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Naloxone reversal of hemorrhagic hypotension in the conscious guinea-pig is impeded by inhibition of the renin-angiotensin II system
Neuroscience Vol. 22, No. I, pp. 313-315, Printed in Great Britain
0306-4522187
1987
$3.00 + 0.00
Pergamon Journals Ltd 6 1987 IBRO
NALOXONE REVERSAL OF HEMORRHAGIC HYPOTENSION IN THE CONSCIOUS GUINEA-PIG IS IMPEDED BY INHIBITION OF THE RENIN-ANGIOTENSIN II SYSTEM V. T. INNANEN,*t
E. JoBErt
and N. KoRoGYIt
*Department of Clinical Biochemistry, University of Toronto, Toronto, Ontario, TDivision of Clinical Biochemistry, Department of Clinical Laboratories, Women’s Toronto, Ontario, Canada
Canada; and College Hospital,
Abstract-Naloxone reverses hemorrhagic hypotension in the conscious guinea-pig. Captopril and saralasin impede this naloxone effect, suggesting that angiotensin II is involved in naloxone action. This is compatible with previous work which has shown that B-endorphin inhibits the centrally mediated pressor action of angiotensin II, and that naloxone blocks this effect. Naloxone may be interacting with
the postulated brain renin-angiotension circulating angiotensin II on a centrally
II system or may be blocking the action of shock-induced located
area such as the hypothalamus.
procedure. Blood pressure (BP) was measured with a Hewlett-Packard model No. 780-9 BP monitor. After an initial equilibration period of 30 min, systolic BP was dropped to approximately 30 mm Hg, by withdrawing blood from the catheter (l-2 min). After bleeding, naloxone was administered as a bolus, intra-arterially (0.5 mg/kg in 0.3 ml of saline). Control animals received 0.3 ml of saline without added naloxone. Captopril was injected intraarterially at the middle (2 mg/kg in 0.3 ml saline) and at the end of the bleeding period (2 mg/kg in 0.3 ml saline) in a similar fashion to that described by Zerbe and Feuerstein in rats.*’ Saralasin was injected in a similar fashion at the middle (40 Rg/kg in 0.3 ml of saline) and at the end of the bleeding period (40 Rg/kg in 0.3 ml of saline). When saline was given in place of captopril or saralasin, naloxone effect was not inhibited. When given in combination with captopril or saralasin, an initial 2 min equilibration period was allowed prior to giving the intra-arterial dose of naloxone (0.5 mg/kg). Naloxone was obtained from the E. I. DuPont Co., Wilmington, Delaware. Captopril was a generous gift from Squibb Canada and saralasin [(AI1 I-sarcosine, I-alanine) Angiotensin II antagonist] was obtained from Calbiochem, California. Statistical analysis was carried out by using ANOVA and the non-paired r-test as described in the figure legends.
Naloxone, an opiate antagonist, reverses hypotension in hemorrhagic, septic and spinal shock.‘,2*4,9,‘2.‘7Its mode of action remains controversial, although there is evidence for involvement of the CNS as well as for direct myocardial action. In addition, a requirement for the presence of adrenal tissue has been described. Holaday et &.“*” suggested that B-endorphin secretion during hemorrhagic and/or septic shock contributes to the hypotension in these states, and therefore proposed that naloxone reverses the hypotension by counteracting the effect of Bendorphin. ‘.9*‘o~”Peters et al.” have shown that naloxone is ineffective in reversing hypotension in endotoxic patients that are hypoadrenocorticotrophic. This has also been shown in rats that have undergone hypophysectomy.” It would appear that a pituitary secretion is necessary for naloxone action, and most likely, this is B-endorphin. Summy-Long et al. *’ have shown that B-endorphin inhibits the centrally mediated vasopressor action of angiotensin II (AII) and that naloxone blocks this action centrally. This may, at least in part explain the action of naloxone in restoration of blood pressure in various states of hypotension. EXPERIMENTAL
RESULTS
As shown in Fig. 1, naloxone caused an initial increase of systolic BP of almost 15 mm Hg on average. Captopril, on the other hand, inhibited the naloxone effect totally and reduced the BP recovery to control levels. Saralasin inhibited the naloxoneinduced increase of systolic BP, but less effectively than captopril. This difference in action may be related to specificity of action (discussion). As seen in Fig. 2, naloxone increased diastolic pressure by a lesser amount than systolic when compared with control values. Captopril and saralasin were both ineffective in inhibiting the diastolic BP increase initiated by naloxone.
