Pergamon Prese
Lìfa Scieace~ Vol. 16, pp " 363-374 Printed in the U.s .l1.
BFFECTS OF PR08TAGIANDIN B2 ON VABCIILAR TON$ AND REACTIVITY) S . Greenberg, 2 F .P .J . Diecke, P.J . Hadowitz and J .P . Long Departments oß Pharmacology, Physiology and Medicine, College oß Medicine, University of Iowa, Iowa City, Iowa 52242 (Received in final
form
January 1, 1975)
3UMMARY Superßused helical stripe oß canine anterior mesenteric arteries and veins and canine dorsal metatarsal veins contract in reepoase to prostaglandin B2 (PGB2) . Reserpine pretreatment and phentolamiae reduce the constrictor response to PGB2 . PGB2 enhancee the contractile responses oß these preparations to potassium, barium and norepinephrine . P(iB2 also produced a shißt to the leßt in the duration oß the barium response curve . The data presented demonstrate that PGH is not an inactive metabolite oß PGA2 metabolism but possesses ~otent constrictor activity probably dependent oa release oß norepinephrine ßrom adrenergic nerves . Furthermore, PGB enhances the responses oß vascular smooth muscle to vasoactive st~muli . INTRODUCTION Prostaglandins oß the B series have been considered to be inactive metabolites oß prostaglandin A metabolism (1-3) .
However,
Saunders and coyorkera (4-8) recently reported that high doses oß PGBg constricted isolated perßueed rat pancreatic arteries . Ia addition PGB2 was reported to cause cutaneous and pulmonary vasoconstriction in doge at doses which resulted in decreases in systemic and renal vascular resistance (7-9) .
It was concluded
that PGB2 was not an inactive metabolite oß PGA2 metabolism (7-9) . y USPHH Grants N85188, N81398 and N84431 and uppor e n per the Iowa Heart Association . 2Present address : Departments oß Cell Biophysics and Pharmacology, Baylor College oß Medicine, 1200 Moureui~d Avenue, Houston, Texas 77025 . Address correspondence to Dr . J .P . Long, Department oß Pharmacology, College oß Medicine, University oß Iowa, Iowa City, Iowa 52242 . 363
364
Effects of P®2 on Vascular Tone/Reactivity
Vol . 16, No . 3
Prostaglandin A2 is not cleared by the lung and its concentrations may increase in blood as a consequence of various pathophysiologic states (10,11) .
Since PGA2 may eventually be metabo
lized to PGB2 (12-14) it is important to know the eîïecta oï PGB2 on vascular reactivity .
The following preliminary study demon-
atratea that PGB2 enhances vascular responses to vasoactive stimuli . METHODS AND MATERIALS Canine anterior mesenteric arteries
(0 .5-0 .8 mm o .d .) and
veins (0 .5-0 .8 mm o .d .) and dorsal metatarsal veins (1-2 mm o .d .) were removed, cut into helical stripe and prepared ïor auperîuaion as previously described (14,15) . under optimal resting tension .
Each vascular strip was mounted The preparations were allowed to
equilibrate 3 hours prior to experimentation .
Isometric con-
tractions were measured with a Grass Ft .03 force-displacement transducer and recorded on a Grass model 5 recorder .
The phyaio-
logic salt solution (PSS) was maintained at 37 .5°C, aerated with 95% O2 and 5~,C02 (pH 7 .4), and contained (mM) : sodium chlor ids (113), potassium chloride (3 .1), sodium bicarbonate (24 .8), calcium chloride (1 .53), glucose (10), magnesium chloride (2 .1), monosodium dihydrogen phosphate (1 .1), calcium dieodium ethylenediaminetetraacetate (0 .028), and pyruvic acid (3 .2) .
The calcium
concentration utilized in these studies was determined by m~aurement of plasma calcium concentration and subtraction ói the plasma protein bound ßraction (~ 45~) .
The îlow rate óf the superîusate
was 3 to 4 ml/min and was maintained constant throughout the experiment . Contractility studies .
Partial dose-response curves were
obtained for norepinephrine (0 .8-8 .0 nanomolee), HaC12 (24 to 98 ~olea) and potassium chloride (50 to 200 moles) prior to, during
Vol . 16, No . 3
365
Bffacts of Pf~Z on Vascular Toae/Raactivity
and 90 minutes after superßusion with PGBg (2 .8 x 10~ M) .
Each
vascular strip was challenged with the 3 doses oß each agonist . The responses to the agonists were reproducible witó time and were independent oß the order oß agonist administration .
These doses
oß agonist used produced approximately 20, 50 and 80~ oß the maximal contractile response oß the tissue ßor the agonist .
The maai-
mal contractile responses to NE were greater than the maximal contractile response to either HC1 or BaC12 .
Each tissue was chal-
lenged with increasing doses oß norepinephrine or RC1 every 15 minutes .
Twenty minutes elapsed between each dose oß HaC12 .
This
procedure resulted in a return to baseline tension after each dose oß agonist prior to obtaining a response to succeeding doses oß agoaiet . Statistical evaluation oß data .
Dose-eßßect data were ana-
lyzed by an analysis oß variance ßor a partially-nested, rando=ized complete block ßactorial design .
llhenever the ßactorial ana
lysis resulted in a significant interaction term the means were analyzed ßor significance by the Duncan's New Multiple Range Test or by Tukey's procedure (17) .
