Prostanoids modulate opioid-induced increases in cerebrospinal fluid vasopressin concentration W. M. ARMSTEAD, R. MIRRO”f, M. SHIBATA, AND C. W. LEFFLER of Physiology and Biophysics, Laboratory for Research in Neonatal Physiology, Departments Pediatrics, and Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee 38163 Armstead, W. M., R. Mirro, M. Shibata, and C. W. Leffler. Prostanoids modulate opioid-induced increases in cerebrospinal fluid vasopressin concentration. Am. J. PhysioZ. 263 (Heart Circ. P!zysioL. 32): H1670-H1674, 1992.-Topical dynorphin and ,&endorphin produce increases in both prostanoid and vasopressin concentrations in cortical periarachnoid fluid of newborn pigs. The present study, in anesthetized piglets with cranial windows implanted, investigated the role of these prostanoids in the mediation of this vasopressin release by opioids. Topical prostaglandin (PC) I, (100 rig/ml) increased pial arteriolar diameter from 145 & 4 to 178 & 4 pm and also increased cerebrospinal fluid (CSF) vasopressin from 1.1 t 0.1 to 4.1 t 0.5 pU/ml, but CSF vasopressin was not changed by PGE2, PGF.),,, and U-46619. Therefore, it is possible that PGI, causes the increase in CSF vasopressin produced by opioids. Consistent with this concept, indomethacin and aspirin blocked dynorphinand P-endorphin-induced vasopressin release. The present data indicate that PGI, contributes to opioid-induced changes in CSF vasopressin concentration and, thereby, to vasopressinergic contributions to opioid-induced cerebral vascular responses. cerebral

circulation;

newborn

have demonstrated an interaction PREVIOUS STUDIES between brain prostanoids and control of vasopressin release. The intracerebroventricular administration of prostaglandin (PC) D2 and PGE2 increases plasma vasopressin concentration (10,13), whereas similar central administration of PGH synthase inhibitors abolished or attenuated the release of vasopressin by central administration of angiotensin II, by hemorrhage, or by increased plasma osmolality (10, 12, 14). Therefore, prostanoids seem to be involved in vasopressin release from the neurohypophysis. Vasopressin, prostanoids, and opioids interact in the control of the cerebral circulation (1, 3, 7). The opioid dynorphin produces tone-dependent responses in piglet pial arterioles (dilation during normotension and constriction during hypotension when cerebrovascular tone is decreased), while P-endorphin elicits only cerebral vasoconstriction. Both of these responses are associated with increases in both cortical periarachnoid cerebrospinal fluid (CSF) prostanoid and vasopressin levels (1, 3). Therefore, it is possible that these prostanoids cause the increase in CSF vasopressin produced by both opioids. Vasopressin also elicits tone-dependent responses (2) and appears to attenuate dynorphin-induced dilation but contributes to P-endorphin- and dynorphin-induced vasoconstriction (1, 8). The present study was designed to investigate the role of prostanoids in the mediation of vasopressin release by opioids. - -t Deceased H1670

