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FINAL TECHNICAL REPORT --- ON NASA GRANT NAGW-490 

Neural Mechanisms by which Gravitational Stimuli 

and Stress Affect the Secretion of Renin and Other Hormones 

William F. Ganong, M.D. 

Department of Physiology 

University of California 

San Francisco, California 9.4143 

Description - of Research 

The NASA grant which supports this research was activated August 1, 1983. 

It was initially administered from NASA Headquarters, but has now been 

transferred to NASA-Ames Research Center and given a new number effective 

February 1, 1987. The long-term goal of the research is delineation of the 

neural pathways and transmitters that mediate changes in the secretion of 

renin and other hormones concerned with regulation of salt and water balance 

in response to gravitational and other stimuli. Evidence from this laboratory 

indicates that stimulation of serotonergic neurons on the dorsal raphe nucleus 

of the midbrain increases renin secretion, and that these neurons project to 

the mediobasal hypothalamus (Karteszi, et al., Neuroendocrinology 34:323-326, 

1982). 

hypothalamus to the renin-secreting cells in the kidney was accomplished by 

pharmacological experiments demonstrating that the pathway was sympathetic 

(Alper and Ganong, 1984; see publication list). The present goal is to 

determine by the production of discrete lesions the parts of the hypothalamus 

and brainstem that are involved in serotonin-mediated increases in renin 

secretion. In addition, we want to determine the role of the brain in the 

renin responses to other stimuli. Therefore, we have developed and 

standardized a variety of stimuli which act in different ways to increase 

renin secretion. These include: 1) administration of the serotonin-releasing 

drug pchloroamphetamine (PCA); 2) the pyschological stress of immobilization; 

3) the postural stress of 45' head-up tilt; 4) the volume depletion stress of 

The initial goal of determining how the message got fron! the 

a low sodium diet; and 5) the acute volume stress of 

hemorrhage. 

Accomplishments 

Major accomplishments, particularly in the past 

following observations: 

nonhypotensive 

year, include the 

1) Like the PCA response, the renin responses to immobilization and headup tilt were shown to be blocked by the B-adrenergic blocking drug 

propranolol, indicating that the final common pathway from the spinal cord to 

the renin-secreting cells in the kidney is sympathetic in all three 

situations. 

2) Although the increase in renin secretion produced by PCA was abolished 

by lesions of the dorsal raphe nucleus, the response to immobilization, head1 . (EASA-CE- 180246) HEUfiAL HIiCEAhZSCS BY WHICH Nt37-1L478 

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up tilt, and a low sodium diet was not. 

not act by increasing the discharge of the serotonergic neurons in the dorsal 

raphe nucleus. 

Therefore, these latter stimuli do 

3) Bilateral lesions of the paraventricular nuclei reduced or abolished 

the increase in plasma renin activity (PRA) produced by PCA, immobilization, 

head-up tilt, and a low sodium diet. However, pareventricular lesions also 

produced a marked, reproducible decline in the plasma concentration of renin 

substrate. Since substrate is rate limiting for the generation of angiotensin 

I in plasma, we remeasured generation of angiotensin I after adding exogenous 

renin substrate, thus measuring plasma renin concentration (PRC). Like the 

PRA response, the PRC response to PCA was also abolished by paraventricular 

lesions. However, the PRC response to immoblization, head-up tilt, and a low 

sodium diet was normal. Consequently, it appears that the renin-stimulating 

serotonergic neurons in the dorsal raphe nucleus project to the 

paraventricular nuclei, but that immoblization, head-up tilt, and a low sodium 

diet do not act via the paraventricular nuclei. 

4) The PRA response to nonhypotensive hemorrhage was normal in rats with 

bilateral paraventricular lesions, but the PRC response was much greater than 

normal. Thus, it appears that the body compensates for the deficient 

production of angiotensin I (and, consequently, of angiotensin 11) by 

producing a stronger stimulation of renin secretion with this particular 

stress when there are lesions of the paraventricular nuclei. 

5) Bilateral lesions of the ventromedial nuclei abolished the PRA 

response to PCA, immobilization, head-up tilt, and a low sodium diet without 

producing any change in plasma substrate concentration (Gotoh, et al., 1987). 

Thus, it appears that the ventromedial nuclei are nodal points in the neural 

pathways responsible for the increase in renin secretion produced by a variety 

of different stimuli. We will soon embark on experiments to determine whether 

these nuclei mediate responses to multiple stimuli or exert some sort of 

overall tonic effect on the responsiveness of the juxtaglomerular cells. 

