Demonstration of Alpha and Beta Adrenergic Receptors in Canine Cerebral Vasculature

Abstract• Our earlier studies revealed a weak alpha-adrenergic and beta-adrenergic activity of the cerebral vessels of the isolated perfused dog brain. The present investigations were undertaken to determine whether vascular adjustments occur in the cerebral circulation during longer periods of catecholamine infusions. The experiments were performed on six isolated canine brains cross perfused from donor dogs. Norepinephrine (2 /*g per minute), epinephrine (2 fig per minute), and isoprenaline (0.2 ng per minute) were applied intra-arterially (i.a.) for a period of ten minutes. Total venous outflow, perfusion pressure in the circle of Willis, and venous O 2 saturation were monitored continuously. Cerebral vascular resistance (CVR) and cerebral O 2 consumption (CMRO 2 ) were calculated. Based on the pressure-flow relationship tested in each brain, the indirect effects of catecholamines on CVR caused by autoregulatory influences were calculated and eliminated. During norepinephrine and epinephrine infusions cerebral blood flow (CBF) was found to be decreased by 10.2 ± 6.0% and 4.1 ± 3.3%, respectively, whereas during isoprenaline infusion CBF increased by 9.3 ± 3.6% (mean values ± SD). The maximal changes of CBF were reached in the first or second minute of catecholamine infusion and persisted up to the end of infusion (P > 0.05). After elimination of the indirect effects of catecholamines on CVR, the direct effects on CVR were reduced to about 50% of the original values and remained constant at the level reached during the whole period of infusion. CMRO 2 was not changed (P > 0.05) during infusion of the different catecholamines. Based on these investigations it is assumed that no pronounced vascular adjustments occur in the cerebral circulation during catecholamine infusions.

Section: Additional Abstract Epinephrine Cerebral Metabolism Cerebrasupporting

confidence: 86%

Effects of Catecholamine Infusions on Cerebral Blood Flow and Oxygen Consumption of the Isolated Perfused Dog Brain

Zimmer

Lang

Oberdörster

1974

“…These results are consistent with experiments in the isolated circulation of the dog 4 and in isolated cerebral arteries of the cat. 17 In summary, with this experimental technique we have demonstrated that norepinephrine and epinephrine produce marked cerebral vasoconstriction by their direct action and isoproterenol produces vasodilation, also by a direct action.…”

Section: Discussionsupporting

confidence: 91%

“…4 The decrease in cerebral blood flow induced by epinephrine and norepinephrine was blocked to a significant extent after local administration of phenoxybenzamine, suggesting the presence of alpha adrenergic receptors in the brain vasculature, which is in agreement with experiments carried out on the isolated cerebral circulation of the dog. 4 The effects of epinephrine and norepinephrine, however, were not reversed after administration of phenoxybenzamine, probably because of the relatively small dose of blocking agent used. 13 Although agreement exists that intravenously administered isoproterenol increases cerebral blood flow, the mechanism responsible remains obscure.…”

Section: Discussionsupporting

confidence: 86%

Evidence for the Direct Effect of Adrenergic Drugs on the Cerebral Vascular Bed of the Unanesthetized Goat

