Maarten van den Buuse

Electrically stimulated [3H]dopamine and [14C]acetylcholine release from nucleus caudatus slices: differences between spontaneously hypertensive rats and Wistar-Kyoto rats

Using an in vitro superfusion method it was found that nucleus caudatus slices of 8- and 12-week-old spontaneously hypertensive rats (SHR) release significantly less [3H]dopamine and [14C]acetylcholine upon electrical stimulation than do slices of normotensive Wistar-Kyoto rats (WKY) at all frequencies tested. At 4 weeks similar trends were seen, but the difference in [14C]acetylcholine release was not significant. That the difference in release of dopamine was already present prior to the onset of the development of hypertension, i.e. at the age of 4 weeks, indicates that it is probably not a consequence of, but rather associated with the development of hypertension. Addition of the dopamine uptake inhibitor nomifensine to the superfusion medium caused an increase in the net release of [3H]dopamine by inhibiting re-uptake, but did not influence the difference in release between SHR and WKY. The release of labelled dopamine and acetylcholine was inhibited in the presence of the dopamine D2 receptor agonist quinpirole. The concentration-response curve for the inhibition of the release of [3H]dopamine, but not that of [14C]acetylcholine, by quinpirole was shifted to the left and the maximum inhibition was higher for SHR than for WKY. These results suggest that the difference in stimulus-evoked release of labelled dopamine in the nucleus caudatus is not the consequence of changes in the uptake mechanism of dopamine, but is associated with differences between SHR and WKY in dopamine D2 autoreceptor regulation.

Brain dopamine depletion by lesions in the substantia nigra attenuates the development of hypertension in the spontaneously hypertensive rat

The involvement of brain dopamine in the development of hypertension in the spontaneously hypertensive rat (SHR) was studied. Intracerebroventricular (i.c.v.) injections of 6-hydroxydopamine (6-OHDA) in young SHR caused depletion of dopamine in frontal cortex and striatum and induced an attenuation of the development of hypertension in SHR. Depletion of noradrenaline and to a lesser extent of serotonin was found as well. The ratio of DOPAC and of HVA to dopamine was increased after 6-OHDA. Pretreatment with the dopamine re-uptake inhibitor GBR-12909 inhibited the effects of 6-OHDA on both blood pressure and brain dopamine content. The effect of 6-OHDA on noradrenaline and serotonin levels were not influenced by pretreatment with GBR-12909. Electrolytic lesions in the substantia nigra delayed the rise in blood pressure in SHR. Lesions in the ventral tegmental area (VTA) were ineffective. After substantia nigra lesions depletion of dopamine was found especially in the nucleus caudatus posterior and the dorsomedial nucleus. After lesions in the VTA substantial dopamine depletion was found in the nucleus accumbens, frontal cortex, lateral septal nucleus and zona incerta. These data suggest that brain dopamine systems play a role in the development of hypertension in SHR and that especially the nigrostriatal system is important in this respect. Moreover, the present results may help to explain the attenuating effect of prehypertensive treatment with 6-OHDA on the development of hypertension.

Vasopressin and oxytocin gene expression in the supraoptic and paraventricular nucleus of the spontaneously hypertensive rat (SHR) during development of hypertension

To study the regulation of hypothalamic vasopressin (VP) and oxytocin (OT) gene expression in relation to the development of hypertension, levels of VP mRNA and OT mRNA were determined in spontaneously hypertensive rats (SHR). Differences in VP and OT mRNA content of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of 4- and 10-week-old SHR and Wistar-Kyoto controls (WKY) were quantitated by dot-blot and Northern blot analysis. VP and OT pituitary content and VP plasma levels were measured by radioimmunoassays. VP mRNA levels were approximately 2-fold and 3-fold higher in the SON and PVN of 4-week-old SHR, respectively, as compared to controls. The OT mRNA levels were approximately 35% lower in both nuclei of the SHR. There was no difference in VP and OT pituitary content between 4-week-old SHR and WKY, but VP plasma levels were higher in SHR. In the 10-week-old SHR VP mRNA levels were still approximately 30-40% higher and the OT mRNA levels were approximately 40% lower in both nuclei when compared to age-matched WKY. Pituitary VP and OT contents were respectively 1.5-fold higher and 20% lower in the 10-week-old SHR than in 10-week-old WKY. VP plasma levels were still elevated in the SHR. The data indicate that in the hypothalamo-neurohypophyseal system of the SHR the VP system is in a higher state of activity, while the OT system is lower in activity.

Regional brain catecholamine levels and the development of hypertension in the spontaneously hypertensive rat: the effect of 6-hydroxydopamine

To investigate the role of central catecholaminergic pathways in the development of hypertension in the spontaneously hypertensive rat (SHR) the effects of intracerebroventricular (i.c.v.) injections of 6-hydroxydopamine (6-OHDA) were compared with those of local injections near the main ascending noradrenergic pathways. The parameters studied were systolic blood pressure, heart rate and regional catecholamine concentrations in micropunched brain areas. I.c.v. treatment with 6-OHDA (three 200 micrograms injections) of young SHR attenuated the development of hypertension and caused widespread depletion of noradrenaline and to a lesser extent of dopamine and adrenaline. 6-OHDA-induced lesions of the dorsal and ventral noradrenergic bundles did not affect the rise in blood pressure but induced a depletion of forebrain noradrenaline comparable to that after the i.c.v. treatment. Dopamine and adrenaline levels were, however, not substantially affected. These results suggest that forebrain noradrenergic innervation may not be of major importance for the development of hypertension in the SHR.