28 February

1992. 0363-6135/92

$2.00

Copyright

METHODS Newborn pigs (l-7 days old) of either sex were used in these experiments. They were anesthetized with ketamine hydrochloride (33 mg/kg im) and acepromazine (3.3 mg/kg im). Anesthesia was maintained with cu-chloralose (30-50 mg/kg initially, supplemented with 5 mg. kg-’ h-l iv). A catheter was inserted into a femoral artery to record blood pressure and to sample for blood gases and pH. Another catheter was placed in a femoral vein for injection of drugs. The trachea was cannulated, and the animals were ventilated with room air. Body temperature was maintained at 37-38°C with a heating pad. For insertion of the cranial window, the scalp was removed and an opening was made in the skull over the parietal cortex. The dura was cut and retracted over the cut bone edge. The cranial window was placed in the hole and cemented in place with dental acrylic. The space under the window was filled with artificial CSF of the following composition (in mg): 220 KCl, 132 MgC&, 221 CaCl,, 7,710 NaCl, 402 urea, 665 dextrose, and 2,066 NaHCO,/l, pH 7.33, Pco:, 46 mmHg, and PO, 43 mmHg. Pial arterioles were observed with a dissecting microscope, a television camera mounted on the microscope, and a video monitor. Vascular diameter was measured with a video microscaler (model VPA 1000, For-A-Corp, Los Angeles, CA). Protocol. Pial arteriolar diameter was determined every minute for a lo-min exposure period after injection under the window of artificial CSF containing no drug and after injection of CSF containing a drug. Diameters were also measured lo-15 min after the highest concentration of a drug with CSF containing no drug was flushed. Typically, l-2 ml of CSF were flushed through the window over 30 s. Needles incorporated into the side of the window allowed infusion of CSF under the window and run off of excess CSF. We measured the peak response, and a CSF sample for vasopressin analysis was collected at the end of the lo-min exposure period. Cerebral cortical periarachnoid CSF (300 ~1) was collected by placing a syringe on an injection port of the cranial window. CSF was collected by slowly infusing artificial CSF into one side of the window and allowing the CSF under the window to drip freely into a collection tube on the opposite side. Responses to topical PGI, (10 and 100 rig/ml; 2 groups of animals used), PGE, and PGF2,, (10 rig/ml), and U-46619 (3 rig/ml; Upjohn, Kalamazoo, MI; 1 group of animals for all 3 prostanoids used) were obtained before and after cyclooxygenase inhibition with indomethacin (5 mg/kg iv; Merck Sharp & Dohme, West Point, PA). Previously, this dose of indomethacin has been shown to reduce cortical periarachnoid CSF prostanoid concentrations to nondetectable levels and inhibit the conversion of exogenous arachidonic acid to prostanoids on the cerebral surface by >90% (18). To investigate the role of prostanoids in mediating the previously observed ability of opioids to increase CSF vasopressin concentration, cortical periarachnoid CSF samples were collected after a lo-min exposure period to dynorphin and P-endorphin (lo-l0 and IO+ M, respectively; Sigma Chemical, St. Louis, MO) in the presence of either indomethacin or aspirin (50 mg/kg iv; Sigma) in two additional series of animals. Although several dynorphin peptides are known to exist, we have chosen to investigate the dynorphin peptide containing 13

0 1992 The

l

American

Physiological

Society

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amino acids (Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-LysLeu-Lys). Throughout the text, this form is referred to simply as dynorphin. Appropriate aliquots of the vehicles for the opioids (0.9% saline) and the prostanoids PGE2, PGFZ,,, and U-46619 (ethanol) were added to CSF infused under the window. This CSF vehicle had no effect on arteriolar diameter. The vehicle for PGIz was a tris(hydroxymethyl)aminomethane (Tris) buffer, pH 10, and addition of this buffer directly under the window had no effect on arteriolar diameter as reported previously (6). In the present study, the effect of Tris on CSF vasopressin concentration was also studied. All drug solutions were made fresh on the day of use. The stock opioid solution (10e3 M) was diluted appropriately and aliquoted for experimentation. These aliquots were stored at -20°C until the day of use, when small aliquots were then added to CSF for topical application. Similarly, the stock solutions of U-46619 (100 pg/ml) and other prostanoids (20 pg/ml) were stored at -60°C until the day of use, when small aliquots were added to CSF for topical application. Vasopressin analysis. CSF samples collected after a lo-min exposure to a drug were analyzed for lysine vasopressin (LVP) using radioimmunoassay by methods described previously (9, 20). Lysine is the form of vasopressin in the pig. Briefly, radioimmunoassay was accomplished by 1) an antiserum produced in rabbits that is highly selective for vasopressin [cross-reacts 100% with arginine vasopressin (AVP)] and does not crossreact with oxytocin, vasotocin, angiotensin I, angiotensin II, methionine enkephalin, leucine enkephalin, dynorphin 13, dynorphin 8, P-endorphin, and U50,488H and 2) lZ51-labeled AVP and World Health Organization LVP International Standard. The minimal level of detection was 0.07 FU/ml (1 MU -4 pg). Average recovery of added vasopressin has been 81 + 4%. Statistical analysis. Pial arteriolar diameter, systemic arterial pressure, and vasopressin levels were analyzed using repeated measures analysis of variance and t test where appropriate. If the F value was significant, the Fisher test was performed. An a-level of P < 0.05 was considered significant in all statistical tests. Values are represented as means + SE of absolute values or as percentages of change from control values. RESULTS

Topical PGI, (10 and 100 rig/ml) increased CSF vasopressin concentration (Fig. 1). The increased CSF vasopressin caused by PC& was not affected by indomethacin (5 mg/kg iv; Fig. 1). The vehicle for PGIe (Tris) had no effect on CSF vasopressin concentration (1 .l + 0.1