A P value oß 0 .05 or less (P
Lìfa Scieace~ Vol. 16, pp " 363-374 Printed in the U.s .l1.
BFFECTS OF PR08TAGIANDIN B2 ON VABCIILAR TON$ AND REACTIVITY) S . Greenberg, 2 F .P .J . Diecke, P.J . Hadowitz and J .P . Long Departments oß Pharmacology, Physiology and Medicine, College oß Medicine, University of Iowa, Iowa City, Iowa 52242 (Received in final
form
January 1, 1975)
3UMMARY Superßused helical stripe oß canine anterior mesenteric arteries and veins and canine dorsal metatarsal veins contract in reepoase to prostaglandin B2 (PGB2) . Reserpine pretreatment and phentolamiae reduce the constrictor response to PGB2 . PGB2 enhancee the contractile responses oß these preparations to potassium, barium and norepinephrine . P(iB2 also produced a shißt to the leßt in the duration oß the barium response curve . The data presented demonstrate that PGH is not an inactive metabolite oß PGA2 metabolism but possesses ~otent constrictor activity probably dependent oa release oß norepinephrine ßrom adrenergic nerves . Furthermore, PGB enhances the responses oß vascular smooth muscle to vasoactive st~muli . INTRODUCTION Prostaglandins oß the B series have been considered to be inactive metabolites oß prostaglandin A metabolism (1-3) .
However,
Saunders and coyorkera (4-8) recently reported that high doses oß PGBg constricted isolated perßueed rat pancreatic arteries . Ia addition PGB2 was reported to cause cutaneous and pulmonary vasoconstriction in doge at doses which resulted in decreases in systemic and renal vascular resistance (7-9) .
It was concluded
that PGB2 was not an inactive metabolite oß PGA2 metabolism (7-9) . y USPHH Grants N85188, N81398 and N84431 and uppor e n per the Iowa Heart Association . 2Present address : Departments oß Cell Biophysics and Pharmacology, Baylor College oß Medicine, 1200 Moureui~d Avenue, Houston, Texas 77025 . Address correspondence to Dr . J .P . Long, Department oß Pharmacology, College oß Medicine, University oß Iowa, Iowa City, Iowa 52242 . 363
364
Effects of P®2 on Vascular Tone/Reactivity
Vol . 16, No . 3
Prostaglandin A2 is not cleared by the lung and its concentrations may increase in blood as a consequence of various pathophysiologic states (10,11) .
Since PGA2 may eventually be metabo
lized to PGB2 (12-14) it is important to know the eîïecta oï PGB2 on vascular reactivity .
The following preliminary study demon-
atratea that PGB2 enhances vascular responses to vasoactive stimuli . METHODS AND MATERIALS Canine anterior mesenteric arteries
(0 .5-0 .8 mm o .d .) and
veins (0 .5-0 .8 mm o .d .) and dorsal metatarsal veins (1-2 mm o .d .) were removed, cut into helical stripe and prepared ïor auperîuaion as previously described (14,15) . under optimal resting tension .
Each vascular strip was mounted The preparations were allowed to
equilibrate 3 hours prior to experimentation .
Isometric con-
tractions were measured with a Grass Ft .03 force-displacement transducer and recorded on a Grass model 5 recorder .
The phyaio-
logic salt solution (PSS) was maintained at 37 .5°C, aerated with 95% O2 and 5~,C02 (pH 7 .4), and contained (mM) : sodium chlor ids (113), potassium chloride (3 .1), sodium bicarbonate (24 .8), calcium chloride (1 .53), glucose (10), magnesium chloride (2 .1), monosodium dihydrogen phosphate (1 .1), calcium dieodium ethylenediaminetetraacetate (0 .028), and pyruvic acid (3 .2) .
The calcium
concentration utilized in these studies was determined by m~aurement of plasma calcium concentration and subtraction ói the plasma protein bound ßraction (~ 45~) .
The îlow rate óf the superîusate
was 3 to 4 ml/min and was maintained constant throughout the experiment . Contractility studies .
Partial dose-response curves were
obtained for norepinephrine (0 .8-8 .0 nanomolee), HaC12 (24 to 98 ~olea) and potassium chloride (50 to 200 moles) prior to, during
Vol . 16, No . 3
365
Bffacts of Pf~Z on Vascular Toae/Raactivity
and 90 minutes after superßusion with PGBg (2 .8 x 10~ M) .
Each
vascular strip was challenged with the 3 doses oß each agonist . The responses to the agonists were reproducible witó time and were independent oß the order oß agonist administration .
These doses
oß agonist used produced approximately 20, 50 and 80~ oß the maximal contractile response oß the tissue ßor the agonist .
The maai-
mal contractile responses to NE were greater than the maximal contractile response to either HC1 or BaC12 .
Each tissue was chal-
lenged with increasing doses oß norepinephrine or RC1 every 15 minutes .
Twenty minutes elapsed between each dose oß HaC12 .
This
procedure resulted in a return to baseline tension after each dose oß agonist prior to obtaining a response to succeeding doses oß agoaiet . Statistical evaluation oß data .
Dose-eßßect data were ana-
lyzed by an analysis oß variance ßor a partially-nested, rando=ized complete block ßactorial design .
llhenever the ßactorial ana
lysis resulted in a significant interaction term the means were analyzed ßor significance by the Duncan's New Multiple Range Test or by Tukey's procedure (17) .
A P value oß 0 .05 or less (P