Open-Field Behaviour and Blood Pressure in Spontaneously Hypertensive Rats

The relation between the development of hypertension and changes in behaviour was investigated. Open-field activity of male and female Spontaneously Hypertensive Rats (SHR) and Wistar-Kyoto controls (WKY) was scored at 4, 6 or 10 weeks of age. SHR generally showed higher locomotor activity and exploratory rearing behaviour, but lower grooming activity and defecation. These changes were found for rearing (3-5 fold increase) and grooming scores at all ages, ambulation at 4 weeks and 10 weeks (ambulation-inner) and defecation at 6 and 10 weeks of age. Differences were generally more pronounced in female rats. SHR showed less habituation than WKY. Already at the age of 4 and 6 weeks blood pressure was increased in SHR compared with WKY (approximately 120 mm Hg vs. 100 mm Hg). Between 6 and 10 weeks of age blood pressure increased rapidly in SHR, leading to a marked difference at the latter age (about 40 mm Hg), in both male and female rats. These experiments show that already at a young age, when blood pressure differences with WKY are small, marked behavioural changes are present in SHR. The altered behaviour could play a role in the development of hypertension in SHR.

Substantia nigra lesions attenuate the development of hypertension and behavioural hyperreactivity in spontaneously hypertensive rats

The possible relation between changes in behaviour and the development of hypertension was investigated. Depletion of striatal dopamine by lesions in the substantia nigra of Spontaneously Hypertensive Rats (SHR) was associated with an inhibition of the development of hypertension. In the open field a decrease in rearing score was found with no effect on other parameters. Rearing activity was significantly correlated with blood pressure as well as with striatal dopamine content. Blood pressure was weakly, although significantly, correlated with striatal dopamine content. Neither blood pressure nor striatal dopamine content was significantly correlated with ambulation activity. In normotensive Wistar-Kyoto rats a decrease was also found in rearing activity after nigra lesions, although this effect was less pronounced. Antihypertensive treatment of SHR with captopril or hydralazine did neither affect striatal dopamine levels nor open-field behaviour. Induction of renal hypertension or DOCA-salt hypertension in Wistar rats did not influence brain dopamine or behaviour. The results support the suggestion that brain dopamine systems may play a role in the development of hypertension in SHR as well as in the changes in behaviour observed in these rats. Changes in behaviour do not appear to be mediated by changes in blood pressure per se.

Beneficial effect of an ACTH-(4-9) analog on peripheral neuropathy and blood pressure response to tyramine in streptozocin diabetic rats.

The autonomic neuropathy in STZ diabetic rats is associated with damage to the sympathetic nervous system and microvascular pathology, affecting control of blood pressure and flow. We now report for the first time that chronic treatment of STZ diabetic rats with the peptide, ORG 2766, prevents the diminished responsiveness to tyramine-induced changes in blood pressure

Cardiovascular effects of central 6-OHDA treatment: a comparison of indirect and direct measurements

The effect of intracerebro-ventricular treatment with 6-hydroxydopamine on blood pressure and heart rate was studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (WKY). When measured with the indirect tail-cuff method, the development of hypertension was found to be markedly inhibited in 6-OHDA treated SHR, while blood pressure was slightly lower in treated WKY. Heart rate was lower in both strains, although the greatest effect was found in SHR. In contrast, direct measurement via an arterial cannula indicated significantly lower blood pressure in 6-OHDA treated SHR only. Heart rate was by this method found to be not different between the SHR groups, but was increased in treated WKY. These results indicate that the mild stress of indirect blood pressure determinations has a marked influence on the results found.

BRAIN NORADRENALINE AND THE DEVELOPMENT OF HYPERTENSION: THE EFFECT OF TREATMENT WITH CENTRAL 6-HYDROXYDOPAMINE OR DSP-4

1. The relative role of brain catecholamines in the development of hypertension in the spontaneously hypertensive rat (SHR) was studied.

Grooming behavior of spontaneously hypertensive rats

In an open field spontaneously hypertensive rats (SHR) exhibited lower scores for grooming when compared to their normotensive controls, the Wistar Kyoto rats (WKY). After i.c.v. injection of 1 μg ACTH1–24 cumulative 50-min grooming scores were lower in SHR. Analysis of subscores indicated that the lesser effect of ACTH in SHR was especially prominent for headwashing and anogenital grooming. Moreover, a time course study revealed that the difference between SHR and WKY occurred in the first 6 observation periods of 5 min and thereafter disappeared. The results are discussed in the light of behavioral and central neurochemical differences between SHR and WKY.