PROCEDURES
Guinea-pigs (350-400 g) were obtained from Charles River Farms. Carotid intra-arterial catheters (PE 50, Clay Adams) were introduced under phenobarbital anesthesia. Five days of recovery were allowed prior to testing. The guinea-pigs were treated under light restraint and were fully awake. They did not appear to suffer ill-effects during the
Address for correspondence: Dr V. T. Innanen, Division of Clinical Biochemistry, Department of Clinical Laboratories, Women’s College Hospital, 76 Grenville Street, Toronto, Ontario, Canada M5S lB2. Abbreviations: AII, angiotensin II; BP, blood pressure. N’i, ,‘, I1
(
313
314
V. T.
INNANEN el
TIME (SW)
Fig. I. The effect of saralasin and captopril on the naloxoneinduced elevation of systolic BP after hemorrhage in the unanesthetized guinea-pig. Normal BP recovery (A, n = I8 and S.E.M.); BP recovery with naloxone (0) II = 17 and S.E.M.); saralasin and naloxone (0, n = 8 and S.E.M.), *P < 0.02 when A P is compared to naloxone activation; captopril and naloxone (A, n = 6 and S.E.M.), **P < 0.01, when A P is compared to naloxone activation. The P values were obtained by the use of the non-paired r-test. The difference in values when compared by ANOVA were significant at a level of P < 0.01.
DISCUSSION
From our results, it is apparent that naloxone elevates both systolic and diastolic BP after hemorrhage in the conscious guinea-pig. The guinea-pig has not been previously used in naloxone experiments. The potential effect of anesthetic agents on naloxone action has not been clarified as pointed out by
5r
1
0
20
40
60
100
TIME (set)
Fig. 2. The effect of saralasin and captopril in the naloxoneinduced elevation of diastolic BP after hemorrhage in the unanesthetized guinea-pig. Normal BP recovery (A, n = 18 and S.E.M.); BP recovery with naloxone (O), n = 17 and S.E.M.), *P < 0.02 when A P is compared to normal recovery; saralasin and naloxone (0 n = 8 and S.E.M.); captopril and naloxone (A, n = 6 and S.E.M.). The P value was obtained by the use of the non-paired r-test.
al.
Lechner et al.” Our results are in accord with previous work using anesthetic agents12m14J6as we]] as those not.‘,’ Captopril was found to totally abolish the effect of naloxone, on systolic BP, suggesting that the renin-AI1 system is involved. Captopril, however, is not specific as a converting enzyme inhibitor. Its effect as a kininase inhibitor (with resultant increase in bradykinin 1eveP) may be involved. In answer to this question, saralasin, which is a specific antagonist of AH (its agonist properties are thought not to be operative in hemorrhagic shock’) was employed. Saralasin inhibited the naloxone effect on systolic BP to a significant degree, although not as effectively as captopril. As indicated, this would reflect on the specificity of action of saralasin. We conclude that AI1 plays a role in naloxoneinduced elevation of systolic BP in hemorrhagic shock, in the conscious guinea-pig. Summy-Long et ~1.