Hypotension induced by vasopressin antagonists in rats: Role of mast cell degranulation

TOXICOLOGY

AND

APPLIED

PHARMACOLOGY

Hypotension

RICHARD

102, 117- 127 ( 1990)

Induced by Vasopressin Antagonists Role of Mast Cell Degranulation

A. MACIA,*

G. K. CAMPBELL,~

in Rats:

ANTHONY C. SILVER,* ROBERT A. GABEL,* N. HANNA,~ AND M. J. DIMARTINot

Departments of *Investigative Toxicology and tImmunology. Smith Kline & French Laboratories, P.O. Box 1539. King qfPrtasia, Pennsylvania 194060939

ReceivedApril 21. 1989; accepted August 23, 1989 Hypotension Induced by Vasopressin Antagonists in Rats: Role of Mast Cell Degranulation. R. A., SILVER, A. C.. GABEL, R. A., CAMPBELL, G. K., HANNA, N.. AND DIMARTINO. M. J. (1990). Toxicol. Appl. Pharmacol. 102, 117-127. SK&F 101926, a synthetic peptide, is MACIA,

a potent antagonist of vasopressin at both the V2 and the V, receptors. Following intravenous administration of SK&F 10 1926 (5 mg/kg). mean arterial pressure (MAP) immediately fell 75 mm Hg. Heart rate increased approximately 50 beats/min. Cutaneous flushing and cyanosis appeared approximately 2 to 5 min after the SK&F 10 1926 administration. Three of the five rats died within 40 min with no improvement in either color or MAP. The two surviving animals slowly recovered from these symptoms. The hypotension and flushing recorded in these studies resembled the effectsduring hypotensive shock. SK&F 10 1926 degranulated rat peritoneal mast cells in vitro as measured by the liberation of histamine. Analogs of SK&F 10 1926 were identified having reduced activity to release histamine from mast cells in vitro. The activity of these analogs to release histamine in vivo was also tested, as reflected by rat paw edema. A positive correlation was found between the potency to produce edema in vivo and the potency to release mast cell histamine in vitro (r = 0.94. p < 0.05). In addition, compounds that released mast cell histamine and induced rat paw edema also produced hypotension and death when administered intravenously, while analogs which produced minimal histamine release in vitro produced minimal or no cardiovascular changes or lethality in vivo at the same dosages (5 mg/kg). Finally. cyproheptadine (10 mg/kg), an antagonist at both the serotonin and the histamine receptors, blunted the effects of SK&F 101926 on MAP and blocked the lethality. Pretreatment with a combination of histamine (H, and Hz) antagonists provided little protection against the SK&F 10 1926-induced toxicity. These data indicate that the cardiovascular toxicity of SK&F 10 1926 (and related peptides) is mediated via the release ofautocoids from mast cells. Serotonin appears to play a major role in mediating the cardiovascular toxicity of SK&F 101926. 6 1990 Academic Press. Inc.

SK&F 10 1926 is a synthetic vasopressin analog with affinity for vasopressin pressor (V,) and antidiuretic (V,) receptors. In the rat, dosages of SK&F 10 1926 in the range of 10 pg/kg or less provide potent antagonism of V, and V2 vasopressin receptors in vivo (Kinter et al., 1988; Manning et al., 1984). The lethal dosage of SK&F 10 1926 in the rat is in the range of several milligrams per kilogram, or nearly lOOO-fold that required for pharmacological efficacy (Kinter et al., 1988). Lethality

is preceded by cutaneous flushing, collapse, and cyanosis suggestive of profound hypotension. Flushing and hypotension have been observed following intravenous administration of vasopressin and other nonvasopressin peptides including the Vz agonist, dDAVP (Pigache, 1984), outgrowth hormone releasing hormone (Gelato et al., 1984) and luteinizing hormone releasing hormone analogs (Morgan et al., 1986), and may be a general phenomenon associated with exogenously 117

0041-008X/90

$3.00

Copyright 0 1990 by Academic Press. Inc. All rights of reproduction in any form reserved.

