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The effect of PGF2a on in vivo cerebral arteriolar diameter in cats and rats
PROSTAGLANDINS
THE EFFECT
OF PGF2,
ON
IN VIVO CEREBRAL ARTERIOLARDIAMETER IN CATS AND RATS
Earl F. Ellisl, Enoch P. Wei, Carolyn S. Cookrell,Sung Choi and Hermes A. Kontos Departmentsof Pharmacologyand Medicine,Medical College of Virginia, Virginia CommonwealthUniversity, Box 613 - MCV Station, Richmond, Virginia 23298 USA ABSTRACT We compared the effect of topical applicationof PGFS, on cerebral arteriolesin cats and rats equippedwith an acutely implanted cranial window. Arterial diameterwas measured using a microscopeand ima e splittingdevice. PGFS, in a concentrationranging from 10-7 to lo-5 M had no effect on large (2100 m> or small (< 100 pm) cat pial arterioles,but induced a dose dependentconstrictionof rat pial arterioleswith a maximum constrictionto 76% of control diameter.Dilation of cat large cerebral arteriolesby topicallyapplied PGES was not affected by simultaneousapplicationof PGFS, and PGES induced dilation of small arterioleswas decreased3% by PGF2,. While we and others have previouslyshown that both oat and rat brain can synthesize PGFz,, it appears that PGFS, is not likely to normally be a major modulator of cerebral arteriolarresistancein all species. INTRODUCTION Prostaglandinsare synthesizedby the brain and have been proposed to be modulatorsof neurotransmission and mediators of cerebral blood flow regulation. PGFS, has been reported to decrease cerebral blood flow in primates and dog and PGFS, has been suggestedas a possible mediator of cerebral vasospasm (l,2,3). Welch et al (3) and Kapp et al (1) found that in the cat a local PGF2, concentrationof 1 ug/ml or more was necessary to induce vasoconstrictionof exposed, in vivo cerebral or pial arterioles. We have previouslyshown that topical applicationof PGD2, PGES, PGGS or PGIS induces dilation of in vivo cat pial arterioles,as measured through a closed cranial window chamber (4). There are no reports in the literatureon the effects of PGFS, on rat cerebral arterioles. Additionally,there is no experimentalliteratureconcerningthe effect of locallyapplied PGFSa on cerebralarteriolar resistancewhen using a closed cranial window, which importantly,maintainsnormal local ~02, pCO2 and pH. We now report that PGFS, is not vasoactiveon pial arteriolesof cats, but causes constrictionof in vivo rat pial arterioles. This suggests that while cat brain readily synthesizesPGF2, this prostaglandin is unlikely to be a direct modulatorof normal cerebral arteriolarcaliber in the cat.
1To whom all correspondenceshould be addressed.
DECEMBER
1983VOL.26N0.6
917
PROSTAGLANDINS
MATERIALS AND METHODS Experimentswere carried out in 2-4 kg cats and 250 g rats. The animals were anesthetizedwith sodium pentobarbital(30 mg/kg, IV). After completionof tracheostomy,each cat was ventilatedwith a positive-pressurerespiratorand receiveddecamethoniumbromide (0.5 mg/Kg) intravenouslyfor skeletal muscle paralysis. The cat's end-expiratory CO2 was continuouslymonitoredwith a Beckman infrared CO2 analyzer and was maintainedat a constant level of approximately30 mm Hg throughout each experimentby adjusting the respiratorrate and volume. Arterial blood pressurewas measured through the femoral artery. Arterialblood samples were periodicallyanalyzed to insure a normal range of ~02, pCO2, pH and hematocrit. Radiometer electrodes.