H1671

CONCENTRATION

vs. 1.0 + 0.2 pU/ml for control and Tris, respectively). The Tris buffer also had no effect on pial arteriolar diameter (145 + 4 vs. 147 rt 4 pm). In contrast, PGE,, PGF2,, and U-46619 had no effect on cortical periarachnoid CSF vasopressin concentration (Fig. 2). PGE2 produced pial arteriolar dilation that was similar in magnitude to PGI, (Table 1; 16 + 1 vs. 21 f 3% dilation for PGI:, and PGEp and 10 rig/ml before indomethacin, respectively). Similarly, PGF2, and U-46619 produced pial arteriolar constriction that was unchanged after indomethacin (Table 1). The vasoconstriction produced by PGF2, and U-46619 was of a similar magnitude [16 f 1 vs. 19 + 2% constriction for PGF2, (10 rig/ml) and U-46619 (3 rig/ml) before indomethacin, respectively]. Dynorphin (lo-lo M) increased CSF vasopressin concentration (Fig. 3). Both indomethacin (5 mg/kg iv) and aspirin (50 mg/kg iv) blocked the dynorphin-induced CSF vasopressin release (Fig. 3). Additionally, indomethacin and aspirin attenuated the release of CSF vasopressin by a higher concentration of dynorphin [ low6 M; 233 f 27 vs. 110 LX 13 and 99 + 13 &J/ml for CSF vasopressin release by dynorphin ( low6 M) in the absence and presence of indomethacin and aspirin, respectively]. Indomethacin blocked dynorphin-induced pial arteriolar dilation, which was consistent with previously published studies. /3-Endorphin (10-l’ M) also increased CSF vasopressin concentration (Fig. 3). Both indomethacin and aspirin similarly blocked ,&endorphin-induced CSF vasopressin release (Fig. 3). /3-Endorphin (10m6 M)-induced CSF vasopressin release was blocked by indomethacin and aspirin [5.3 + 1.3 vs. 0.9 + 0.1 and 1.3 + 0.3 pU/ml for CSF vasopressin release by P-endorphin (10m6 M) in the absence and presence of indomethacin and aspirin, respectively]. /3-Endorphin produced vasoconstriction in the presence of either indomethacin or aspirin, which was consistent with previously published studies. Indomethatin produced pial arteriolar constriction of a similar magnitude to aspirin (9 z!z1 vs. 10 + 2% for indomethacin and aspirin, respectively). Blood gases, pH, and mean arterial blood pressure were measured at the beginning and at the end of all experiments. These values were 7.42 +- 0.01 vs. 7.43 +- 0.02, 34 +- 1 vs. 33 +: 1, 89 + 1 vs. 90 + 2, and 60 + 4 vs. 58 rt 5

INDO 6

i 3

-2 z 73 ” 21

0

10

0 100 PGl2(ng/ml)

0

10

0 100

0 0 10 PGE 2

0

10 PGF2cl

0 3 U 46619

( ng / ml)

Fig. 1. Influence of PGIl (10 and 100 rig/ml) on cortical periarachnoid cerehrospinalfluid (CSF) vasopressin[lysine vasopressin(LVP) pU/ Fig. 2. Influence of PGEz(10 rig/ml), PGF,,, (10 rig/ml), and U-46619 ml] in absenceand presenceof indomethacin (5 mg/kg iv); n = 6 pigs. (3 rig/ml) on cortical periarachnoid CSF vasopressinconcentration (LVP, pU/ml); n = 6 pigs, control = 0. * P < 0.05 comparedwith correspondingcontrol (0). Downloaded from www.physiology.org/journal/ajpheart by ${individualUser.givenNames} ${individualUser.surname} (129.215.017.188) on January 19, 2019.

H1672

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AND CSF VASOPRESSIN

Table 1. Pial arteriolar

diameters in response to PGI, PGE2, PGF,,, and U-46619 before and after indomethacin Before Indomethacin

After Indomethacin

PGIs Control 127+6t 139+6 10 rig/ml 162rt7* 152+7* Control 145f4 133+4t 100 rig/ml 178+4* 168+5* PGEs Control 136+3 122*4t 164+4* 150+3* 10 rig/ml PGFz,, 136rt3 125?3t Control 114+3* 103+3* 10 rig/ml U-46619 147+5 134+6t Control 119+6* 106+6* 3 rig/ml Values are means k SE in lrn; n = 6 pigs. Indomethacin, 5 mg/kg iv. P < 0.05 compared with corresponding control (*) and corresponding value in absence of indomethacin (t).