Lluch

Reimann

Glick

1973

Evidence for the Direct Effect of Adrenergic Drugs on the Cerebral Vascular Bed of the Unanesthetized Goat• Despite considerable research, the question of whether adrenergic drugs exert direct effects on the cerebral circulation has remained unresolved. With the development of a method for monitoring continuously the entire blood flow to one hemisphere in the unanesthetized goat, we have been able to study this problem directly. The effects of epinephrine, norepinephrine, and isoproterenol administered by close intra-arterial injection were investigated in 15 goats in which an electromagnetic flowmeter had been implanted previously on the internal maxillary artery, which, in this animal, provides the sole blood supply to a hemisphere. Both epinephrine and norepinephrine (0.1 to 5.0 fig) produced dose-dependent reductions in cerebral blood flow, a decrease of 55 ± 3% (SEM) occurring with the highest dose. Alpha receptor blockade of the ipsilateral hemisphere with phenoxybenzamine totally or partially abolished this cerebral vasoconstriction. Isoproterenol (0.01 to 1.0 fig) produced dose-dependent increases in cerebral blood flow, an increment of 75 ± 6% occurring with the highest dose. Beta blockade with propranolol totally or partially abolished the cerebral vasodilation induced by isoproterenol. Thus, epinephrine, norepinephrine, and isoproterenol exert powerful direct effects on the cerebral circulation of the unanesthetized goat, and these effects appear to be mediated by alpha and beta receptors.Additional Key Words cerebral blood flow epinephrine cerebral vascular resistance alpha adrenergic receptors norepinephrine beta adrenergic receptors isoproterenol 5-hydroxytryptamine papaverine phenoxybenzamine propranolol electromagnetic flowmeter• The cerebral circulation, encased as it is within the bony cranium and generally furnished by a dual blood supply from the carotid and vertebral arterial systems, has been slow to reveal the regulatory mechanisms that control it. Thus, previous reports concerning the effects of vasoactive substances on cerebral blood flow have been inconclusive and conflicting. 1 " 0 Recent reviews point out the difficulties of differentiating between the direct effects of drugs on cerebral vessels and the secondary effects resulting from changes in heart rate, systemic arterial pressure, and cardiac output.7 " 10 Definitive delineation of the pharmacological mechanisms that control cerebral blood flow has not been possible because of the lack of an experimental model that permits the effects of various interventions to be assessed on a Supported in part by Grant HE-06375 from the National Heart Institute and by a General Research Support Grant. 50beat-to-beat basis in an unanesthetized animal in which the effects of extracerebral blood flow have been eliminated. We have recently developed in our laboratory an experimental preparation, utilizing the goat, that obviates these difficulties.11 In this animal, each internal maxillary artery, a branch of the external carotid artery,...

“…20 Edvinsson and Owman" have demonstrated blockade of isoproterenol-induced constrictions of cerebral arteries in vitro by propranolol and cited this as further evidence for the presence of beta-receptors. In contrast, Rosenblum 22 and Kuschinsky and Wahl 28 could not show significant alterations in pial arterial diameter by either isoproterenol or propranolol.…”

mentioning

confidence: 99%

Direct evidence for absence of beta-adrenergic receptors in rat cerebral vessels histochemical study with a fluorescent beta-blocker.

Melamed¹,

Atlas²,

Lahav³

1977

SUMMARY A fluorescent marker for beta-adrenergic receptor sites, 9-amino-acridin propranolol (9-AAP), was administered intravenously to rats. In contrast to other tissues which are known to contain beta-adrenergic receptors, 9-AAP fluorescence was not observed in the walls of the pial as well as parenchymal cerebral vessels. These negative findings strongly suggest that in the rat, betaadrenergic receptors are not present in the cerebral vasculature. The role of the alpha-adrenergic receptors needs more study.CONSIDERABLE EVIDENCE has demonstrated that the mammalian cerebral arteries and arterioles are innervated by an extensive network of norepinephrine-containing nerve terminals. 17 An abundant literature has dealt with the long and yet unsolved dispute concerning the role of the sympathetic nervous system in the control and regulation of the cerebral circulation.8 " 10 However, little information was available about the type of the post-synaptic receptors which mediate the effects of norepinephrine in the cerebral arterial system.The methods which have been used for the identification of alpha-and beta-adrenergic receptors in various tissues are largely indirect. These are based on the evaluation of the potency order of different catecholamines in producing certain pharmaco-physiological effects and on the ability of specific blocking agents to antagonize these responses. Similar approaches have been recently employed in the search for cerebrovascular beta-adrenergic receptors.Several studies in humans and in experimental animals have shown that the potent beta-adrenergic antagonist propranolol reduces cerebral blood flow (CBF). "16 These findings were interpreted as evidence for the presence of beta-receptors in the cerebral vessels. On the other hand, other authors reported that no significant CBF changes had occurred either following administration of propranolol,"• " or of the classical beta-receptor agonist isoproterenol." Propranolol can reduce the cerebral metabolic rate for both oxygen 1 *-l5> " and glucose. 1 " It may, therefore, be suggested that propranolol decreases CBF not by a primary direct effect on cerebrovascular beta-receptors but secondarily, through reduction of cerebral metabolism. In addition, propranolol may induce bradycardia and arterial hypotension through a direct effect on the heart or by a specific action on cerebral cardiovascular centers.18 -" These effects may further contribute to the observed reduction in CBF after administration of propranolol.A study of canine cerebral vessels suggested betaadrenergic receptor mediated changes in cerebral vascular