Blood gas tension and pH were measured with
Cat pial precapillaryvessels were visualizedusing a cranial window techniquepreviouslydescribedin detail (5). The cranial window was implanted just caudal to the suture connectingthe frontal and parietal bones. The cranial window contains 3 ports which allow for drug inlet and outlet and continuousmeasurementof intracranialpressure. Intracranialpressure was measuredwith a strain gauge and was maintainedconstantat 7 mm Hg throughoutthe experimentsby connecting the outlet to plastic tubing whose free end was placed at a fixed height. A rat window chamber was preparedas follows because the thin skull of the rat does not allow implantationof the stainlesssteel window as used in cats. The skin was removed from the midline of the rats' skull the skull. posed skull were at the
and a 2 x 4 mm craniectomy was performed on the midline of Two 20 gauge needles were glued to the surface of the exwith cyanoacrylate glue such that the points of the needle edge of the crainectomy. When completedthese two needles
served as the drug inlet and outlet ports. After the needles were glued in place, a small crown of dental acrylate was placed around the edges of the craniectomyand when dried served as a barrier to prevent a second applicationof dental acrylate from flowing onto the brain surface. Next a cover slip was placed over the craniectomyand a third applicationof dental acrylate applied around the edges of the cover slip to form a closed cranial window chamber. Vessel diameter was measured with a Vickers image-splittingdevice attached to a Leitz Ultrapak microscopeequipped with an 11 x objective and 10 x eyepieces. The space under the window and the plastic tubing connectedto it were filled with artificialcerebrospinalfluid (CSF). Before pharmacologicexperimentswere conducted,normal pial arteriolar reactivitywas insured by demonstratingnormal vasoconstrictionin response to arterial hypocapniaproducedby hyperventilation. PGF2, tromethaminesalt was obtainedfrom the Upjohn Co. and was dissolved directly in artificial CSF. This fluid was equilibratedwith gas containing6% 02, 6.5% CO2 and 87.5% N2 to give gas tensions and pH in the normal range for CSF. Two mls of each drug-containingsolution was flushed -through the cat cranial window and 0.25 mls was flushed through the rat cranial window.
918
The drug application is carried out at
DECEMBER
1983 VOL.26N0.6
PROSTAGLANDINS
a slow rate so that intracranial pressure is not increased. Immediately after each topical application the dialmeterof 6-8 different arterioles is measured in a continuously rotating fashion to ascertain when the maximum response i3 achieved. Ten minutes after applying a particular concentration of PGF2,, the cranial window was flushed with artificial CSF containing the next higher concentration of PGF2, to be tested. PGE2 (Upjohn Co.) stock solutions (1 and 10 m&ml) were prepared in absolute ethanol. PGE2 was added to gased artificial CSF such that the Before applying PGE2 to the maximum alcohol concentration was 1 @/ml. sial vessels a 1 ul/ml concentration of alcohol in artificial CSF was applied to the vessels to make certain the ethanol vehicle had no effect on arteriolar diameter. After a solution containing PGE2 was applied to the vessels, diameter was read continuously to ascertain when the maximum dilator response was achieved. The diameter was then recorded and the next PG solution applied. The effect of PGF2, concentration on arteriolar diameter was tested by linear regression analysis and the effect of PGF2, on PGE2 induced dilation was tested by a paired t-test. A P value of 0.05 or less was considered to indicate a significant difference. RESULTS Control blood pressure, Pa02, PaC02 and pH + SEM in the 6 cats which received only PGF2a was 127 2 16, 85 z 5, 31 + 1 mm I& and 7.32 + 0.01, respectively. As can be seen in Fig. 1, toTica1 application of TGF2a had no effect on cat cerebral arteriolar diameter. Continuous measurement of arteriolar diameter in cats after the application of PGF2, showed that PGF2, had no effect regardless of the time period following the topical application. In addition, PGF2, locally applied had no effect on mean arterial blood pressure in cats. Since we originally expected to observe vasoconstriction in response to PGF2, we considered the possibility that our PGF2, had decomposed. This possibility was excluded since derivatization of PGF2, and structural examination by gas chroinatography/massspectrometry produced only the mass spectrum of Also, PGF2, gave the expected decrease in systemic blood PGF2a (6). pressure when given intraveneously to the cat (7). In order to determine if the lack of pial arteriolar response to PGF2, waa species dependent, we next measured the pial arteriolar response to PGF2, in 6 rats. The control mean arterial blood pressure, Pa02, PaC02 and pii + SEX in these rats was 114 + 11, 73 + 8, 32 + 1 mm Hi:and 7.45 + 0.017 respectively. A3 shown in Fig. 2,PGF2, produced a dose-depe;dent vasoconstriction of rat cerebral arterioles. Topical application of PGF2, had no effect on rat mean arterial blood pressure. Since PGF2, itself is not vavoactive in cerebral arterioles of the cat, we next determined whether PGF2, might influence the normal pial arteriolar dilator response to PGE2. In a separate series of 11 cats we tested the effect of 4 different increasing concentrations of PGE2 in the presence or absence of an equal, simultaneous concentration of PGF2,. Six of the cats received PGE2 plus PGF2, first and then only PGE2 while tineremaining animals first received PGE2 only and then PGE2 plus PGF2,. The control mean arterial blood pressure, Pa02, PaC02 and
DECEMBER
1983 VOL. 26 NO. 6
919
PROSTAGLANDINS
Fig. 1. The effect of PGF2a on the diameter of large and small cat cerebral arterioles. Linear regressionanalysis showed no relationship between increasing PGF2, concentrationand the diameter of large and small arterioles. A total of 23 large and 23 small arterioleswere analyzed in 6 cats.