118

MACIA

administered peptides. The intent of this study was to characterize the effects of SK&F 10 1926 on cardiovascular function and to investigate the underlying mechanism of SK&F 10 1926 toxicity in the rat. METHODS

AND

MATERIALS

Cardiovascular function studies. Male Sprague-Dawley rats (Charles River Breeding Laboratories, 225-350 g) were anesthetized with 35 mg/kg Na-methohexital (ip). A standard carotid artery and jugular vein cutdown and catheterization was performed. The catheters were exteriorized at the nape of the neck by subcutaneous tunneling. The incisions were closed with surgical staples and the animals were allowed to recover for 3-4 hr in individual plastic cages. After recovery, the animals were transferred to rodent restrainers and the carotid catheters connected to a Statham transducer/Sensormedics recorder for the continuous monitoring of systolic (sBP) and diastolic (dBP) blood pressure and heart rate (HR). Mean arterial pressure (MAP) was calculated [MAP = ((sBP - dBP)/3) + dBP)]. After a stabilization period (5 min), the animals were injected with test peptides through the jugular vein catheter over a 5-set period. Some of the animals were administered antagonists through the jugular vein 10 min prior to peptide administration. The animals were monitored for 20 to 40 min following peptide administration. Rat mast cell histamine release in vitro. Mast cells were obtained by peritoneal lavage of male Sprague-Dawley rats using Tyrode’s buffer containing BSA (0.1%) and heparin (1 U/ml). The peritoneal cells from several rats were pooled for each experiment, stained with toluidine blue, and counted on a coulter counter. The percentage of mast cells were determined and constituted 1 to 9% of the total cell population. Test compounds, diluted in Tyrode’s buffer containing 0. I % BSA, were incubated with equal volumes of peritoneal cell suspensions containing IO5 mast cells/ml for 10 min at 37°C. The reaction was terminated by addition of ice-cold Tyrode’s buffer. Cell-free supernatants were obtained by centrifugation (800~) for 8 min at 4°C. Following protein precipitation with perchloric acid. the supernatant and cellular histamine concentrations were determined fluorometrically (Shore et al.. 1959). The mean + SD was determined from triplicate samples. Percentage histamine release was calculated using the formula percentage histamine release = [(supernatant histamine/ total histamine) X 1001. All peptides were tested at a final concentration of 10 FM. Rat paw edema preparation. Test compounds diluted in Tyrode’s buffer containing 0.1% BSA were injected (0.1 ml of a 20 pM solution) subplantar into the right hindpaw of conscious male Lewis rats (Charles River. 1SO-280 g). Hindpaw volumes were measured plethysmographically by water displacement. Paw edema was

ET AL. expressed as the difference in hindpaw volume (ml) from preinjection volumes 10 to 15 min after injection or as a percentage of vehicle control. Results are expressed as the means -t SD of five to eight rats. Data analysis. Cardiovascular data were summarized at selected time points with the time of peptide injection equal to 0 min. Data were analyzed by repeated measures analysis of variance (GLM, SAS Institute, 1986) for changes in the recorded parameters. Mast cell histamine and hindpaw edema data were analyzed by Student’s t test. Levels of p < 0.05 and p < 0.01 were considered to be statistically different. Compounds. Vasopressin analogs were supplied by the Peptide Chemistry Department of SK&F Laboratories. They were prepared as 5 mg/ml solutions in 0.9% NaCl. Cyproheptadine (Merck Sharp & Dohme, West Point, PA) was dissolved in 25% DMSO and infused intravenously over a 4-min period for cardiovascular studies. Pyrilamine (Sigma Chemical Co., St. Louis. MO) and tiotidine-HCl (ICI Americas, Inc., Wilmington, DE) were dissolved in 0.9% NaCl and delivered by bolus injection. Antagonists used in the rat paw edema studies were administered orally 2 hr prior to peptide injection into the paw. Indomethacin, chlorpheniramine-maleate (Sigma Chemical Co., St. Louis), and cyproheptadine were suspended in 0.5% Tragacanth for the oral studies.