'1

DYNORPHIN

0 ENDORPHIN

Fig. 3. Influence of dynorphin (10-l” M) and fl-endorphin (lo-lo M) on cortical periarachnoid CSF vasopressin concentration (fold change in LVP concentration) in absence [previously published (1)] and presence of either indomethacin (5 mg/kg iv) or aspirin (50 mg/kg iv); n = 6 pigs. * P < 0.05 compared with corresponding control.

mmHg for pH, Pco~, PO,, and blood pressure, respectively (n = 30). DISCUSSION

Results of the present study show that PC& increases cortical periarachnoid CSF vasopressin concentration, whereas PGE,, PGF2,, and U-46619 have no effect on CSF vasopressin. Because the dilations produced by PGIz and PGEz were of equal magnitude, a change in blood flow, per se, cannot account for the increased CSF vasopressin concentration. The concentrations of prostanoids used in this study were chosen on the basis that these concentrations produced similar percentage changes in pial arteriolar diameter [dilation for PGE2 and PGI, at 10 rig/ml and constriction for PGFZo (10 rig/ml) and U-46619 (3 rig/ml)]. A higher concentration of PG12 was used also to determine whether a dose-response relationship existed. Although it is uncertain what concentration of active prostanoid exists at the receptor level, the inactive metabolite 6-keto-PGFi, has been observed in periarachnoid cortical CSF at a concentration of - 10 rig/ml in response to a variety of strongly physiological stimulatory treatments (3,519). Assuming that PGIz acts in a paracrine manner, during active synthesis the local concentration of PGI, would be much higher.

CONCENTRATION

The origin of the vasopressin detected in this and previous studies is uncertain. The presence of vasopressinimmunoreactive nerve fibers has been demonstrated in guinea pig pial arterioles and rat brain microvessels (15, 17). Recently, a preliminary communication has reported that vascular tissue obtained from the aorta, vena cava, renal artery, and the mesenteric artery of both SpragueDawley and hypophysectomized rats contains immunoreactive stores of vasopressin (22). These data suggest that vascular stores of vasopressin could be of nonpituitary origin (22). The origin of the CSF vasopressin therefore could be locally derived from pial vessel stores for vasopressin or from nerves associated with those vessels. Once released, this vasopressin could also affect the cerebral circulation, because similar vasopressin concentrations have been observed to produce tone-dependent responses in the piglet cerebral circulation (dilation during normotension and vasoconstriction during hypotension when cerebrovascular tone is reduced; Ref. 2). Previous studies have addressed the role of brain prostanoids in the control of vasopressin release. The intracerebroventricular administration of PGD, and PGEB increases plasma vasopressin concentration (10, 13), whereas similar central administration of PGH synthase inhibitors abolished or attenuated the release of vasopressin by central administration of angiotensin II, by hemorrhage, and by increased plasma osmolality (10, 12, 14). Because PGIz increases CSF vasopressin concentration, it is possible that this prostanoid causes the increase in CSF vasopressin produced by dynorphin and P-endorphin. In fact, two structurally dissimilar PGH synthase inhibitors, indomethacin and aspirin, blocked /3-endorphin-induced vasopressin release. These data suggest that it is highly unlikely that the blockade by PGH synthase inhibitors of the stimulation of vasopressin release is due to another effect of the inhibitors. Furthermore, both PGH synthase inhibitors blocked the ability of a physiological concentration of dynorphin (4) to release CSF vasopressin. Additionally, indomethacin and aspirin attenuated the release of CSF vasopressin by a pharmacological concentration of dynorphin. The mechanism for opioid-induced vascular activity has been of considerable interest. Opioid-induced vascular effects could be caused directly by opioids acting on vascular receptors or indirectly as a consequence of an alteration in metabolism. Recently, we observed that opioid-induced vascular effects do not result from secondary changes in cerebral metabolic utilization of glucose (7). On the other hand, methionine enkephalin, leucine enkephalin, and dynorphin-induced pial arteriolar dilation and @-endorphin-induced pial arteriolar constriction are associated with increased periarachnoid cortical CSF prostanoid levels (3). Indomethacin blocks methionine enkephalin, leucine enkephalin, and dynorphin-induced dilation but potentiates P-endorphin-induced constriction and dynorphin-induced constriction during hypotension (3). Therefore, prostanoids appear to mediate methionine enkephalin, leucine enkephalin, and dynorphin-induced dilation but attenuate P-endorphin-induced constriction and the constriction caused by dynorphin in