[PGFza]- M
Fig. 2. The effect of PGF2, on the diameter of rat cerebral arterioles. Linear regressionanalysis showed that e.nincreasing PGF2, concentration was associated with a decrease in diameter. A total of 25 arterioles were analyzed in 6 rats. Unlike the oat data, only one control diameter category is reported since rats do not have larger pial arterioles. *IndicatesP < 0.01, oompared to control.
920
DECEMBER
1983 VOL. 26 NO. 6
PROSTAGLANDINS
CONTROL < 100 >I00
DIAMETER 63.7
2.3rm
174.5+4.4rm
flE
q E ANDF
r 8.5xIO’‘M
2.81dO’~M 8.5xIO*M
2.8~10%
Fig. 3. The effect of PGF2a on PGE2 induced dilation of large and small cat cerebralarterioles. Analysis by the paired t-test showed that PGF2, did not affect PGE2 induced dilation of large arteriolesbut did reduce PGE2 induced dilation of small arteriolesby an average of 3%. A total of 42 large arteriolesand 32 small arterioleswere studied in 11 cats. *indicatesP < 0.02, compared to PGE2 only.
pH + SE3\1 in these cats was 128 2 5, 98 + 3, 31 + 1, mm Q and 7.35 2 .Ol, respectively. In agreement with our previous report (21, figure 3 shows that PGE2 alone induces a dose dependentarteriolardilation. As shown in figure 3, the presence of PGF2, had no effect on the normal pial dilator response to PGE2 in large arterioles. For small arteriolesthe mean dilator response to each dose of PGE2 was decreased by 3% when PGF2, was present in an equal concentration(P < 0.02).
DECEMBER
1983
VOL.26N0.6
921
PROSTAGLANDINS
DISCUSSION Despite the fact that the cat brain has a large capacity to aynthesize PGF2, and PGF2, is a vaaoconatrictorin many species,the present experilnenta show that PGF2, alone is likely to have little or no direct vaaoactivityat in viva concentrationsin the cat cerebralmicrocirculation. Therefore,since our previoua studies have shown that PGI2 and PGD2 are pial arteriolardilators (4) it appears that the predominant effect of PGs on cerebral arteriolesin the cat is vasodilation. However the present results do show that PGF2, was able to reduce PGE2 induced dilation of small arteriolesby 3%. When the responsesto all dosea of PGE2 are combined, the average dilator response is 25%. Therefore a reductionto 22% dilation by t'nesimultaneouspresence of PGF2, is actuallya 12% decrease from the effect of PGE2 alone. Therefore under certain circumstancesPGF2, may play a role in reducing the dilator effect of other PGa on small arterioles. It is difficultto exactly compare our results with PGF2, in the cat with previous studies of the cerebrovaaculareffects of PGF2, in the , previous studies used an in vivo cat because, unlike our experiments arterial preparationwhich waa exposed to air. Nevertheless,Welch et al (10) found that concentrationsof lo-100 pg/ml were needed to cause a 17% decrease in oat pial arteriolardiameter in an open cranial preparation. These lo-100 pug/mlconcentrationsare 2-3 orders of magnitude greater than the PGF2, levels which we have found in quick frozen cat cortical tissue (6). Also, Kapp et al (1) reported that the minimum concentrationto cause constrictionof the tranaorallyexposed cat basilar artery was 0.1 - to 1 ~&ml. Examinationof the literatureon the systemic effects of PGF2, in cats also supportsthe concept that ?GFza has a limited direct effect on vascular tone. Kosa and Nakano (7) showed that IV injectionof 6 ,ug/Kg PGFza caused an increase in pulmonaryarterial pressure and a decrease in heart rate with