RESULTS Within 5 min after administration of 5 mg/ kg SK&F 10 1926 to conscious rats, MAP fell approximately 75 mm Hg. In the same time frame, a 50 beat/min rise in heart rate occurred which was statistically different from preinjection values only at the 3-min time point (Fig. I ). Cutaneous flushing appeared within the first 2 min. followed by cyanosis (5 min). Cyanosis continued for the remainder of the experimental period. The fall in MAP was monitored for a maximum of 40 min (Fig. 1). Three of five animals died within this time frame. The remaining rats slowly recovered (1 to 2 hr). Mast cell degranulation was considered to be a possible mechanism of the SK&F 101926-induced hypotension and cyanosis. SK&F 10 1926 released 7 1% of the histamine in rat peritoneal mast cells in vitro (Table 1). SK&F 10 1498 (the Gly9 analog of SK&F 10 1926) released 85% of mast cell histamine (Table 1). Substitution of the alkylated D-tyrosine residue at position 2 (D-Tyr(Et)2) of

MAST

CELLS IN AVP ANTAGONIST

119

HYPOTENSION

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100

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10

20

30

1

Time (min)

FIG. I. Time course of the mean arterial pressure and heart rate of conscious rats administered SK&F 101926 (5 mg/kg, iv) (arrow). Symbols represent means f SE. Values in parentheses represent the number of rats. Asterisks represent statistical difference from time of injection (Time = 0) p < 0.05.

SK&F 10 1498 with an L-Tyr(Et) (SK&F 100398) halved histamine release to 36%. An almost complete loss of the ability to release histamine was achieved with elimination of the alkyl group on the D-Tyr* (SK&F 100885,3%) or by the substitution of both LTyr(Me) and Gln at positions 2 and 4, respectively (SK&F 100273, 3%) (Table 1). Arginine vasopressin (AVP) and the relatively selective Vz agonist, dDAVP, were associated with only minimal release of mast cell histamine (Table 1). Representative peptides were selected for subplantar injection into Lewis rats to determine the ability of these compounds to degranulate mast cells in viva as reflected by hindpaw edema. The in vitro histamine-releasing ability of these compounds and the ability to produce hindpaw edema were positively correlated (Y = 0.94, p < 0.05). SK&F

10 1498, an effective and potent releaser of mast cell histamine, induced a 0.25-ml increase in hindpaw volume (Fig. 2). SK&F 100885. a less potent histamine releaser in vitro, produced minimal hindpaw edema (Fig. 2). SK&F 100398, associated with 36% histamine release in vitro, did not induce paw edema greater than those compounds which produced minimal or no release of histamine in vitro. Pharmacologic inhibition of the edema response induced by the most potent releaser of mast cell histamine (SK&F 10 1498) was attempted. Chlorpheniramine (an H, receptor antagonist), indomethacin (an arachidonic acid pathway inhibitor). or cyproheptadine (a dual serotonin/histamine receptor antagonist) was administered to Lewis rats, all at dosages which have been previously determined in our laboratory to inhibit the edema response associated with

Phe Phe

W-W

D-Tyr TV

Pw

Pmp Pv

SK&F 100885 SK&F 100273

Val Gln

Val Val

Val

Gln Gln

4

Asn Asn

Asn Asn

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5

Position

CYS CYS

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CYS CYS

CYS CYS

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Pro Pro

Pro Pro

Pro

Pro Pro

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Gly-NH2 Gly-NH2

A% A% A% Arts

desGly’

Gly-NH2 Gly-NH2

9

Gly-NH2 Gly-NH2

A%

Arg D-Arg

8

INVITRO

8.81 10.58

N.A.

9.12

N.A: 9.40

Agonist

VI antagonist activity (PAZ)’

RATPERITONEALMASTCELLS

220

6.8

5.6

0.4 1.2

Agonist Agonist

V2 antagonist activity (K,) b

BYVASOPRESSINANALOGS

1 F

3 ck0.6 3 f 0.4

85 f 6.0** 36 f 2.0**

7 1 f 2.0**

11 + 7.0* 8 f 0.3*

Percentage histamine release’

