Changes in central catecholaminergic neurons in the spontaneously (genetic) hypertensive rat.

Abstract

SUMMARY Catecholamines and catecholamine-synthesizing enzymes have been examined in specific brain areas during the development of spontaneously (genetic) hypertensive (SH) rats. Changes in catecholamine metabolism were localized to regions of the brain implicated in the regulation of blood pressure. Norepinephrine levels and dopamine-/3-hydroxylase (DBH) activities were decreased in specific nuclei of the hypothalamus and in the nucleus interstitialis striae terminalis ventralis, in both young and adult rats. The decrease in the formation of norepinephrine can result in a reduced activation of central a-adrenergic receptors which may be related causally to the onset of hypertension. The activity of the epinephrine-forming enzyme, phenylethanolamine-A'-methyltransferase (PNMT), was increased in the A, and A 2 areas of the brainstem in young SH rats, but it was normal in adult hypertensive animals. These results implicate adrenergic neurons in the brainstem and noradrenergic neurons in the hypothalamus in the development of spontaneous (genetic) hypertension in rats.CATECHOLAMINES have been implicated in the pathophysiology of hypertension. "4 The most compelling evidence of the involvement of catecholamines in hypertension is the demonstration that many drugs therapeutically useful in the treatment of hypertension also affect the adrenergic nervous system at a variety of sites, modifying the uptake, release, and storage of the neurotransmitter or acting directly on the adrenergic receptors. 5It now is recognized that not only peripheral catecholaminergic nerves and the adrenal medulla play roles in the physiological regulation of blood pressure and in the expression of at least some forms of hypertension, but that central catecholaminergic neurons also are implicated.1 ' 4 ' 6 Some of the catecholamine-rich areas in the brain that have been proposed to be involved in cardiovascular regulation are localized in the anterior hypothalamus and in the brainstem (areas A, and A 2 ). These areas are densely supplied with noradrenergic nerves. Area A, of the rat brain contains the cell bodies of the catecholaminergic neurons that send axons to the spinal cord, 7 " and area A 2 corresponds in part to the nucleus of the tractus solitarii in which the majority of the fibers of the carotid sinus nerve terminate. 4 ' 7 In addition to norepinephrine, the A, and A 2 areas of the brainstem have the highest levels of the epinephrineforming enzyme, phenylethanolamine jV-methyltransferase (PNMT) found in the brain.9 ' 10 Epinephrine also has been detected in the A, region" and in the A 2 area as well (Saavedra et al., unpublished results).By the use of sensitive isotopic-enzymatic micromethods Received April 15, 1977; accepted for publication, November 17, 1977. volved in their formation in discrete brain areas associated with central autonomic control and blood pressure regulation is now possible.An examination of norepinephrine content and the norepinephrine-forming enzyme in specific brain areas during the development o...

Sympathetic nerve activity and blood pressure in normotensive backcross rats genetically related to the spontaneously hypertensive rat.

“…Several studies suggest, however, an abnormality in central adrenergic pathways, which results in either excessive activity of excitatory centers or inadequate activity of inhibitory centers. Saavedra et al 19 have recently shown a reduction in dopamine-beta-hydroxylase activity and norepinephrine levels in specific nuclei of the hypothalamus, as well as abnormally high activity of phenylethanolamine-N-transferase in the brain stem of the SHR. We have recently demonstrated that Ldopa, presumably by increasing catecholamine levels in certain areas of the brain, is a potent depressor agent in the SHR.…”

“…The precise location(s) within the CNS of the abnormalities leading to excessive SNA remains unknown, although several recent studies suggest involvement of the hypothalamus and/or the brain stem. 19 ' m Similarly, the neurochemical basis of the CNS abnormality is unknown. Several studies suggest, however, an abnormality in central adrenergic pathways, which results in either excessive activity of excitatory centers or inadequate activity of inhibitory centers.…”

Decrease in noradrenergic activity in hypothalamic nuclei during the development of spontaneous hypertension

“…It seems that differences in this parameter emerge at a later stage31, ~z. It should be noted that Saavedra et al 22 reported a decreased noradrenaline concentration in various hypothalamic nuclei of both 4-and 14-week-old SH-rats as compared with WK-rats of the same age. The reason for these discrepancies with our present and previous81,32, a4 findings is not known.…”

“…Much of the neurochemical data supporting this hypothesis originates from studies comparing the spontaneously hypertensive rat (SH-rat), which was established as an inbred strain by Okamoto and associates (see ref. 17), with rats of the parent Wistar-Kyoto strain (WK-rat) 3,12,22,24,26,31,32,34,35,37. Part of the available data concerns the possible participation of adrenaline-containing neurons in this effect 22, 24,31,32,34,35. It seems highly likely that noradrenaline is involved as wella, 14,22,31.…”

“…17), with rats of the parent Wistar-Kyoto strain (WK-rat) 3,12,22,24,26,31,32,34,35,37. Part of the available data concerns the possible participation of adrenaline-containing neurons in this effect 22, 24,31,32,34,35. It seems highly likely that noradrenaline is involved as wella, 14,22,31. The finding by De Jong et al 3 and Versteeg et al 31 of higher levels of noradrenaline in the pons/medulla and in the discrete regions within these structures respectively, for SHrats rather than for WK-rats at several ages, shows that differences exist but does not show in what direction catecholamine metabolism has altered in the SH-rat.…”