‘~have shown that B-endorphin inhibits the centrally mediated vasopressor action of AI1 and that naloxone blocks this effect centrally. A likely CNS location for this action is the hypothalamus since it is known that this area contains a high concentration of AI1 receptors. r8,19Naloxone may be interacting with the postulated brain renin-AI1 system,@” or it may inhibit the action of circulating AII. It is known that hemorrhagic hypotension results in extremely high circulating AI1 levels,” and it may be that naloxone is interacting with AI1 derived from the circulation. Although experiments by Feuerstein et al.’ showed that naloxone was effective in the anephric cat, it was clear from their experiments that at the 10 minute data point, post hemorrhage, naloxone was more effective in the intact cat in both absolute and relative terms. This suggests that a kidney related factor or factors is required for most effective naloxone action. One such kidney factor would be renin and its subsequent action to produce AH. This centrally located action of naloxone would explain why the systolic pressure is affected rather than the diastolic (Fig. 2). Blocking AII action peripherally should have involved a diastolic pressure change by reducing the pressor action directly on blood vessels. Koyama et a1.l2 have previously shown that naloxone works by increasing central sympathetic discharge in the endotoxic cat. Our experiments would indicate that part of this discharge (that associated with AII) is directed toward the myocardium with a consequent increase in stroke volume and little effect on the diastolic BP. Because the effect of saralasin is not total, it is probable that other factors are operational as well, such as direct potentiation of catecholamine action on the myocardium as suggested by Lechner et LZ~.‘~.‘~ or involvement of the adrenal gland as suggested by Patton et al..” Acknowledgemenrs-The authors wish to thank E. I. Dupont Pharmaceuticals for their gift of naloxone and Squibb Canada Pharmaceuticals for captopril. This work was supported by the Women’s College Hospital Research Fund.
Naloxone reversal
315
REFERENCES
1. Faden A. I. and Holaday J. W. (1980) Experimental endotoxin shock: The pathophysiologic function of endorphins and treatment with opiate antagonists. J. If. Dis. 142, 229-238. 2. Faden A. I. and Holaday J. W. (1981) Endorphins in traumatic spinal injury. Mod. Probl. Pharmacopsychiat. 17, 158-174.
3. Feuerstein G., Ailam R. and Bergman F. (1980) Reversal by naloxone of hemorrhagic shock in anephric cats. Eur. J. Pharmac. 65, 93-96.
4. Feuerstein G., Chiueh C. C. and Kopin I. J. (1981) Effect of naloxone on the cardiovascular and sympathetic response to hypovolemic hypotension in the rat. Eur. J. Pharmac. 75, 65-69. 5. Feuerstein G. and Cohen S. (1979) Modification by SQ 14225 of blood pressure and adrenal catecholamine response to hemorrhage. Eur. J. Pharmac. 55, 203-206. 6. Feuerstein G. and Siren A. (1986) Effect of naloxone and morphine on survival of conscious rats after hemorrhage. Circulatory Shock 19, 293-300.
6a. Ganten D., Printz M., Unger T. and Lang R. E. (1984) The brain renin-angiotension system: problems and answers. In Topics in the Pathogenesis of Hypertension (eds Villareal H. and Sambhi M. P.), pp. 440-458. Martinius Nijhoff, Boston. 7. Hock C. E., Passmore J. C., Levin J. I. and Neiberger R. E. (1982) Angiotensin II and a-adrenergic control of the intrarenal circulation in hemorrhage. Circulatory Shock 9, 81-94. 8. Holaday J. W. and Faden A. I. (1978) Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock. Narure 275, 45&45 1. 9. Holaday J. W. and Faden A. I. (1981) Naloxone treatment in shock. Lancer, July 25, 201. 10. Holaday J. W. and Faden A. I. (1981) The pathophysiologic role of endorphins in experimental shock. J. Inf Dis. 143, X63-864.