‘PAZ, antagonism of pressor actions of vasopressin in the rat (Stassen et al., 1984). b Ki (X10e9 M) against vasopressin-stimulated adenylate cyclase in rat renal membranes (Kinter etal., 1988). ’ Percentage histamine release from rat peritoneal mast cells in vitro (see Methods and Materials). Data represent means k S.D. of four to five experiments. Peptides administered at a final concentration of 10 PM. Asterisks represent statistical difference from buffer only control (2 t 1), *I, < 0.05. **p < 0.0 1. All peptides have &sulfide bridges between amino acids I and 6. d AVP. arginine vasopressin. ’ dDAVP, desamino-8-D arginine vasopressin. ‘-Not available. g Pmp, 1-&mercapto-&fl cyclopentamethylenepropionic acid. h Tyr(Et) or Tyr(Me), (O-ethyl or O-methyl)tyrosine. ’ desGly. desglycine.

Phe Phe

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Compound no. or name

VASOPRESSINANTAGONISTACTIVITIESANDINDUCTIONOFHISTAMINERELEASEFROM

TABLE 1

L0

MAST

CELLS

IN

AVP

ANTAGONIST

0.5 -

0.4 -

f‘ E s

0.3 -

n

Vehicle

x E 2

AVP 0.2 dDAVP

q

SK&F

100398

0

SK&F

100885

n

SK&F

101926

q

SK&F

101498

0.1 -

o.oL

Compound

FIG. 2. Rat paw edema (ml) measured 10-l 5 min after subplantar injection of vasopressin analogs (0.1 ml of 20 /IM solutions). Values represent means f SD of five to eight animals. Asterisks represent statistical difference from control buffer. *p < 0.05. **p < 0.01.

the appropriate agonists. Indomethacin provided no protection, chlorpheniramine provided partial protection, and cyproheptadine

HYPOTENSION

provided nearly complete protection against the SK&F 10 1498-induced edema (Fig. 3). Intravenous administration of SK&F 10 1498 (5 mg/kg) produced hypotension, cutaneous flushing, cyanosis, and 100% lethality (Fig. 4A). However, 5 mg/kg SK&F 100273 or SK&F 100885 (weak releasers of histamine in vitro) was associated with minimal or no hypotensive activity, respectively (Figs. 4B and 4C). To investigate the role of vasopressin (V:) receptors in hypotension. dDAVP (5 mg/kg) was administered to five rats by intravenous bolus injection. An immediate increase in MAP of 35 mm Hg and a 40 bpm fall in heart rate followed the dDAVP administration (Fig. 4D). Cyproheptadine (10 mg/kg, 4 min iv infusion) administered 10 min prior to a 5 mg/kg dosage of SK&F 101926 blunted the hypotensive response (from approximately 75 mm Hg in control animals to only 10 mm Hg in drug-treated animals; Fig. 5). In addition, no deaths and no flushing or cyanosis were associated with SK&F 10 1926 administration when the animals were pretreated with cyproheptadine. Pyrilamine (an H, antagonist, 1 mg/kg, iv) and tiotidine (an Hz antagonist, 1 mg/kg, iv), in combination, had little effect

140

ZL E s $

80 60 Cyproheptadine 40

lndomethacin

q

Chlorpheniramine

Treatment

FIG. 3. Rat paw edema (percentage control) produced lo-15 min after subplantar injection of SK&F 101498 (0.1 ml of 20 PM). Effect of cyproheptadine (50 mg/kg, PO), indomethacin (5 mg/kg, po) or chlorpheniramine (50 mg/kg, po) administration 2 hr prior to SK&F 101498. Values represent means f SD of five to eight animals. Asterisks represent statistical difference from vehicle (0.5% Tragacanth) control, *p < 0.05. **pi 0.01.

121

122

MACIA

ET AL.

