Clinical Science and Molecular Medicine (1975) 49, 625-628.

SHORT COMMUNICATION

Plasma prostaglandin E during neurogenic hypertension in tetraplegic man C. J. MATHIAS,*? K. HILLIER,$(') H . L. F R A N K E L ? A N D J. M. K . SPALDING*

* Department of Neurology, Oxford Hospitals, Oxford, Centre, Stoke Mandeville Hospital, Aylesbury, and Nufield Department of Obstetrics and Gynaecology, University of Oxford

7 National Spinal Injuries

(Received 28 May 1975)

Summary 1. Arterial blood pressure and heart rate were

measured before, during and after cutaneous and visceral stimulation in subjects tetraplegic due to severe cervical spinal cord damage. Stimulation resulted in marked hypertension as a result of reflex sympathetic overactivity. 2. Mixed venous blood from a catheter situated in the right atrium was obtained before and after stimulation and plasma prostaglandin E and prostaglandin F were measured. A consistent and significant rise in plasma prostaglandin E, but not plasma prostaglandin F, accompanied the hypertension. 3. It is suggested that prostaglandin E is released during this sympathetic nervous activity and may be related to neurogenic hypertension. Key words : hypertension, prostaglandin E, prostaglandin F, sympathetic nervous system, tetraplegia.

organs in response to stimulation of their sympathetic nerves (Davies, Horton & Withrington, 1967; Davis & Horton, 1972; Needleman, Douglas, Jakschik, Stoecklein & Johnson, 1974). However, this phenomenon has not been subsantially documented in man during increased sympathetic nervous activity. We therefore studied subjects who were tetraplegic due to cervical spinal cord damage. In these subjects, cutaneous and visceral stimulation results in severe arterial hypertension due to exaggerated reflex sympatheticactivity mediated via the spinal cord (Corbett, Frankel & Harris, 1971; Debarge, Christensen, Corbett, Eidelman, Frankel & Mathias, 1974). PGE(*) and PGF concentrations in mixed venous plasma were measured before and after such episodes of neurogenic hypertension. Mixed venous blood from the right atrium was used, as PGE and PGF are rapidly metabolized in the lungs (Ferreira & Vane, 1967; Samuelsson, 1972).

Subjects and methods Four male subjects with severe cervical spinal cord damage were examined on five occasions (Table 1). None had any systemic disease or complication and all drugs were withdrawn 48 h previously. All subjects were studied in the supine position. A catheter was introduced percutaneously into a peripheral artery and connected via saline-filled manometer tubing

Introduction An increase in prostaglandin concentrations has been demonstrated in the venous oufflow of animal (') Present address: Department of Physiology, Medical and Biological Sciences Building, University of Southampton, Southampton, Hants. Correspondence: Dr C. J. Mathias, Department of Neurology, Churchill Hospital, Oxford OX3 7LJ.

( 2 ) Abbreviations: PGE, prostaglandin E; PGF, prostaglandin F.

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TABLE 1. Personal data and details of cardiovascular and prostaglandin measurements at rest ( R ) and during stimulation (S) in tetraplegic subjects

Subjects nos. 1, 2 and 3 had physiologically complete cervical spinal cord transections, and subject no. 4 had a few patches of sensation below the level of the lesion. n.s.=Not significant. Blood pressure (mmHg) Subject no.

Level of lesion

1 2 3 4a 4b

Mean fSEM Mean change P

c4/5 c4 c4 C8 C8

Time since injury (months) 6 17 8 5 5

Systolic R

S

105 100 125 158 110 120 10.5

170 190 150 185 230 185 13.2

Heart rate (beatslmin)

Diastolic S

R

S

55 55 65 75 65 63 3.7

80 95 75 84 90 85 3.5

72 70 85 103 80 82 5.9

110 127 100 118 137 118 6.4

+ 54

+ 35

+44

< 0.0 1

< 0.01

< 001

F

E

Mean

R

to an electromanometer so that arterial blood pressure and beat-to-beat heart rate (derived from the blood pressure signal) were continuously recorded. A radio-opaque polytetrafluoroethylene catheter was introduced via the right median cubital vein and advanced into the right atrium as indicated by pressure recordings and radiography. On three occasions, continuous right atrial pressure was also recorded. Blood for estimation of plasma PGE and PGF was withdrawn via a three-way connector attached to the right heart catheter. A control sample was withdrawn after rest in the supine position for 30 min and then after 3-6 min of cutaneous and visceral stimulation. On four occasions (Table 1 : 1-4a), stimulation was induced by 3-4 min of suprapubic percussion of the bladder, through the anterior abdominal wall. On one occasion (Table 1: 4b), it was effected with an electrode in the rectum. This was intended for the production of ejaculation and collection of semen for artificial insemination. A blood sample on this occasion was withdrawn after 6 min of sustained hypertension. Informed consent was obtained from all patients. The procedures were approved by the Ethics Committee of the Hospital. Patient no. 4 requested the stimulation of his own accord. Immediately blood was withdrawn (20 ml), it was