subsequentfall in ayatemiopressure.Bilateral vagotomy abolishedall these effects except the increase in pulmonarypressure. This implies that the only direct effect of PGF2, on the cat vasculature is a constrictionof the pulmonaryvaaculature. More recently, Gillia et al (8) have reported that PGF2, administeredinto the lateral and third cerebral ventriclesof cats has no effect on heart rate or blood pressure whereas PGE2 increasedheart rate and blood pressure. There are no previouslypublishedreports on the in vivo cerebral arteriolareffects of PGF2, in rats, but our finding of cerebral vasoconstrictionis consistentwith the effects of systemicallyadminiatered PGF2, in rats. We have previouslyshown that in the rat IV PGF2, conatrictaskeletal muscle arteriolesand increasesblood pressure and pulse pressure (9). These effects of PGF2, were greater in intact apontaneoualyhypertensiverata (SHR) but not in SHR'a with pharmacologic blockade of their alpha-adrenergicreceptors,suggestinga sympathetic componentin the response to IV PGF2, in rata (9). Feurateinet al (10) have recently confirmed that PGF2, injected into the cerebroventricular ayatem in rata increases blood pressure by a peripheralsympathetic
922
DECEMBER
1983VOL.26 NO.6
PROSTAGLANDINS
mechanism. The fact that we did not observe any blood pressure effects with topical cortical administration with PGF2, in rats is consistent with the findings of Fourstein et al (10) that the central effect of PGF2, in rats is mediated by deeper brain structures. In summary, our finding that PGF2, is not vasoactive in the cat supports the concept that PGF2, is not a universal constrictor of the cerebral vasculature. Therefore, even though the cat cortex has a high capacity for PGF2, formation, any possible function of PGF2, in the cat cerebral circulation remains obscure.
ACKNOWLEDGEMENTS We thank Dr. J. Pike of the Upjohn Co. for generously providing prcstaglandins. The secretarial skills of Ms. Rebecca Harris and technical skills of Ms. Amy Richardson are gratefully acknowledged. This study was supported by NS-12587. REFERENCES
1)
Kapp, J.P., J.T. Robertson and R.P. White. Spasmogenic qualities of prostaglandin F2, in the cat. J. Neurosurg. 2: 173-175, 1376.
2)
Pickard, J.D. Role of prostaglandins and arachidonic acid derivatives in the coupling of cerebral blood flow to cerebral netabolism. J. Cerebral Blood Flow and Metab. 1: 361-384, 1981.
3)
Welch, K.M.A., L. Knowles and P. Spira. Local effects of prostaglandins on cat pial arteries. Eur. 3. Pharmaccl. 2: 155-158, 1974.
4)
Ellis, E.F., E.P. Wei and H.A. Kontos. Vasodilation of cat oerebra1 arterioles by prostaglandins D2, E2, G2 and 12. Amer. J. Physiol. -237: H381-385, 1979.
5)
Lavasseur, J.E., E.P. Wei, A.J. Haper, H.A. Kontos and J.L. Patterson. Detailed description of a cranial window technique for acute and chronic experiments. Stroke 5: 308-316, 1977.
6)
Ellis, E.F., K.F. Wright, E.P. Wei and H.A. Kontos. Cyclooxygenase products of arachidcnic acid metabolism in cat cerebral oortex after experimental concussive brain injury. J. Neurochem. 2: 892-896.1981.
7)
Koss, M.C. and J. Nakano. Cardiac arrythmias induced by prostaglandin F2, in cats. Prostaglandins 8: 179-186, 1974.
8)
Gillis, R.A., J.A. Quest, J.D. Sousa, P.A. Kot and P.W. Ramwell. Blood pressure and heart rate effects of prostaglandin E2 and F2a produced by intracerebroventricular injections in cats. Prostaglandins 22: 1003-1012, 1981.
