Eric H. Mills

N‐METHYL‐d‐ASPARTATE RECEPTORS IN THE SPINAL CORD MEDIATE PRESSOR RESPONSES TO STIMULATION OF THE ROSTRAL VENTROLATERAL MEDULLA IN THE RAT

1. Activation of bulbospinal neurons projecting from the C1 area of the rostral ventrolateral medulla evokes a pressor response. The nature of the neurotransmitters involved in mediating this response at spinal cord level has not been established.

Effect of intrathecal amino acid receptor antagonists on basal blood pressure and pressor responses to brainstem stimulation in normotensive and hypertensive rats

The importance of spinal cord amino acid receptors in the regulation of blood pressure was investigated in normotensive (Wistar Kyoto, WKY), spontaneously hypertensive (SHR), and stroke-prone spontaneously hypertensive (SPR) rats. Also investigated was the possible role of these spinal cord receptors in mediating pressor changes evoked by electrical stimulation of two separate areas of the rostral ventrolateral medulla (RVLM) containing different neuronal populations, either the adrenaline-containing Cl area or the serotonincontaining B3 area. Intrathecal administration of the amino acid receptor antagonist kynurenate (KYN), or the selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (2APV), reduced basal blood pressure in anesthetized SHR and SPR in a dose-dependent manner, but were ineffective or elicited only small decreases in WKY. In all three strains, electrical stimulation in RVLM, in either the Cl or B3 area, evoked frequency-dependent pressor responses. Administration of 2APV or KYN was effective in attenuating these pressor responses in all three strains of rats. The effects of stimulation in the RVLM-B3 area were virtually abolished by administration of 2APV followed by the serotonin receptor antagonist methysergide. The results suggest that spinal cord excitatory amino acid receptors are important in blood pressure regulation in rats. Amino acid receptors, perhaps of the NMDA subtype, appeared to mediate pressor responses to stimulation of the RVLM-C1 and RVLM-B3 regions in both normotensive and hypertensive animals. On the other hand, excitatory amino acid receptor antagonists reduced basal blood pressure only in the hypertensive rats. It is possible that the increased activity of bulbospinal excitatory amino acid pathways from Cl and B3 areas of RVLM contributes to the hypertension observed in SHR and SPR.

CENTRAL SEROTONERGIC MECHANISMS IN CARDIOVASCULAR REGULATION

SummaryThis paper reviews the role of central serotonin-containing neurons in the control of blood pressure. Central serotonin nerves have their cell bodies in the brainstem in a number of discrete collections, from where they ascend to ramify throughout the brain, descend to terminate in the spinal cord, or send shorter projections terminating in medulla, pons, and midbrain. Activation of one important ascending serotonin pathway innervating the preoptic region of the hypothalamus causes an increase in blood pressure. Activation of a bulbospinal serotonin projection descending from the ventrolateral medulla (the B3 cell group) to terminate in the intermediolateral cell column (IML) also evokes a pressor response. This pressor response is independent of that elicited by stimulation of the ventrolateral medulla in the adjacent but separate area containing the C1 adrenaline cell group. The pressor action appears to depend on increased release of serotonin, as detected by microdialysis in the area of the IML, and to be mediated by serotonin receptors of the 5HT1 subclass, probably located on sympathetic preganglionic neurons. It is possible that neuroactive excitatory amino acids, such as glutamate or aspartate, and neuropeptides such as substance P, also play a part in the pressor response evoked by stimulation of the ventrolateral medulla in the area of the lateral B3 serotonin cells. This descending serotonin pathway also appears important in mediating the hypotensive action of the antihypertensive drugs methyldopa and clonidine.

Effects of intrathecal administration of methysergide, phentolamine, and pindolol on pressor responses to electrical stimulation of the rostral ventrolateral medulla

Neurons projecting from the rostral ventrolateral medulla (RVLM) to the spinal cord are important in blood pressure control. The present experiments examined the role of spinal adrenoreceptors and serotonin receptors in mediating the pressor effects of electrical stimulation of the RVLM. Accordingly the effects on blood pressure of electrical stimulation of the RVLM were studied before and after intrathecal administration of adrenergic or serotonergic antagonists in normotensive and hypertensive rats. Electrical stimulation in the area of the RVLM-B3 serotonin-containing neurons in Wistar-Kyoto (WKY) rats increased blood pressure, and the pressor responses were reduced by intrathecal methysergide (30 and 100 micrograms). Similar findings were seen in spontaneously hypertensive rats (SHR). In WKY, electrical stimulation in the area of the RVLM-C1 epinephrine-containing neurons, increased mean arterial pressure (MAP), but the pressor responses were unaffected by intrathecal phentolamine (15 micrograms), pindolol (2 micrograms), or methysergide (30 and 100 micrograms), or saline. The results suggest that the pressor effects of stimulation of the RVLM-B3 area are mediated at least in part through activation of spinal serotonin receptors. The lack of effect of phentolamine and pindolol on the RVLM-C1 area pressor responses raises a question regarding the importance of spinal adrenergic receptors in mediating these effects.