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PROSTANOIDS

AND

CSF

VASOPRESSIN

hypotensive piglets, acting, in all these cases, as dilator influences. Alternatively, opioids could contribute to the regulation of cerebral hemodynamics through interactions with other vasoactive systems. For example, opioids have been observed to be localized with vasopressin in the posterior pituitary and could therefore influence vasopressin secretion (16). Previously, it has been shown that intracerebroventricular and intravenous administration of opioids can both stimulate and inhibit plasma vasopressin release (23, 24). Additionally, it has been shown that dynorphin increases plasma vasopressin concentration and that a &-receptor antagonist blocked the pressor response to dynorphin in the fetal lamb (11). Recently, it has been observed that vasopressin modulates opioid cerebrovascular responses in the newborn pig (1 , 8). For example, dynorphin-induced dilation (a K-opioid agonist), @-endorphin-induced constriction (an E-opio lid agonist), and dynorphin-induced constriction during hypotension were all associated with increased periarachnoid cortical CSF vasopressin concentration (1 ). Furthermore, a Qreceptor antagonist potentiated dynorphin-induced dilation but attenuated ,6-endorphin-induced constriction and the constriction produced by dynorphin during hypotension (8). In contrast, responses to methionine enkephalin (a p-opioid agonist) and leucine enkephalin (a &opioid agonist) were not associated with a change in CSF vasopressin concentration, and the dilator responses were unchanged by a VI-receptor antagonist (1, 8). Therefore, vasopressin appears to attenuate dynorphin-induced dilation but contributes to @-endorphin-induced constriction a nd constriction to dynorphin during hypotension through the activation of V1 receptors. The mechanisms by which prostanoids stimulate vasopressin release are not known. We speculate that activation of dynorphin and ,&endorphin opioid receptors results in the release of PG12, which is an important link in the sequence of events that results in the release of vasopressin. An analogy for this can be found in the observation that PGE2 is important in the stimulation by norepinephrine of the release of luteinizing hormonereleasing hormone from the rat hypothalamus, where the role of PGE2 is at least, in part, to mobilize intracellular calcium (21). Figure 4 summarizes our present understanding of the interactions between the opioids (dynorphin and ,&endorphin), PG12, and vasopressin in the elicitation of the resulting vascular response. In normotension, dynorphin constricts cerebral vessels. Dynorphin also stimulates the release of PG12, which, in turn, releases vasopressin. Both PG12 and vasopressin are dilators during normotension and oppose dynorphininduced constri ction. Because the effect of dynorphin on pial arterioles of normotensive piglets is dil .ation, the resulting net vascular effect of PGIz and vasopressininduced dilation versus dynorphin-induced constriction must be dilation (Fig. 4). During hypotension, dynorphin similarlv constricts pial arterioles and stimulates the release of PG12, which opposes dynorphin-induced constriction (3). However, the newly released PG12 also stimulates the release of vasopressin. Vasopressin elicits tone-dependent responses in the cerebral circulation.

H1673

CONCENTRATION

NORMOTENSION DYNORPHIN ARTERIOLE

-

+

ARTERIOLE

-

-

HYPOTENSION DYNORPHIN

NORMOTENSION

LVP D ENDORPHIN ARTERIOLE

/

-

Fig. 4. Schematic diagram showing interactions among opioids, PG12, vasopressin (LVP), and resulting vascular response. -, Constriction; +, dilation.