250

500

200

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MAP

-

HR

400

2 E Q

150

300

2 : it a

p a e s d

3 &

100

200

50

100

3

r g I

: %

A 0 -10

3 0

10

20

30

110

Time (min)

FIG. 4. Time course of the mean arterial pressure and heart rate of conscious rats administered 5 mg/kg. iv (A) SK&F 101498: (B) SK&F 100885: (C) SK&F 100273; and(D) dDAVP (arrow). Symbols represent means + SE of four to six animals. Asterisks represent statistical difference from time of injection (Time = 0) p < 0.05.

on the SK&F 10 1926-induced hypotension and tachycardia (data not shown). DISCUSSION SK&F 10 1926 is one of a series of peptidergic vasopressin antagonists under study as selective water diuretic agents. In early toxicity testing, high (3- 10 mg/kg) intravenous dosages of SK&F 10 1926 produced flushing, cyanosis, and lethality in rats. In the present studies, SK&F 10 1926 (5 mg/kg) reduced systemic blood pressure (Fig. 1) and was lethal to 60% of the animals. In addition to the hypotension, SK&F 10 1926 produced severe cutaneous flushing and cyanosis. These observations are not species specific and have been demonstrated previously in rhesus

monkeys, where hypotension and flushing were observed after administration of SK&F 10 1926 at high and pharmacologically active dosages (Brooks et al., 1988). Since the observed symptoms show resemblance to those seen in hypotensive shock, attention focused on the release of endogenous vasoactive autocoids. Certain peptides, including analogs of luteinizing releasing hormone (Morgan et al.. 1986) are known to induce the release of histamine from mast cells in vitro (DeVillier et al., 1985; Erjavec et al., 1981) as well as in vivo (Erjavec et al., 1981; Carraway et al.. 1982). Our studies extend these observations. SK&F 10 1926 released histamine from isolated rat peritoneal mast cells in vitro (Table 1). Further, SK&F 10 1926 induced rat paw edema, which is suggestive of mast cell degranulation and subse-

MAST CELLS IN AVP ANTAGONIST

123

HYPOTENSION

2mr

500

200-

400

150300

lOO200

-

MAP

-

HR

50-

o* -10

z e al ;i K r : =

100

B -I-

0

10 Time FIG.

20

0

30

(min)

4-Continued

quent histamine release in vivo (Fig. 2). In addition, with analogs of SK&F 101926, the ability to release histamine from rat mast cells was either enhanced (SK&F 101498) or greatly reduced (SK&F 100885, Table 1). Only SK&F 101926 and SK&F 101498, which degranulated mast cells in vitro, produced significant paw edema in vivo. SK&F 100885, which had no appreciable effect on the release of mast cell histamine, produced minimal edema (Fig. 2). However, there is no explanation at present for the failure of SK&F 100398 to induce rat paw edema considering it released 36% of the mast cell histamine in vitro. A number of other mediators including arachidonic acid metabolites and serotonin are known to induce edema and are released upon degranulation of mast cells (Metcalfe et al., 198 1). In this study. the dual serotonin/ histamine antagonist, cyproheptadine, markedly attenuated the SK&F 10 1498-induced

edema (Fig. 3). On the other hand, the histamine Hi receptor antagonist, chlorpheniramine, produced only marginal inhibition (~20%). Pretreatment with a cyclooxygenase inhibitor (indomethacin) was ineffective in preventing the SK&F 10 1498-induced edema, suggesting that cyclooxygenase products of arachidonic acid were not involved (Fig. 3). These results indicate that the rat paw edema response was mediated by serotonin alone or in combination with histamine. Further evidence of the role of serotonin in the toxicity of SK&F 101926 was demonstrated when cardiovascular function was monitored in conscious rats pretreated with cyproheptadine. In the presence of cyproheptadine, SK&F 101926 produced minimal changes in cardiovascular function, no flushing, no cyanosis, and no lethality (Fig. 5). Pretreatment with a combination of histamine Hi and Hz antagonists provided no protection against the cardiovascular effects of

124

MACIA

ET AL. 500

400

300

g [I s 2 2

200

r g I

-

MAP

-

HR

100

0 0

10 Time

20

30

40

(min)

