Autoradiographic comparison of muscarinic M1 and M2 binding sites in the CNS of spontaneously hypertensive and normotensive rats.
Spontaneously hypertensive rats (SHR) respond with exaggerated pressor responses of central origin in response to pharmacologic stimulation of brain muscarinic receptors when compared with those to normotensive Wistar Kyoto (WKY) rats. At least part of the enhanced response to central muscarinic stimulation may be due to alterations in the expression of one or more of the five subtypes of muscarinic receptors. SHR are also known to exhibit regional alterations in the levels of mRNA encoding the M1, M2 and M4 receptors. In this study, we estimated the number of specific muscarinic receptor binding sites in 12-week-old SHR and WKY by measuring the binding of M1- and M2-selective ligands. Using standard autoradiographic techniques, coronal sections obtained from 12-week-old SHR and WKY were incubated with [3H]pirenzepine or [3H]AFDX 384 to label M1 and M2 receptors, respectively. Although both strains exhibited similar distribution patterns for both binding sites, sections derived from SHR expressed a significant increase in the number of [3H]pirenzepine binding sites compared to normotensive WKY in caudate putamen, CA3 region of the hippocampus, cingulate cortex, substantia nigra, posterior hypothalamic area and tuberomammillary nucleus. An increased number of [3H]AFDX 384 binding sites in SHR were observed in the olfactory tubercle, nucleus accumbens, basolateral amygdaloid nucleus, rostroventrolateral medulla and nucleus paragigantocellularis. Decreases in the number of [3H]AFDX 384 binding sites in SHR were also observed in the parietal cortex, medial geniculate, and lateral hypothalamic area. Statistically significant site-selective differences in binding densities between strains ranged from 4.0% to 35.5% of WKY means. These alterations in the expression of M1 and M2 binding sites in cardiovascular regions may contribute to the strain's hyper-responsiveness to cholinergic drugs and possibly to the appearance of other autonomic or behavioral phenotypes exhibited by SHR, including the hypertensive state itself.
Gattu
M
M
Department of Pharmacology and Toxicology/Alzheimer's Research Center, Medical College of Georgia, Augusta 30912-2300, USA.
Pauly
J R
JR
Urbanawiz
S
S
Buccafusco
J J
JJ
D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology; D001923:Brain Chemistry / Q000235:genetics; D002490:Central Nervous System / Q000033:anatomy & histology / Q000378:metabolism*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics; D010276:Parasympatholytics / Q000493:pharmacokinetics; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011976:Receptors, Muscarinic / Q000378:metabolism*
D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; C065959:AFDX 384; D010890:Pirenzepine