Plasma prostaglandin (PmoW)

R

R

S

75 70 68 68 100

60 50 60 55 65

0.50 0.28 0.16 0.65 0.38

58 2.5

0.39 0.09

16 6.1

- 24 P>0.01

- 10 n.s.

transferred to ice-cooled lithium heparin tubes, and centrifuged at 4°C. The plasma was pipetted into ice-cooled plastic storage tubes and stored at - 20°C until assayed. At no time was the plasma temperature allowed to rise above 4°C before extraction. PGE and PGF were assayed in the same sample by a modification of the technique of Hillier & Dilley (1974). The method now utilizes silicic acid chromatography but with similar solvent conditions to separate individual groups of prostaglandins. Further characterization of prostaglandins of E and F groups other than group separation was not attempted and the results are expressed as PGE or PGF equivalents. Concentrations are corrected for procedural losses ; mean recoveries were 62 k SD 5.8 % for PGE and 73 f 6 % for PGF respectively. Each sample extract was assayed at three different dilutions and the mean value taken. The interassay coefficient of variation for repeated estimates of a pooled plasma sample was 10.6% for PGE and 18.8% for PGF, and intra-assay coefficient of variation was 8.9% for PGE and 11.8% for PGF. 0.14 pmol of PGE, or 0.07 pmol of PGF2. in the assay system can be measured significantly, as defined by the mass of prostaglandin required to reduce radioactivity bound to the antibody to a level of twice the SD of radioactivity bound in the absence of added prostaglandin. Specificity was

Plasma PGE during neurogenic hypertension

ensured by the completeness of column separation (Hillier & Dilley, 1974) and the specificity of the antibodies used. Cross-reactivity of the PGE2 antibody was: PGE2, 100; PGEI, 86; PGF,,, 7.5; PGA2, 0.01). In subject no. 4a there was a spontaneous muscle spasm and elevation in blood pressure which occurred during the withdrawal of the sample. This could account for an elevated control PGE value when compared with his other one. Mean PGF concentrations in the same samples were 0.21 pmol/ml(77 pg/ml) at rest and 0.19 pmol/ ml (68 pg/ml) after stimulation, there being no significant change. Discussion

Studies on animal organs have demonstrated an increased release of PGE during sympathetic stimulation (Horton, 1973). Green & Samuelsson (1971) reported increased synthesis of PGE in rats exposed to cold stress, which increases sympathetic activity. This was, however, based on measurements of urinary metabolites of PGE. Stimulation in the tetraplegic subjects was characterized by a significant increase in blood pressure, and such hypertension is due to reflex sympathetic overactivity

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(Corbett et al., 1971). In our subjects a rise in central venous plasma PGE concentration but not PGF concentration occurred during this induced hypertension. The findings therefore suggest that PGE, but not PGF, is released during such sympathetic nervous activity, and is consistent with conclusions from animal studies. The injection or infusion of catecholamines into isolated organs results in release of prostaglandins (Ferreira & Vane, 1967; McGiff, Crowshaw, Terragno, Malik & Lonigro, 1972). Noradrenaline infusions in intact animals also release PGE-like material (Gryglewski& Ocetkiewicz, 1974).Although a rise in concentration of plasma noradrenaline occurs in tetraplegic subjects during visceral stimulation (Debarge et al., 1974), the values do not exceed the resting limits for normal man. The massive outbursts of sympathetic nervous activity therefore may be a principal reason for release of PGE in our subjects. In animals, stimulation of the vagus nerve releases PGE (Bennett, Friedmann & Vane, 1967). In our subjects, a significant bradycardia accompanied the hypertension and is probably due to a baroreceptor reflex effect (Heymans & Neil, 1958), the afferent pathways being the vagus and glossopharyngeal nerves, and the efferent path the vagus. Parasympathetic activity may therefore also play a part in the rise in plasma PGE in these subjects. PGE is thought to exert a negativefeedbackcontrol on sympathetic neurotransmission (Hedqvist, 1973). Infusion of PGE inhibits transmitter release during sympathetic nerve stimulation in animal organs (Hedqvist, 1970; Hedqvist & Wennmalm, 1971), and also inhibits release of dopamine P-hydroxylase (Johnson, Thoa, Weinshilboum, Axelrod & Kopin, 1971). PGE can modify the effector response to sympathomimetic agents in uitro (Clegg, 1966) and in viuo (Bergstrom, Carlson, Ekelund & Oro, 1964). It is not yet known whether the elevated circulating concentrations of PGE produced in tetraplegic patients are sufficient to exert such effects and whether its release modulates the hypertension resulting from sympathetic nervous activity. The use of prostaglandin synthesis inhibitors may help in answering these questions. The results of our investigations indicate an increase in plasma PGE during sympathetic nervous overactivity in tetraplegic subjects and suggest that PGE may be part of a system involved in blood pressure homeostasis in man.

