulation: the vagal nerve endings, the brain, and the heart.