9)
Ellis, E.F. and P.M. Hutchins. Increased cardiovascular responses to prcstaslandin F2a in spontaneously hypertensive rats: Evidence for neural mediation. Microvascular Res. 3: 19-27, 1977.
10)
Feurstein, G., C.J. Helke, R.T. Zerbe, Kopin. Mechanisms involved in cent-al prcstaglandin F2a. Amer. J. Physicl.
DECEMBER
1983 VOL. 26 NO. 6
D.M. Jacobowitz and I.J. cardiovascular effects of -242: R545-551, 1982.
923
THE EFFECT
OF PGF2,
ON
IN VIVO CEREBRAL ARTERIOLARDIAMETER IN CATS AND RATS
Earl F. Ellisl, Enoch P. Wei, Carolyn S. Cookrell,Sung Choi and Hermes A. Kontos Departmentsof Pharmacologyand Medicine,Medical College of Virginia, Virginia CommonwealthUniversity, Box 613 - MCV Station, Richmond, Virginia 23298 USA ABSTRACT We compared the effect of topical applicationof PGFS, on cerebral arteriolesin cats and rats equippedwith an acutely implanted cranial window. Arterial diameterwas measured using a microscopeand ima e splittingdevice. PGFS, in a concentrationranging from 10-7 to lo-5 M had no effect on large (2100 m> or small (< 100 pm) cat pial arterioles,but induced a dose dependentconstrictionof rat pial arterioleswith a maximum constrictionto 76% of control diameter.Dilation of cat large cerebral arteriolesby topicallyapplied PGES was not affected by simultaneousapplicationof PGFS, and PGES induced dilation of small arterioleswas decreased3% by PGF2,. While we and others have previouslyshown that both oat and rat brain can synthesize PGFz,, it appears that PGFS, is not likely to normally be a major modulator of cerebral arteriolarresistancein all species. INTRODUCTION Prostaglandinsare synthesizedby the brain and have been proposed to be modulatorsof neurotransmission and mediators of cerebral blood flow regulation. PGFS, has been reported to decrease cerebral blood flow in primates and dog and PGFS, has been suggestedas a possible mediator of cerebral vasospasm (l,2,3). Welch et al (3) and Kapp et al (1) found that in the cat a local PGF2, concentrationof 1 ug/ml or more was necessary to induce vasoconstrictionof exposed, in vivo cerebral or pial arterioles. We have previouslyshown that topical applicationof PGD2, PGES, PGGS or PGIS induces dilation of in vivo cat pial arterioles,as measured through a closed cranial window chamber (4). There are no reports in the literatureon the effects of PGFS, on rat cerebral arterioles. Additionally,there is no experimentalliteratureconcerningthe effect of locallyapplied PGFSa on cerebralarteriolar resistancewhen using a closed cranial window, which importantly,maintainsnormal local ~02, pCO2 and pH. We now report that PGFS, is not vasoactiveon pial arteriolesof cats, but causes constrictionof in vivo rat pial arterioles. This suggests that while cat brain readily synthesizesPGF2, this prostaglandin is unlikely to be a direct modulatorof normal cerebral arteriolarcaliber in the cat.
1To whom all correspondenceshould be addressed.
DECEMBER
1983VOL.26N0.6
917
PROSTAGLANDINS
MATERIALS AND METHODS Experimentswere carried out in 2-4 kg cats and 250 g rats. The animals were anesthetizedwith sodium pentobarbital(30 mg/kg, IV). After completionof tracheostomy,each cat was ventilatedwith a positive-pressurerespiratorand receiveddecamethoniumbromide (0.5 mg/Kg) intravenouslyfor skeletal muscle paralysis. The cat's end-expiratory CO2 was continuouslymonitoredwith a Beckman infrared CO2 analyzer and was maintainedat a constant level of approximately30 mm Hg throughout each experimentby adjusting the respiratorrate and volume. Arterial blood pressurewas measured through the femoral artery. Arterialblood samples were periodicallyanalyzed to insure a normal range of ~02, pCO2, pH and hematocrit. Radiometer electrodes.