How Do Adrenocortical Steroid Hormones Produce Hypertension

ACTH dependent and independent adrenocortical steroid hypertension in experimental animals is thought to be due to the mineralocorticoid and/or glucocorticoid activity of the steroid/s. Studies in sheep examining ACTH and adrenocortical steroid hypertension have provided evidence for a hypertensinogenic class of steroid activity. A hypothesis is proposed to explain how the hypertensinogenic actions of a steroid may produce hypertension. It is suggested that effects mediated via mineralocorticoid and glucocorticoid receptors may modulate or amplify the hypertensinogenic activity. Individual steroids may express any, all or none of these three types of steroid hormone activity.

THE HAEMODYNAMIC EFFECTS OF CYCLOSPORIN A IN SHEEP

SUMMARY

ADRENOCORTICAL STEROID REQUIREMENTS FOR INITIATION OF ACTH‐DEPENDENT HYPERTENSION IN SHEEP

1. Previous studies demonstrated that the combined infusion of cortisol (F), aldosterone (ALDO), deoxycorticosterone (DOC), corticosterone (B), 11‐deoxycortisol (S), 17α‐hydroxyprogesterone (17αOHP) and 17α, 20α‐dihydroxy‐4‐pregnane‐3‐one (17α20αOHP), at rates equivalent to their production during adrenocorticotrophic hormone (ACTH) treatment, reproduced the pressor and metabolic responses to ACTH administration in sheep.

The effect of intrathecal serotonergic antagonists on the pressor response to stimulation of the brainstem in the rat.

Previous studies from our laboratory have shown that stimulation of the brainstem in the area of the descending lateral serotonin containing neurons of the B3 group in the rostral ventrolateral medulla (RVLM), increases blood pressure and serotonin release in the spinal cord. The present experiments were designed to investigate the spinal cord serotonin receptor subtypes involved in mediating this pressor response. The area of the B3 neurons in the RVLM was electrically stimulated and the effects of intrathecally administered methysergide, an antagonist of 5HT1 and 5HT2 receptors, of ketanserin, a 5HT2 receptor antagonist or of ICS 205930 (ICS) or MDL 72222 (MDL), antagonists of 5HT3 receptors, were examined. Electrical stimulation of the area of the B3 serotonin-containing neurons in the RVLM increased mean arterial pressure. Intrathecal methysergide treatment attenuated the pressor response, but intrathecal MDL, ICS, ketanserin or saline were without effect. These results suggest that the pressor responses seen after stimulation of the area of the B3 serotonin neurons in the RVLM may be mediated through activation of spinal 5HT1 receptors.

Blood pressure and metabolic effects of 18-OXO-cortisol in sheep

18-Oxo-cortisol (18-oxo-F) has been isolated from the urine of subjects with primary aldosteronism. This study examines the pressor, mineralocorticoid and glucocorticoid effects of 18-oxo-F in conscious sheep--a well studied species for the assessment of the pressor effect of steroid hormones. 18-oxo-F (24 mg/day i.v. for 5 days, n = 3) increased mean arterial pressure MAP (64 +/- 2 mmHg control and 75 +/- 6 mmHg on day 5 P less than 0.001). There was no change in heart rate. Plasma [K+] decreased from a control of 4.3 +/- 0.1 mmol/l control to 2.9 +/- 0.3 mmol/l on day 5 (P less than 0.001). Urinary Na+ excretion decreased on the first infusion day (233 +/- 18 mmol/day control and 124 +/- 20 mmol/day on infusion day 1 P less than 0.001). Urinary K+ excretion was reduced on days 1, 4 and 5 of the infusion. Thus in sheep, 18-oxo-F increased blood pressure associated with in vivo evidence of mineralocorticoid activity.

Steroid antagonism of the ‘hypertensinogenic’ activity of 9α-fluoroprednisolone

We have previously reported that adrenocortical steroids raise blood pressure by a hypertensinogenic mechanism of action which is not simply related to their classical mineralocorticoid or glucocorticoid actions. This study presents evidence for specific antagonism of this hypertensinogenic activity. The effects of separate IV infusions of prednisolone (P) 100 mg/d and 9 alpha-fluoro-prednisolone (9 alpha F-P) 0.6 mg/d on mean arterial pressure (MAP), plasma [K], plasma [glucose] and urinary Na excretion (UNaV) after 2 days were studied in sheep. In the same group of sheep which received P alone for 2 days, 9 alpha F-P was given for a further 2 days while continuing the P infusion (P + 9 alpha F-P). P alone had no effect on MAP or plasma [K] or UNaV but increased plasma [glucose], effects which are characteristic of glucocorticoid activity. 9 alpha F-P alone increased MAP by 14 mmHg (P less than 0.001) and reduced plasma [K] and UNaV but had no effect on plasma [glucose]. Thus 9 alpha F-P exhibited both hypertensionogenic and mineralocorticoid activity. In the sheep which received the combined P + 9 alpha F-P infusion, the increase in MAP normally produced by 9 alpha F-P was blocked. Although pretreatment with P blocked the pressor effect of 9 alpha F-P, it did not alter the mineralocorticoid effects, namely hypokalaemia and urinary Na retention, produced when 9 alpha F-P was infused alone. These results provide further evidence for our concept of a hypertensinogenic class of steroid activity and are the first demonstration of specific antagonism of steroid induced hypertension.