FIG. 4-Continued

SK&F 101926 (data not shown) indicating that histamine plays a much less significant role, if any, in the cardiovascular toxicity of SK&F 101926. The cardiovascular actions of serotonin are varied from species to species and depend on the anesthetic state of the animal and the speed of injection. In general, serotonin produces a triphasic cardiovascular response upon intravenous administration: a depressor, a pressor, and last a second depressor (Douglas, 1980). Intravenous administration to rats of the precursor of serotonin, 5-hydroxytryptophan (5-HTP), produces a depressor profile which is similar to that of SK&F 101926 (Yao et al., 1982). Thisdepressor action of 5-HTP is not direct evidence that serotonin plays a role in the toxicity of SK&F 10 1926; however, it demonstrates that a hypotension similar to that seen with SK&F 10 1926 injection can occur as a result of sero-

tonin, an autocoid released by the degranulation of mast cells. The final piece of data which implicates the role of mast cell degranulation in the cardiovascular toxicity of SK&F 101926 was evidenced when the analogs were administered intravenously to conscious rats. SK&F 101498, the most potent releaser of mast cell histamine and a potent inducer of rat paw edema, altered cardiovascular function in a manner nearly identical to that of SK&F 101926 (Fig. 4A). However, SK&F 100885 and SK&F 100273, ineffective mast cell degranulating agents, produced a minimal effect on cardiovascular function (Figs. 4B and 40 These data suggest that the ability to produce the cardiovascular toxicity was related to the ability to degranulate mast cells. Although the role of mast cell degranulation in the cardiovascular toxicity of SK&F 10 1926 has been defined in these studies, the

MAST

CELLS

IN

AVP

ANTAGONIST

HYPOTENSION

125

D -10

0

10

20

30

40

Time (min) FIG.

4-Continued

mechanism by which these compounds degranulate mast cells is unclear. All of the vasopressin analogs used in these studies maintain high affinity for V, and V2 receptors. As SK&F 101926 and SK&F 101498 are the most potent VZ antagonists studied (Table l), it would initially appear that the V2 receptor plays a role in the degranulation process. SK&F 100885 is also relatively potent at the V2 receptor, with only a sixfold difference in antagonist potency between it and SK&F 10 1498. Given the very high concentrations and/or dosages used in the present studies, small differences in V2 antagonist potency would seem to be minimized if not eliminated. However, SK&F 100885, unlike SK&F 10 1498, did not release histamine in vitro or produce hypotension in vivo. The VI receptor also does not appear to play a role in the responses. SK&F 100273, the most potent VI antagonist in this series, did not degranulate mast cells.

Further evidence for the lack of V, or V2 vasopressin-receptor involvement in the hypotension was found with the V2 receptor agonist dDAVP. Although dDAVP has been shown to produce flushing and hypotension in humans (Pigache, 1984) dDAVP produced a pressor response in the rat. Likewise, both dDAVP and AVP were relatively ineffective in releasing histamine from rat peritoneal mast cells in vitro and were unable to produce significant rat paw edema. These data suggest that neither the vasopressin VI nor V2 receptors are responsible for mast cell degranulation and the subsequent cardiovascular responses to SK&F 10 1926. These data do not eliminate the possibility that the hypotensive activity of SK&F 10 1926 is mediated by a vasopressin-like vasodilatory receptor on the vasculature as suggested by Liard (1986) but these data do suggest that this receptor would be sufficiently different from V, and V2 receptors that compounds of similar po-

126

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ET

AL

250

50I-

CI-r-

-10

-5

0

5

HR

10

15

20

Time (min) FIG. 5. Time course of the mean arterial pressure and heart rate of conscious rats administered kg cyproheptadine (iv, bolus) IO min prior to 5 mg/kg SK&F 101926 (arrow). Symbols represent f SE of six animals. Asterisks represent statistical difference from time of SK&F 101926 injection = 0) p < 0.05.

tency at the V, and V, receptors (SK&F 100273 and SK&F 100885, respectively) do not activate or inhibit them. In conclusion, SK&F 10 1926 produces hypotension and death in rats as a result of the degranulation of mast cells and subsequent liberation of serotonin, which is the major contributing factor in the cardiovascular events in the rat. The mechanism by which SK&F 10 1926 degranulates mast cells has not been identified in these studies; however, vasopressin Vi or Vz-receptors do not play a role in the degranulation process. ACKNOWLEDGMENTS The authors thank Dr. W. Huffman and colleagues for the peptides used in these studies and Drs. L. B. Kinter,

