Histamine H3 receptor enhanced negative feedback control in rat brain during the progression of hypertension
Histamine receptors provide feedback inhibition for the synthesis and release of histamine from the hypothalamus, as well as inhibition of other neurotransmitters, such as acetylcholine from intestinal cholinergic nerves, and norepinephrines from the retina and cerebral cortex. Our previous results suggest that the regulation of histamine release by histamine H3 receptors changes with the progression of hypertension in Spontaneously Hypertensive Rats (SHR). Therefore, we believe that the histamine H3 receptor plays a role in the promotion and sustained development of hypertension. Analysis of saturation binding data from Spontaneously Hypertensive Rat cerebral cortex indicate that as animals aged from six to sixteen weeks the maximal number of receptor sites (Bmax) increased whereas the affinity of [3H]-N-a-methylhistamine for these sites decreased. B max was 38 + 1.58, 59.63 + 2.48, 79.17 + 5.02, and 84.41 + 3.72 fmol/mg of protein at six, nine, twelve, and sixteen weeks, respectively. ^ High performance liquid chromatography (HPLC) was used to determine brain histamine levels in the cerebral cortex. Our results indicated that histamine content increased as the animals aged. HPLC analysis revealed a 66, 43, 56, and 57% higher histamine concentration in the cortex of Wistar Kyoto (WKY) animals for 6, 9, 12, and 16 week animals than in SHR in the same age group, respectively. Therefore, histamine content is greater in WKY rats as compared to SH rats. ^ Furthermore, RT-PCR analysis indicated a change in H3 receptor genomic expression between WKY and SH rats. Four bands resulting from PCR-product were yielded by WKY animals as seen on a 1.2% agarose gel. The bands were seen at base pairs of 1000, 600 500, and 200 kd, respectively. These bands were present throughout all ages (6, 9, 12, and 16 weeks). In SH rats, only two bands (500, and 200 bp) resulting from PCR-product were seen when run on a 1.2% agarose gel. These bands were seen at all ages (6, 9, 12, and 16 weeks) of SH rat, respectively. These findings indicate that distinct changes are present between normotensive (WKY) and hypertensive (SHR) phenotypes regarding the histamine H3 receptor. ^ In conclusion, there may be a down regulation of the isoforms during the development of hypertension. This down regulation may also be a contributor to the promotion and sustained development of hypertension. Furthermore, by the mechanism of our proposed feedback model, we conclude that histamine release is dependent on the enhancement of control of the histamine H3 receptor as an autoregulator. This evidence could possibly lead to selective antagonistic drugs being synthesized could block the actions of specific isoforms of the H3 receptor which may be responsible for the development and promotion of hypertension. ^
Biology, Animal Physiology
James Brandon Shaw,
"Histamine H3 receptor enhanced negative feedback control in rat brain during the progression of hypertension"
ETD Collection for Tennessee State University.