11. Holaday J. W., O’Hara M. and Faden A. I. (1981) Hypophysectomy alters cardiorespiratory variables: central effects of oituitarv endornhins in shock. Am. J. Phvsiol. 241. H479-H485. 12. Koyama S., Santidsteban H. L., Ammons WI S. and Manning J. W. (1983) The effects of naloxone on the peripheral sympathetics in cat endotoxin shock. Circularory Shock 10, 7-13. 13. Lechner R. B., Gurll N. J. and Reynolds D. G. (1985) Role of the autonomic nervous system in mediating the response to naloxone in canine hemorrhagic shock. Circulatory Shock 16, 279-295. 14. Lechner R. B., Gurll N. J. and Reynolds D. G. (1985) Naloxone potentiates the cardiovascular effects of catecholamines in canine hemorrhagic shock. Circulatory Shock 16, 347-361. 15. Morton J. J., Semple P. F., Ledingham I. M., Stuart B., Tehrani M. A., Garcia A. R. and McGarrity G. (1977) Effect of angiotensin-converting enzyme inhibitor (SQ 20881) on the plasma concentration of Angiotensin I, Angiotensin II and Arginine Vasopressin in the dog during hemorrhagic shock. Circulatory Res. 41, 301-308. 16. Patton M. L., Gurll N. J., Reynolds D. G. and Vargish T. (1983) Adrenalectomy abolishes and cortisol restores naloxone’s beneficial effects on cardiovascular function and survival in canine hemorrhagic shock. Circulatory Shock 10, 317-327. 17. Peters W. P., Johnson M. W., Friedman P. A. and Mitch W. E. (1981) Pressor effect of naloxone in septic shock. Lancer, March 7, 529-532. 18. Simpson J. B. (1981) The circumventricular organs and central actions of angiotensin. Neuroendocrinology 32,248-256. 19. Sirett N. W., Hubbard J. I. and Bray J. J. (1982) Brain angiotensin II receptors. Expl Brain Res, Suppl. 4, 233-241. 20. Summy-Long J. Y., Keil L. C., Deen K., Rosella L. and Severs W. B. (1981) Endogenous opioid peptide inhibition of the central actions of angiotensin. J. Pharmac. exp. Ther. 217, 619429. 21. Zerbe R. L., Feuerstein G. and Kopin I. J. (1981) Effect of captopril on cardiovascular, sympathetic and vasopressin responses to hemorrhage. Eur. J. Pharmac. 72, 391-395. (Accepted 11 November 1986)
0306-4522187
1987
$3.00 + 0.00
Pergamon Journals Ltd 6 1987 IBRO
NALOXONE REVERSAL OF HEMORRHAGIC HYPOTENSION IN THE CONSCIOUS GUINEA-PIG IS IMPEDED BY INHIBITION OF THE RENIN-ANGIOTENSIN II SYSTEM V. T. INNANEN,*t
E. JoBErt
and N. KoRoGYIt
*Department of Clinical Biochemistry, University of Toronto, Toronto, Ontario, TDivision of Clinical Biochemistry, Department of Clinical Laboratories, Women’s Toronto, Ontario, Canada
Canada; and College Hospital,
Abstract-Naloxone reverses hemorrhagic hypotension in the conscious guinea-pig. Captopril and saralasin impede this naloxone effect, suggesting that angiotensin II is involved in naloxone action. This is compatible with previous work which has shown that B-endorphin inhibits the centrally mediated pressor action of angiotensin II, and that naloxone blocks this effect. Naloxone may be interacting with
the postulated brain renin-angiotension circulating angiotensin II on a centrally
II system or may be blocking the action of shock-induced located
area such as the hypothalamus.
procedure. Blood pressure (BP) was measured with a Hewlett-Packard model No. 780-9 BP monitor. After an initial equilibration period of 30 min, systolic BP was dropped to approximately 30 mm Hg, by withdrawing blood from the catheter (l-2 min). After bleeding, naloxone was administered as a bolus, intra-arterially (0.5 mg/kg in 0.3 ml of saline). Control animals received 0.3 ml of saline without added naloxone. Captopril was injected intraarterially at the middle (2 mg/kg in 0.3 ml saline) and at the end of the bleeding period (2 mg/kg in 0.3 ml saline) in a similar fashion to that described by Zerbe and Feuerstein in rats.*’ Saralasin was injected in a similar fashion at the middle (40 Rg/kg in 0.3 ml of saline) and at the end of the bleeding period (40 Rg/kg in 0.3 ml of saline). When saline was given in place of captopril or saralasin, naloxone effect was not inhibited. When given in combination with captopril or saralasin, an initial 2 min equilibration period was allowed prior to giving the intra-arterial dose of naloxone (0.5 mg/kg). Naloxone was obtained from the E. I. DuPont Co., Wilmington, Delaware. Captopril was a generous gift from Squibb Canada and saralasin [(AI1 I-sarcosine, I-alanine) Angiotensin II antagonist] was obtained from Calbiochem, California. Statistical analysis was carried out by using ANOVA and the non-paired r-test as described in the figure legends.