H. Solleveld, and W. R. Hewitt manuscript review.

for their

10 mg/ means (Time

assistance

in

REFERENCES BROOKS, D. P., KOSTER, P. F., STASSEN, F. L.. ALBRIGHTSON, C. R., HUFFMAN. W. F., WASSERMAN, M. A.. AND KINTER, L. B. (1988). Flushing and haemodynamic responses to vasopressin peptides in the rhesus monkey. Brit. J. Pharmacol. 94.159-764. CARRAWAY, R., COCHRANE, D. E., LANSMAN. J. B., LEEMAN. S. E., PATERSON, B. M.. AND WELCH, H. J. (1982). Neurotensin stimulates exocytotic histamine secretion from rat mast cells and elevates plasma histamine levels. J. Physiol. 323,403-4 15. DEVILLIER, P., RENOUX, M., GIRO~D, J. P., AND REGOLI, D. ( 1985). Peptides and histamine release from rat peritoneal mast cells. Eur. J Pharrnacol. 117,89-96. DOUGLAS, W. W. (1980). Histamine and 5-hydroxytryptamine and their antagonists. In The Pharmacolo~icnl Basis of Therapeutics (A. G. Gilman, L. Goodman,

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and A. Gilman. Eds.), pp. 608-646. Macmillan Co., MORGAN, J. E.. O’NEIL, C. E., COY, D. H., HOCART, New York. S. J., AND NEKOLA, M. V. (1986). Antagonists analogs ERJAVEC, F., LEMBECK, F., FLORJANC-IRMAN, T.. of luteinizing hormone-releasing hormone are mast SKOFUSCH, G., DONNERER, J., SARIA, A., AND cell secretagogues. Int. .4rch. Allergy Appl. Immunol. HOLZER, P. (1981). Release of histamine by substance P. 80,70-75. Naunyn-Schmiedebergk Arch. Pharmacol. 317,61-70. PIGACHE. R. M. (1984). Facial flushing induced by vasoGELATO, M. C.. PESCOVITZ,0. H.. CASSORLA, F., LORIpressin-like peptides lacking pressor activity. Rrif. J. AUX. D. L., AND MIRRIAM, G. R. (1984). Dose-reClin. Pharmacol. 17, 369-372. sponse relationship for the effects of growth hormoneSHORE, P. A.. BURKHALTER. A., AND COHN, V. H. releasing factor-( I -44)-NH2 in young adult men and (1959). A method for the fluorometric assay of histawomen. J. Clin. Endocrino(. Metal?. 59, 197-201. mine in tissue. J. Pharmacol. Exp. Ther. 127. 182KINTER, L. B.. HUFFMAN, W. F., AND STASSEN, F. L. 186. ( 1988). Antagonists ofthe antidiuretic activity of vasoSTASSEN. F., BERKOWITZ, B.. HUFFMAN, W.. WIEBEpressin. Amer. J. Physiol. 254, F165-FI 77. LHAUS, V.. AND KINTER. L. B. (1984). Molecular LIARD. J. F. (1986). Cardiovascular effects associated pharmacology and mechanisms of action of aquarwith antidiuretic activity of vasopressin after blockade etic agents. In Diurelics: Chemistq). Pharmaiolog~ of its vasoconstrictor action in dehydrated dogs. Circ. and Clinical Applications (J. Puschette and Res. 58,63 l-640. A. Greenberg. Eds.). pp. 64-7 I. Elsevier, New MANNING, M.. OLMA, A., KLIS. W., KOLODZI~CZYX, A., York. NAWROCXA, E.. MISICKA, A., SETO, J.. AND SAWYER, YAO. T., ANDERSSON. S.. AND THOREN. P. (1982). W. H. (I 984). Carboxy terminus of vasopressin required Long-lasting cardiovascular depressor response folfor activity by not binding. Nature (London) 308, 652lowing sciatic stimulation in spontaneously hyperten653. sive rats. Evidence for the involvement of central enMETCALFE, D. D., KALINER. M., AND DONLON, M. A. dorphin and serotonin systems.Brain Re.s.244, 295( 198 1). The mast cell. CRC Crit. Rev.Immunol. 3,2374. 303.