M. E. SAFAR, A. F. HORNYCH, J. A. LEVENSON, A. CH. SIMON,. Haemodynamic Laboratory of the Hypertension Research Centre and U-28 INSERM, ...
Clinical Science (1981) 61,323s-325s
Central haemodynamics and plasma prostaglandin E2in borderline and sustained essential hypertensive patients before and after indomethacin
M. E. S A F A R , A. F . H O R N Y C H , J . A . L E V E N S O N , A . C H . S I M O N , G. M. L O N D O N , J . L. B A R I E T Y . A N DP . L. M I L L I E Z Haemodynamic Laboratory of the Hypertension Research Centre and U-28 INSERM, Broussais Hospital, Paris, France
Summary 1. In basal conditions, plasma arterial prostaglandin (PG) E, was significantly increased in borderline hypertensive patients (BH) (28.5 f 6-7 pg/ml) in comparison with sustained essential hypertensive patients (EH) (11.6 f 3 - 2 pg/ml) and in comparison with control normotensive subjects (NTS) (5.8 5 1.4 pg/ml). 2. Plasma arterial PGE, was positively significantly correlated with cardiac index and negatively significantly correlated with total peripheral resistance in basal conditions. 3. Indomethacin induced more pronounced haemodynamic changes in borderline than in sustained hypertensive patients, with a significant increase in arterial blood pressure and total peripheral resistance and a significant decrease in stroke volume and cardiac index. 4. Indomethacin significantly decreased arterial PGE, in borderline hypertensive patients. The decrease was less important in sustained hypertensive patients. 5 . In the overall population, a significant positive correlation between arterial PGE, concentration and cardiac index was observed before and after indomethacin treatment. 6. The study suggests an important role of PGE, in the regulation of cardiac output (positive inotropic effect) and blood pressure of essential hypertensive patients. Key words: borderline and sustained hypertension, haemodynamics, indomethacin, prostaglandin E,. Correspondence: Dr A. Hornych, Hypertension Laboratory, U-28 INSERM,Broussais Hospital, 96, . rue Didot, 75674 Paris Cedex 14, France.
Abbreviations: BH, borderline hypertensive; EH, essential hypertensive; PG, prostaglandin. Introduction A significant increase of plasma prostaglandin (PG) E, has been observed in borderline hypertension (BH) and from this finding it has been suggested that haemodynamic abnormalities in BH could be P G dependent [ l , 21. In order to have more direct evidence, we measured plasma PGE, and haemodynamics before and after inhibition of prostaglandin synthesis by indomethacin in patients with either borderline or sustained essential hypertension. Patients and methods Fifteen male patients were included in the present study: eight borderline hypertensive, mean age 25 f SEM 1 year, and seven sustained essential hypertensive, mean age 42 f 4 years, classified as borderline or sustained as measured after 1 year’s out-patient care, as previously described t31. All patients were kept in hospital, placed on standard 100 mmol of Na/day diet and their therapy was discontinued 4 weeks before the study. On day 3 of hospitalization, a transcutaneous catheter was placed in a subclavian vein for the injection of indocyanine green and another one in a brachial artery for the measurements of intra-arterial blood pressure and cardiac output by the dye-dilution method as previously described [31. Prostaglandins were measured in arterial blood taken in plastic sterile syringes; the blood was transferred into chilled plastic tubes containing EDTA (2 mg/ml) and indomethacin powder (0.1. mg/ml) (Merck, Sharp and Dohme). The plasma
M . E. Safar et al.
was separated by centrifugation at 4500 rev./min for 20 min at 4OC; 3 ml was extracted twice with ethyl acetate, PG were separated by silicic acid column chromatography [41 and PGE, was measured by radioimmunoassay [5, 61. As previously described [21 normal peripheral PGE, concentrations in normotensive subjects are: (a) 20-25 years, 5-5 f 0.9 pg/ml; (b) 25-50 years, 6.8 f 1-3pg/ml; (c) in central venous blood 10.8 f 3.7 pg/ml for persons aged 25-50 years. Supine haemodynamics and control PG measurements were performed before and 60 min after the intramuscular administration of indomethacin (1 mg/kg). Results
