Mm. Zhao et Kh. Muntz, DIFFERENTIAL DOWN-REGULATION OF BETA-2-ADRENERGIC RECEPTORS IN TISSUECOMPARTMENTS OF RAT-HEART IS NOT ALTERED BY SYMPATHETIC DENERVATION, Circulation research, 73(5), 1993, pp. 943-951
With agonist stimulation, cardiac beta2-adrenergic receptors (beta2ARs
) are downregulated to a much greater extent than are beta1ARs. It has
been hypothesized that this effect is due to sympathetic innervation
inhibiting the downregulation of beta1ARs. To test this hypothesis, th
e technique of coverslip autoradiography was used to localize and quan
tify beta1AR and beta2AR subtypes in tissue compartments of the heart
in rats subjected to sympathetic denervation by two intravenous inject
ions of 6-hydroxydopamine (50 mg/kg per dose). After denervation, the
rats were infused with L-isoproterenol (400 mug.kg-1.h-1 for 7 days) o
r vehicle (0.0001N HCl) by implantation of osmotic minipumps. Sections
were incubated with 70 pmol/L of the betaAR antagonist [I-125]iodocya
nopindolol (ICYP) alone or in the presence of 5 mumol/L DL-propranolol
or 5x10(-7) mol/L CGP 20712A (a beta1AR antagonist). Binding of ICYP
to sections of rat hearts was saturable and stereoselective and was di
splaced by betaAR agonists with the rank order of potency expected for
betaARs. There was an 89% reduction in catecholamine concentration in
rat ventricles after 1 week of 6-hydroxydopamine treatment, before im
plantation of the minipumps. Chronic infusion of isoproterenol induced
significant downregulation (63% to 74%) of beta2ARs in atrial and ven
tricular myocytes, coronary arterioles, and connective tissue but no c
hange in beta1ARs in these regions in rats with intact sympathetic inn
ervation. Similar changes were seen in denervated animals. There was a
marked reduction in beta2ARs but small insignificant decreases in bet
a1ARs, despite the fact that in the denervated animals there was upreg
ulation of beta1ARs in atrial and ventricular myocytes (almost-equal-t
o 25%). Our study suggests that beta1ARs in the heart are not signific
antly downregulated by chronic agonist exposure and that this is unrel
ated to sympathetic innervation. The underlying mechanism of preferent
ial regulation of betaAR subtypes remains to be elucidated but may be
related to differences in the molecular structure between beta1ARs and
beta2ARs.