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GREEN,K. & SAMUELSSON, B. (1971) Quantitative studies on the synthesis in vivo of prostaglandins in the rat. European Journal of Biochemistry, 22, 391-395. We thank Dr J. J. Walsh for facilities, and Mrs S. GRYGLEWSKI, R.J. & OCETKIEWICZ, A. (1974) A release of Dilley, Mrs J. Rose and Mr R. Hill for valuable prostaglandins may be responsible for acute tolerance to technical assistance. The World Health Organisation norepinephrine infusions. Prostaglandins, 8, 3 1-42. HEDQVIST, P. (1970) Control by prostaglandin E2 of symprovided support for K.H. C.J.M. is a Rhodes pathetic neurotransmission in the spleen. Life Sciences, Scholar at the University of Oxford. 9,269-278. HEDQVIST,P. (1973) Autonomic neurotransmission. In: The Prostaglandins, pp. 101-131. Ed. Ramwell, P.W. References Plenum Press, New York. HEDQVIST, P. & WENNMALM, A. (1971) Comparison of the BENNETT, A., FRIEDMANN, C.A. & VANE,J.R. (1967) Release effects of prostaglandins El, E2 and F2. on the symof prostaglandin El from the rat stomach. Nature(London), pathetically stimulated rabbit heart. Acta Physiologica 216, 873-876. BERGSTROM, S., CARLSON, L.A., EKELUND, L.G. & ORO, L. Scandinavica, 83, 156-162. HEYMANS, C. & NEIL, E. (1958) Reflexogenic Areas of the (1 964) Cardiovascular and metabolic response to infusions Cardiovascular System. Churchill, London. of prostaglandin El and to simultaneous infusions of HILLIER,K. & DILLEY,S.R. (1974) Separation and radionoradrenaline and prostaglandin El in man. Acta Physioimmunoassay of F a prostaglandins using silica gel micro Iogica Scandinavica, 64, 332-339. columns. Prostaglandins, 5, 137-150. CLEGG,P.C. (1966) The effect of prostaglandins on the HORTON,E.W. (1973) Prostaglandins at adrenergic nerveresponse of isolated smooth-muscle preparations to endings. British Medical Bulletin, 29, 148-1 51. sympathomimetic substances. Memoirs Society for JOHNSON, D.G., THOA, N.B., WEINSHILBOUM, R., AXELROD, Endocrinology, 14, 119-135. J. & KOPIN,I.J. (1971) Enhanced release of dopamine CORBETT, J.L., FRANKEL, H.L. &HARRIS, P.J. (1971) Cardio/I-hydroxylase from sympathetic nerves by calcium and vascular reflex responses to cutaneous and visceral phenoxybenzamine and its reversal by prostaglandins. stimuli in spinal man. Journal of Physiology (London), 215, Proceedings of the National Academy of Sciences of the 395409. United States of America, 68, 2227-2230. DAVIES, B.N., HORTON, E.W. & WITHRINGTON, P.G. (1967) MCGIFF,J.C., CROWSHAW, K., TERRAGNO, N.A., MALIK, The occurrence of prostaglandin E2 in splenic nerve K.U. & LONIGRO, A.J. (1972) Differential effect of norstimulation. Journal of Physiology (London), 1 8 8 , 3 8 ~ - 3 9 ~ . adrenaline and renal nerve stimulation on vascular DAVIS,H.A. & HORTON,E.W. (1972) Output of prostaresistance in the dog kidney and the release of a prostaglandins from the rabbit kidney, its increase on renal glandin E-like substance. Clinical Science, 42, 223-233. nerve stimulation and its inhibition by indomethacin. NEEDLEMAN, P., DOUGLAS,J.R., JR, JAKSCHIK,B., British Journal of Pharmacology, 46, 658-675. STOECKLEIN, P.B. &JOHNSON, E.M., JR (1974) Release of DEBARGE, O., CHRISTENSEN, N.J., CORBETT, J.L., EIDELMAN, renal prostaglandin by catecholamines: relationship to B.H., FRANKEL, H.L. & MATHIAS,C.J. (1974) Plasma renal endocrine function. Journal of Pharmacology and catecholamines in tetraplegics. Paraplegia, 12, 4 4 4 9 . Experimental Therapeutics, 188, 453-460. FERREIRA, S.H. & VANE,J.R. (1967) Prostaglandins: their SAMUELSSON, B. (1972) Biosyntbesis of prostaglandins. disappearance from and release into the circulation. Federation Proceedings, 31, 1442-1450. Nature (London), 216, 868-873.

Acknowledgments

Plasma prostaglandin E during neurogenic hypertension in tetraplegic man.

1. Arterial blood pressure and heart rate were measured before, during and after cutaneous and visceral stimulation in subjects tetraplegic due to sev...
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