Naloxone, an opiate antagonist, reverses hypotension in hemorrhagic, septic and spinal shock.‘,2*4,9,‘2.‘7Its mode of action remains controversial, although there is evidence for involvement of the CNS as well as for direct myocardial action. In addition, a requirement for the presence of adrenal tissue has been described. Holaday et &.“*” suggested that B-endorphin secretion during hemorrhagic and/or septic shock contributes to the hypotension in these states, and therefore proposed that naloxone reverses the hypotension by counteracting the effect of Bendorphin. ‘.9*‘o~”Peters et al.” have shown that naloxone is ineffective in reversing hypotension in endotoxic patients that are hypoadrenocorticotrophic. This has also been shown in rats that have undergone hypophysectomy.” It would appear that a pituitary secretion is necessary for naloxone action, and most likely, this is B-endorphin. Summy-Long et al. *’ have shown that B-endorphin inhibits the centrally mediated vasopressor action of angiotensin II (AII) and that naloxone blocks this action centrally. This may, at least in part explain the action of naloxone in restoration of blood pressure in various states of hypotension. EXPERIMENTAL
RESULTS
As shown in Fig. 1, naloxone caused an initial increase of systolic BP of almost 15 mm Hg on average. Captopril, on the other hand, inhibited the naloxone effect totally and reduced the BP recovery to control levels. Saralasin inhibited the naloxoneinduced increase of systolic BP, but less effectively than captopril. This difference in action may be related to specificity of action (discussion). As seen in Fig. 2, naloxone increased diastolic pressure by a lesser amount than systolic when compared with control values. Captopril and saralasin were both ineffective in inhibiting the diastolic BP increase initiated by naloxone.
PROCEDURES
Guinea-pigs (350-400 g) were obtained from Charles River Farms. Carotid intra-arterial catheters (PE 50, Clay Adams) were introduced under phenobarbital anesthesia. Five days of recovery were allowed prior to testing. The guinea-pigs were treated under light restraint and were fully awake. They did not appear to suffer ill-effects during the
Address for correspondence: Dr V. T. Innanen, Division of Clinical Biochemistry, Department of Clinical Laboratories, Women’s College Hospital, 76 Grenville Street, Toronto, Ontario, Canada M5S lB2. Abbreviations: AII, angiotensin II; BP, blood pressure. N’i, ,‘, I1
(
313
314
V. T.
INNANEN el
TIME (SW)
Fig. I. The effect of saralasin and captopril on the naloxoneinduced elevation of systolic BP after hemorrhage in the unanesthetized guinea-pig. Normal BP recovery (A, n = I8 and S.E.M.); BP recovery with naloxone (0) II = 17 and S.E.M.); saralasin and naloxone (0, n = 8 and S.E.M.), *P < 0.02 when A P is compared to naloxone activation; captopril and naloxone (A, n = 6 and S.E.M.), **P < 0.01, when A P is compared to naloxone activation. The P values were obtained by the use of the non-paired r-test. The difference in values when compared by ANOVA were significant at a level of P < 0.01.