After indomethacin administration, mean arterial blood pressure increased from 98 f 1 mmHg to 107 t 4 mmHg (P < 0.05) in borderline hypertensive patients (BH) and from 118 f 6 mmHg to 127 t 3 mmHg in patients with sustained essential hypertension patients (EH). Cardiac index of BH decreased from 5318 f 469 to 4155 f 290 ml min-' m-' (P < 0.005) and stroke index decreased from 64 t 1 to 58 t 2 ml/m2 (P < 0.025). Cardiac index of EH decreased from 3661 f 366 to 2895 f: 330 ml min-I m-, (P < 0.001) and stroke index decreased from 48 t 4 (P< 0-005vs BH) to 43 & 3 ml/m2 (P< 0.025). Heart rate decreased in BH from 83 6 to 71 f 5 beats/min (P < 0.02) and in EH from 77 t 5 to 67 t 6 beatdmin (P < 0.005). Total peripheral resistance increased in BH from 1562 f 146 to 2127 t 121 dyn s ~ m m2 - ( ~ P< 0.001) and increased in EH from 2706 255 (P < 0.005 vs BH) to 3747 f 363 dyn s ~ m m2 - (P ~ < 0.005). Arterial PGE, decreased in BH from 28.5 f 6.7 to 22.9 f 6.8 pg/ml (P < 0-02), and in sustained hypertensive patients from 11a 5 f 2.9 to 10.6 f 3.2 pg/ml. Basal arterial PGE, concentration in BH, 28.5 f 6.7 pg/ml, was significantly higher than the peripheral venous PGE, concentration of control normotensive age-matched men ( n = 7, 5-4 f 0 - 9 pg/ml, P < 0.01) and also significantly higher in comparison with basal arterial PGE, concentrations, 11.5 t 2.5 pg/ml, in EH (P < 0.02). The last value was not significantly different from peripheral venous PGE, concentrations in age-matched normotensive men ( n = 6,6.9 & 1.3 pg/ml). Plasma arterial PGE, concentration was positively correlated in both groups of patients with cardiac index before treatment ( n = 14, r = 0.70, P < 0.01) and after treatment (n = 14, r = 0.63, P < OmOS), and with all values before and after treatment (n = 28, r = 0.64, P < 0 4 0 1 )
FIG. 1. Relationship between cardiac index and arterial PGE, concentrations (semi-logarithmic scale) in borderline (0,0 ) and sustained essential (0, W) hypertensive patients before and after indomethacin administration (28 determinations; arterial blood was not available for P G determinations in two patients). 0 ,0, Control; 0 , 1 indomethacin. R = 0.64; P < 0.001.
(Fig. 1). Arterial PGE, was negatively correlated with total peripheral resistance before treatment (n = 14, r = -0.67, P < 0.01) and with all values before and after treatment ( n = 28, r = -0.52, P < 0.01). Discussion In this study we have found significantly increased plasma PGE, levels in borderline hypertensive patients in comparison with control normotensive subjects and patients with sustained hypertension. These results were observed in arterial blood, suggesting PGE, may exercise a systemic effect. There were also significant differences in haemodynamics between borderline and sustained essential hypertensive patients in the basal state. These differences may depend on different levels of arterial PGE,, because higher levels of PGE, were associated with higher cardiac index (Fig. 1) and lower total peripheral resistance and vice versa. These relationships are also documented by the positive significant correlation between PGE, and cardiac index (P < 0.01) and by the negative significant correlation between PGE, and total peripheral resistance (P < 0.01). The results could suggest positive inotropic and vasodilatory effects of PGE, in man . They also support the hypothesis that increased cardiac output and normal or decreased total peripheral resistance in borderline hypertension could be explained by increased plasma PGE, levels [ 11.
Plasma prostaglandins and haemodynamics These conclusions are corroborated by the effects of indomethacin treatment. This drug induced a significant decrease of plasma PGE,, mainly in borderline hypertensive patients. The decrease of plasma PGE, concentration under indomethacin treatment was associated with a significant increase of arterial blood pressure and total peripheral resistance and a significant decrease of cardiac index and stroke index. The decrease of PGE, was more pronounced in patients having the higher initial levels of PGE,, i.e. borderline hypertensive patients. Such observations suggest an important role of PGE, in the regulation of cardiac output and arterial blood pressure in hypertensive man. Acknowledgments
We are grateful to Dr J. E. Pike, Upjohn Company, Kalamazoo, U.S.A., for the generous gift of prostaglandin standards, to Dr EspiB, Merck, Sharp and Dohme Laboratories, for the
gift of indomethacin, and to Mrs Pillet and Mrs Krief for their excellent technical assistance. References [11 HORNYCH, A., LONDON,G., SAFAR,M., WEISS,Y., SIMON,A., GUYENE, T.T., BARIETY, J. & MILLIEZ, P. (1980) L'himodynamique de I'hypertension artirielle labile et les prostaglandines. Archives des Maladies du Coeur el des Vaisseaux, 73 (No. spkial), 32-38. I21 HORNYCH, A. (1980) Role of prostaglandins in control of blood pressure. In: Proslaglandin Synthefase Inhibifors: New Clinical Applications, pp. 231-256. Ed. P. Ramwell, A. R. Liss Inc., New York. [31 SAFAR,M.E., WEISS,Y.A., LEVENSON, J.A., LONDON,G.M. & MILLIEZ,P.L. (1973) Hemdynamic study of 85 patients with American Journal of Cardiolom, 31, borderline hypertension. .. 315-3 19. IAFFE, B.M., BEHRMAN,H.R. & PARKER,C.W. (1973) Radioimmunoassay measurement of prostaglandins E, A, and F in human plasma. Journal of Clinical Investigalion, 52, 398-405. HORNYCH, A., WEISS, Y., MENARD, J., CORVOL, P., FONTALIRAN, F., BARIET, J. & MILLIE&P. (1976) Radioimmunoassay of prostaglandins A and B in human plasma. Prostaglandins. 12,383-391. DRAY, F., CHARLIONEL, B. & MACLOUF,J. (1975) Radioimmunoassay of Prostaglandins F alpha, E, and E, in human plasma. European Journal of Clinical Investigafion, 5, 3 11318.