6) Confirming others, we found that paraventricular lesions block the 

ACTH response to stress but do not decrease resting plasma ACTH. Since 

adrenal glucocorticoids, estrogens, and thyroid hormones all stimulate the 

secretion of renin substrate by the liver, it seems likely that the effects of 

paraventricular lesions on substrate are due to endocrine changes. 

paraventricular nuclei are involved in the regulation of TSH as well as ACTH 

secretion, and hypophysectomy has been shown by us to produce a decrease in 

renin substrate (Alper, et al., 1986). In preliminary experiments, the time 

course of the decline of substrate produced by paraventricular lesions 

paralleled that produced by hypophysectomy. However, this experiment needs to 

be confirmed, expanded, and supplemented with hormone replacement experiments. 

This will be an important goal of the research during the coming year. 

The 

7) To see if vasopressin-secreting efferents from the hypothalamus to the 

cardiovascular regulatory areas in the brainstem and spinal cord are involved 

in the regulation of renin secretion, the renin secretory responses to the 

stimuli we have been employing were tested in Brattleboro rats that were 
unable to produce vasopressin in their brains. Responses to all the stresses 

were greater than normal. Conversely, intraventricular injection of 

vasopressin appeared in very preliminary experiments to inhibit renin 

secretion and intraventricular administration of an oxytocin agonist appeared 

to stimulate renin secretion. Further experiments of this type are planned. 

8) Blood pressure, heart rate, and vasopressin responses to head-up tilt 

have been measured in addition to renin during the past year. 

differences in blood pressure and heart rate between rats with lesions of the 

paraventricular nuclei and controls. In very preliminary experiments with 

vasopressin and renin antagonists, it appeared that it was primarily the 

renin- angiotensin system rather than vasopressin that maintained blood 

pressure during head-up tilt. 

There were no 

9) Additional data were obtained in the previously described 

collaborative experiment with Keil at NASA-Ames in which ACTH, corticosterone, 

PRA, and vasopressin levels are being measured with long-term head-down 

suspension in rats. 

Significance -- of These Accomplishments 

The experiments with PCA have now demonstrated that there is a 

serotonergic pathway which projects from the dorsal raphe nuclei to the 

paraventricular nuclei and the ventromedial nuclei of the hypothalamus; that 

the projection from the paraventricular nuclei to the brainstem and spinal 

cord may be oxytocinergic, although this point needs additional research; and 

that the pathway from the spinal cord to the renin secreting cells is 

sympathetic. The demonstration that paraventricular lesions lower circulating 

renin substrate is important because it raises the possibility that substrate 

secretion is under neural control, either via the pituitary or by direct 

neural pathways. If the endocrine pathways prove to be key, this once again 

demonstrates the importance of neuroendocrine mechanisms in the maintanence of 

cardiovascular homeostasis. The discovery that lesions of the ventromedial 

nuclei appear to abolish the increase in renin secretion produced by many 

different stimuli without affecting the concentration of renin substrate in 

the plasma makes the position of the hypothalamus in the regulation of fluid 

and electrolyte balance more prominent than previously suspected. 

Publications: 

Alper, R.H. and W.F. Ganong 

Pharmacological evidence that the sympathetic nervous system mediates the 

increase in renin secretion produced by para-chloroamphetamine. 

Neuropharmacology 23: 1237-1240, 1984. 

Ganong, W.F., J.P. Porter, T.D. Bahnson and S.I. Said 

Peptides and neurotransmitters that affect renin secretion. 

Journal of Hypertension 2( Suppl. 1 ) : 75-82, 1984. 

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Ganong, W.F., E. Gotoh and R.H. Alper 

Neural mechanisms by which gravitational stimuli and stress affect the 

secretion of renin and other hormones. Annual Symposium, NASA Space 

Biology Program, NASA Conference Publication 2336: 69-70, 1985. 

Gotoh, E., T.D. Bahnson, R.H. Alper and W.F. Ganong 

Role of the hypothalamus in the regulation of renin secretion in rats. 

The Physiologist 28:313, 1985 (abstract). 

Ganong, W.F., E. Gotoh, K. Murakami and M.K. Steele 

Neuropeptides, cardiovascular homeostasis, and hypertension. 

Japanese Journal of Hypertension 8:55-70, 1986. 

Alper, R.H., C.F. Geschepper and W.F. Ganong 

Effect of hypophysectomy on dipsogenic stimuli: evidence for angiotensin 

supersensitivity. 

Am. J. Physiol. 251:R53-R58, 1986. 

Gotoh, E., K. Murakami, R. Golin and W.F. Ganong 

Hypothalamic regulation of plasma renin activity. 

Abstracts of the 1st International Congress of Neuroendocrinology, p. 86, 

1986 (abstract). 

Gotoh, E., K. Murakami, T.D. Bahnson and W.F. Ganong 

Role of brain serotonergic pathways and the hypothalamus in the 

regulation of renin secret ion. 

Am. J. Physiol. 1987 (in press) 

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