DISCUSSION
From our results, it is apparent that naloxone elevates both systolic and diastolic BP after hemorrhage in the conscious guinea-pig. The guinea-pig has not been previously used in naloxone experiments. The potential effect of anesthetic agents on naloxone action has not been clarified as pointed out by
5r
1
0
20
40
60
100
TIME (set)
Fig. 2. The effect of saralasin and captopril in the naloxoneinduced elevation of diastolic BP after hemorrhage in the unanesthetized guinea-pig. Normal BP recovery (A, n = 18 and S.E.M.); BP recovery with naloxone (O), n = 17 and S.E.M.), *P < 0.02 when A P is compared to normal recovery; saralasin and naloxone (0 n = 8 and S.E.M.); captopril and naloxone (A, n = 6 and S.E.M.). The P value was obtained by the use of the non-paired r-test.
al.
Lechner et al.” Our results are in accord with previous work using anesthetic agents12m14J6as we]] as those not.‘,’ Captopril was found to totally abolish the effect of naloxone, on systolic BP, suggesting that the renin-AI1 system is involved. Captopril, however, is not specific as a converting enzyme inhibitor. Its effect as a kininase inhibitor (with resultant increase in bradykinin 1eveP) may be involved. In answer to this question, saralasin, which is a specific antagonist of AH (its agonist properties are thought not to be operative in hemorrhagic shock’) was employed. Saralasin inhibited the naloxone effect on systolic BP to a significant degree, although not as effectively as captopril. As indicated, this would reflect on the specificity of action of saralasin. We conclude that AI1 plays a role in naloxoneinduced elevation of systolic BP in hemorrhagic shock, in the conscious guinea-pig. Summy-Long et ~1.‘~have shown that B-endorphin inhibits the centrally mediated vasopressor action of AI1 and that naloxone blocks this effect centrally. A likely CNS location for this action is the hypothalamus since it is known that this area contains a high concentration of AI1 receptors. r8,19Naloxone may be interacting with the postulated brain renin-AI1 system,@” or it may inhibit the action of circulating AII. It is known that hemorrhagic hypotension results in extremely high circulating AI1 levels,” and it may be that naloxone is interacting with AI1 derived from the circulation. Although experiments by Feuerstein et al.’ showed that naloxone was effective in the anephric cat, it was clear from their experiments that at the 10 minute data point, post hemorrhage, naloxone was more effective in the intact cat in both absolute and relative terms. This suggests that a kidney related factor or factors is required for most effective naloxone action. One such kidney factor would be renin and its subsequent action to produce AH. This centrally located action of naloxone would explain why the systolic pressure is affected rather than the diastolic (Fig. 2). Blocking AII action peripherally should have involved a diastolic pressure change by reducing the pressor action directly on blood vessels. Koyama et a1.l2 have previously shown that naloxone works by increasing central sympathetic discharge in the endotoxic cat. Our experiments would indicate that part of this discharge (that associated with AII) is directed toward the myocardium with a consequent increase in stroke volume and little effect on the diastolic BP. Because the effect of saralasin is not total, it is probable that other factors are operational as well, such as direct potentiation of catecholamine action on the myocardium as suggested by Lechner et LZ~.‘~.‘~ or involvement of the adrenal gland as suggested by Patton et al..” Acknowledgemenrs-The authors wish to thank E. I. Dupont Pharmaceuticals for their gift of naloxone and Squibb Canada Pharmaceuticals for captopril. This work was supported by the Women’s College Hospital Research Fund.
Naloxone reversal
315
REFERENCES
1. Faden A. I. and Holaday J. W. (1980) Experimental endotoxin shock: The pathophysiologic function of endorphins and treatment with opiate antagonists. J. If. Dis. 142, 229-238. 2. Faden A. I. and Holaday J. W. (1981) Endorphins in traumatic spinal injury. Mod. Probl. Pharmacopsychiat. 17, 158-174.
3. Feuerstein G., Ailam R. and Bergman F. (1980) Reversal by naloxone of hemorrhagic shock in anephric cats. Eur. J. Pharmac. 65, 93-96.
