Enhanced NE uptake by isolated hypothalamic storage vesicles of hypertensive rats.

Abstract

The in vitro uptake of 3 H-NE by storage vesicles from the hypothalamus of age-matched spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats has been studied using a new reliable procedure for the isolation of biochemically active storage vesicles. In each of 13 paired studies, done in triplicate, storage vesicles of SHR took up more 3 H-NE than those of WKY. (The mean difference was 37% more uptake by SHR.) Electron-microscopic examination of normotensive samples showed a concentration of intact synaptic vesicles; whereas SHR subfractions were composed of fragmented membranes that resembled swollen, distorted vesicles. These findings in the brain tissues of SHR parallel our previous results found in SHR peripheral tissues. Taken together, we interpret the results to indicate that the membranes of synaptic vesicles of SHR are altered structurally and biochemically. (Hypertension 5: 3-7, 1983) KEY WORDS • norepinephrine uptake • isolated hypothalamic storage vesicle spontaneously hypertensive rats N UMEROUS studies have implicated the hypo-thalamus with cardiovascular control mechanisms. l " 4 Some investigators focused on responses of single units of the hypothalamus to stimulation of baroreceptor afferent input while others studied cardiovascular and plasma catecholamine responses to stimulation of different areas of the hypothalamus. 2 ' 3-5-6 To investigate the role of the hypothalamus in hy-pertension, we elected to study the Okamoto strain of rats with spontaneous hypertension (SHR), since their hypertension is associated with elevated indices of sympathetic activity.'"* Hypothatamic lesions,** or separation of connections between hypothalamus and mesencephalon," cause a significantly greater decrease of blood pressure in SHR than in Wistar-Kyoto (WKY) control rats. Conversely, electrical stimulation of the posterior hypothalamus 12 l3 elicits greater blood pressure increases in the SHR than in control WKY. Furthermore, SHR show changes in hypothalamic catecholamine metabolism in those areas which affect blood pressure. Thus, Nagaoka and Lovenberg 14 reported that during the early development of hyper-tension in the SHR, the activities of both tyrosine hy-droxylase and dopamine-B-hydroxylase (DBH) in the hypothalamus were significantly higher than in the control WKY rats. Nevertheless, a lower NE content in the hypothalamus of SHR was reported as early as 1970 by Yamori et al. 15 and recently by Saavedra et al. 9 andTsobe et al. TS The concentration of epinephrine was elevated in the hypothalamus of SHR as reported by Gianutsos and Moore. 17 Other approaches to studies of the hypothalamus in SHR have focused on adrenocep-tor activity and, at present, the findings are conflicting .'*-20 We recently reported results of in vitro 3 H-NE uptake by peripheral tissues in SHR and WKY. 21-n In the present study, we examined the in vitro uptake of 3 H-NE by isolated hypothalamic storage vesicles from age-matched SHR and WKY rats. Results show that the Mg 2+-activated ATPase dependent amine uptake of SHR h...

The use of viral gene transfer in studies of brainstem noradrenergic and serotonergic neurons

“…First, based on our previous observations described earlier, we investigated whether CA in SHR may be stored and released differently. This hypothesis was supported by previously published evidence of morphological changes in storage vesicles in SHR and their increased ability to take-up 3 H-NA (Rho et al 1983), higher expression of norepinephrine transporter in SHR brainstem cultures (Veerasingham et al 2005) and increased tyrosine hydroxylase expression in the SHR ventrolateral medulla (Reja et al 2002). We therefore reasoned that the structural differences in CA-storing vesicles and/or NA synthesis and transport could translate into enhanced packaging and release of CA in SHR.…”

Area-Specific Differences in Transmitter Release in Central Catecholaminergic Neurons of Spontaneously Hypertensive Rats

“…Higher output from large events was a combination of their much higher transmitter load (≈270%) and higher frequency relative to WRs. Increase in the size of these events may be because of a higher norepinephrine transporter activity in the SHR brain stem7; an increased expression of tyrosine hydroxylase, the key enzyme of NA/ADR biosynthesis, in the SHR ventral medulla,44; and/or alterations in the vesicular storage apparatus 6. These changes, when combined, possibly alter the way the vesicles are formed or filled.…”

“…This hypothesis is based on evidence of morphological changes in storage vesicles in SHRs and their increased ability to take up 3 H-NA,6 higher expression of norepinephrine transporter in SHR brain stem cultures,7 and increased tyrosine hydroxylase expression in the SHR ventrolateral medulla 8. Structural differences in NA-storing vesicles and/or NA synthesis and transport could translate into enhanced packaging and release of catecholamine (CA) in SHRs.…”

Altered central catecholaminergic transmission and cardiovascular disease

“…Vesicle properties Interestingly, NA storage vesicles may be structurally and/or biochemically altered in SHR. It was reported that storage vesicles of SHR took up 37% more [ 3 H]NA than those of WKY rats and the speed of uptake was also significantly faster (Rho et al 1983). At the electron microscopic level, WKY rats displayed intact, largely well‐delineated dense‐cored vesicles, while in SHR these vesicles appeared swollen and distorted.…”

“…At the electron microscopic level, WKY rats displayed intact, largely well‐delineated dense‐cored vesicles, while in SHR these vesicles appeared swollen and distorted. This raises the possibility that in SHR NA is stored and released from an altered pool of vesicles with, possibly, a different transmitter load and cotransmitter composition (Rho et al 1983).…”