During hypotension, vasopressin produces vasoconstriction, which appears to contribute to dynorphin-induced constriction because a vasopressin-receptor antagonist blunts dynorphin-induced constriction (8). The net effect in this instance is vasoconstriction for dynorphin during hypotension. The mechanism for ,6-endorphin could involve similar constriction and release of PG12, which, in turn, releases vasopressin. Indomethacin potentiates ,&endorphin-induced constriction (3)) indicating that PG12 opposes ,&endorphin-induced constriction. Surprisingly, a vasopressin-receptor antagonist also blunts ,&endorphin-induced constriction (8), indicating that vasopressin contributes to ,&endorphin-induced constriction. However, during normotension, vasopressin is a vasodilator. The mechanism(s) by which changes in vascular tone can alter a vascular response is not known. Possibly, the change is not tone, per se, but of the cellular messengers that cause the change in tone. We speculate that a PG12-induced activation of adenylate cyclase could result in the conversion of vasopressin from a dilator to a constrictor. The net vascular effect for ,&endorphin therefore would be vasoconstriction, which is attenuated by the PGIZ produced but enhanced by the vasopressin. In conclusion, the present data indicate that PGIz contributes to opioid-induced changes in CSF vasopressin concentration and, thereby, to vasopressinergic contributions to opioid-induced cerebral vascular responses. The authors thank M. Jackson, A. Fedinec, and G. Festavan for technical assistance in the performance of the experiments. We also thank J. Crofton and Dr. L. Share for helpful discussions in the preparation of this manuscript. This research was supported by grants from the National Institutes of Health. Address for reprint requests: W. M. Armstead, Dept. of Anesthesia, Children’s Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, PA 19104. Received

15 January

1992; accepted

in final

form

24 July

1992.

REFERENCES 1. Armstead, W. M., J. T. Crofton, L. Share, R. Mirro, S. L. Zuckermaa, and C. W. Leffler. The influence of opioids on CSF vasopressin concentration in the newborn pig. Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H862-H867, 1992. 2. Armstead, W. M., R. Mirro, D. W. Busija, and C. W.

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AND

CSF

VASOPRESSIN

Leffler. Vascular responses to vasopressin are tone dependent in the cerebral circulation of the newborn pig. Circ. Res. 64: 136-144, 1989. Armstead, W. M., R. Mirro, D. W. Busija, and C. W. Leffler. Prostanoids modulate opioid cerebrovascular responses in newborn pigs. J. Pharmacol. Exp. Ther. 255: 1083-1089, 1990. Armstead, W. M., R. Mirro, D. W. Busija, and C. W. Leffler. Opioids in cerebrospinal fluid in hypotensive newborn pigs. Circ. Res. 68: 922-929, 1991. Armstead, W. M., R. Mirro, C. W. Leffler, and D. W. Busija. Acetylcholine produces cerebrovascular constriction through activation of muscarinic-1 receptors in the newborn pig. J. Pharmacol. Exp. Ther. 247: 926-933, 1988. Armstead, W. M., R. Mirro, C. W. Leffler, and D. W. Busija. The role of prostanoids in the mediation of responses to KC 404, a novel cerebrovasodilator. J. Pharmacol. Exp. Ther. 244: 138- 143, 1988. Armstead, W. M., R. Mirro, S. Zuckerman, D. W. Busija, and C. W. Leffler. The influence of opioids on local cerebral glucose utilization. Brain Res. 571: 97-102, 1992. Armstead, W. M., R. Mirro, S. L. Zuckerman, and C. W. Leffler. Vasopressin modulates cerebrovascular responses to opioids in newborn pigs. J. Pharmacol. Exp. Ther. 260: 1107-l 112, 1992. Brooks, D. P., J. T. Crofton, L. Share, J. Mitchell, R. J. Grekin, T. Tenhave, and D. F. Bohr. Increased urinary vasopressin excretion in the DOCA hypertensive pig. Clin. Exp. Hypertens. 45: 1717-1734, 1983. Brooks, D. P., L. Share, and J. T. Crofton. Role of brain prostaglandins in the control of vasopressin secretion in the conscious rat. Endocrinology 118: 1716-1722, 1986. Dunlap, C. E., III, and N. K. Valego. Cardiovascular effects of dynorphin A (1- 13) and arginine vasopressin in fetal lambs. Am. J. Physiol. 256 (Regulatory Integrative Comp. Physiol. 25): Rl318R1324, 1989. Hoffman, P. K., L. Share, J. T. Crofton, and R. E. Shade. The effect of intracerebroventricular indomethacin on osmotically stimulated vasopressin release. Neuroendocrinology 34: 132- 139, 1982. Hoffman, W. E., and P. G. Schmid. Cardiovascular and

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Prostanoids modulate opioid-induced increases in cerebrospinal fluid vasopressin concentration.

Topical dynorphin and beta-endorphin produce increases in both prostanoid and vasopressin concentrations in cortical periarachnoid fluid of newborn pi...
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