4. Feuerstein G., Chiueh C. C. and Kopin I. J. (1981) Effect of naloxone on the cardiovascular and sympathetic response to hypovolemic hypotension in the rat. Eur. J. Pharmac. 75, 65-69. 5. Feuerstein G. and Cohen S. (1979) Modification by SQ 14225 of blood pressure and adrenal catecholamine response to hemorrhage. Eur. J. Pharmac. 55, 203-206. 6. Feuerstein G. and Siren A. (1986) Effect of naloxone and morphine on survival of conscious rats after hemorrhage. Circulatory Shock 19, 293-300.
6a. Ganten D., Printz M., Unger T. and Lang R. E. (1984) The brain renin-angiotension system: problems and answers. In Topics in the Pathogenesis of Hypertension (eds Villareal H. and Sambhi M. P.), pp. 440-458. Martinius Nijhoff, Boston. 7. Hock C. E., Passmore J. C., Levin J. I. and Neiberger R. E. (1982) Angiotensin II and a-adrenergic control of the intrarenal circulation in hemorrhage. Circulatory Shock 9, 81-94. 8. Holaday J. W. and Faden A. I. (1978) Naloxone reversal of endotoxin hypotension suggests role of endorphins in shock. Narure 275, 45&45 1. 9. Holaday J. W. and Faden A. I. (1981) Naloxone treatment in shock. Lancer, July 25, 201. 10. Holaday J. W. and Faden A. I. (1981) The pathophysiologic role of endorphins in experimental shock. J. Inf Dis. 143, X63-864.
11. Holaday J. W., O’Hara M. and Faden A. I. (1981) Hypophysectomy alters cardiorespiratory variables: central effects of oituitarv endornhins in shock. Am. J. Phvsiol. 241. H479-H485. 12. Koyama S., Santidsteban H. L., Ammons WI S. and Manning J. W. (1983) The effects of naloxone on the peripheral sympathetics in cat endotoxin shock. Circularory Shock 10, 7-13. 13. Lechner R. B., Gurll N. J. and Reynolds D. G. (1985) Role of the autonomic nervous system in mediating the response to naloxone in canine hemorrhagic shock. Circulatory Shock 16, 279-295. 14. Lechner R. B., Gurll N. J. and Reynolds D. G. (1985) Naloxone potentiates the cardiovascular effects of catecholamines in canine hemorrhagic shock. Circulatory Shock 16, 347-361. 15. Morton J. J., Semple P. F., Ledingham I. M., Stuart B., Tehrani M. A., Garcia A. R. and McGarrity G. (1977) Effect of angiotensin-converting enzyme inhibitor (SQ 20881) on the plasma concentration of Angiotensin I, Angiotensin II and Arginine Vasopressin in the dog during hemorrhagic shock. Circulatory Res. 41, 301-308. 16. Patton M. L., Gurll N. J., Reynolds D. G. and Vargish T. (1983) Adrenalectomy abolishes and cortisol restores naloxone’s beneficial effects on cardiovascular function and survival in canine hemorrhagic shock. Circulatory Shock 10, 317-327. 17. Peters W. P., Johnson M. W., Friedman P. A. and Mitch W. E. (1981) Pressor effect of naloxone in septic shock. Lancer, March 7, 529-532. 18. Simpson J. B. (1981) The circumventricular organs and central actions of angiotensin. Neuroendocrinology 32,248-256. 19. Sirett N. W., Hubbard J. I. and Bray J. J. (1982) Brain angiotensin II receptors. Expl Brain Res, Suppl. 4, 233-241. 20. Summy-Long J. Y., Keil L. C., Deen K., Rosella L. and Severs W. B. (1981) Endogenous opioid peptide inhibition of the central actions of angiotensin. J. Pharmac. exp. Ther. 217, 619429. 21. Zerbe R. L., Feuerstein G. and Kopin I. J. (1981) Effect of captopril on cardiovascular, sympathetic and vasopressin responses to hemorrhage. Eur. J. Pharmac. 72, 391-395. (Accepted 11 November 1986)