Blood gas tension and pH were measured with
Cat pial precapillaryvessels were visualizedusing a cranial window techniquepreviouslydescribedin detail (5). The cranial window was implanted just caudal to the suture connectingthe frontal and parietal bones. The cranial window contains 3 ports which allow for drug inlet and outlet and continuousmeasurementof intracranialpressure. Intracranialpressure was measuredwith a strain gauge and was maintainedconstantat 7 mm Hg throughoutthe experimentsby connecting the outlet to plastic tubing whose free end was placed at a fixed height. A rat window chamber was preparedas follows because the thin skull of the rat does not allow implantationof the stainlesssteel window as used in cats. The skin was removed from the midline of the rats' skull the skull. posed skull were at the
and a 2 x 4 mm craniectomy was performed on the midline of Two 20 gauge needles were glued to the surface of the exwith cyanoacrylate glue such that the points of the needle edge of the crainectomy. When completedthese two needles
served as the drug inlet and outlet ports. After the needles were glued in place, a small crown of dental acrylate was placed around the edges of the craniectomyand when dried served as a barrier to prevent a second applicationof dental acrylate from flowing onto the brain surface. Next a cover slip was placed over the craniectomyand a third applicationof dental acrylate applied around the edges of the cover slip to form a closed cranial window chamber. Vessel diameter was measured with a Vickers image-splittingdevice attached to a Leitz Ultrapak microscopeequipped with an 11 x objective and 10 x eyepieces. The space under the window and the plastic tubing connectedto it were filled with artificialcerebrospinalfluid (CSF). Before pharmacologicexperimentswere conducted,normal pial arteriolar reactivitywas insured by demonstratingnormal vasoconstrictionin response to arterial hypocapniaproducedby hyperventilation. PGF2, tromethaminesalt was obtainedfrom the Upjohn Co. and was dissolved directly in artificial CSF. This fluid was equilibratedwith gas containing6% 02, 6.5% CO2 and 87.5% N2 to give gas tensions and pH in the normal range for CSF. Two mls of each drug-containingsolution was flushed -through the cat cranial window and 0.25 mls was flushed through the rat cranial window.
918
The drug application is carried out at
DECEMBER
1983 VOL.26N0.6
PROSTAGLANDINS
a slow rate so that intracranial pressure is not increased. Immediately after each topical application the dialmeterof 6-8 different arterioles is measured in a continuously rotating fashion to ascertain when the maximum response i3 achieved. Ten minutes after applying a particular concentration of PGF2,, the cranial window was flushed with artificial CSF containing the next higher concentration of PGF2, to be tested. PGE2 (Upjohn Co.) stock solutions (1 and 10 m&ml) were prepared in absolute ethanol. PGE2 was added to gased artificial CSF such that the Before applying PGE2 to the maximum alcohol concentration was 1 @/ml. sial vessels a 1 ul/ml concentration of alcohol in artificial CSF was applied to the vessels to make certain the ethanol vehicle had no effect on arteriolar diameter. After a solution containing PGE2 was applied to the vessels, diameter was read continuously to ascertain when the maximum dilator response was achieved. The diameter was then recorded and the next PG solution applied. The effect of PGF2, concentration on arteriolar diameter was tested by linear regression analysis and the effect of PGF2, on PGE2 induced dilation was tested by a paired t-test. A P value of 0.05 or less was considered to indicate a significant difference. RESULTS Control blood pressure, Pa02, PaC02 and pH + SEM in the 6 cats which received only PGF2a was 127 2 16, 85 z 5, 31 + 1 mm I& and 7.32 + 0.01, respectively. As can be seen in Fig. 1, toTica1 application of TGF2a had no effect on cat cerebral arteriolar diameter. Continuous measurement of arteriolar diameter in cats after the application of PGF2, showed that PGF2, had no effect regardless of the time period following the topical application. In addition, PGF2, locally applied had no effect on mean arterial blood pressure in cats. Since we originally expected to observe vasoconstriction in response to PGF2, we considered the possibility that our PGF2, had decomposed. This possibility was excluded since derivatization of PGF2, and structural examination by gas chroinatography/massspectrometry produced only the mass spectrum of Also, PGF2, gave the expected decrease in systemic blood PGF2a (6). pressure when given intraveneously to the cat (7). In order to determine if the lack of pial arteriolar response to PGF2, waa species dependent, we next measured the pial arteriolar response to PGF2, in 6 rats. The control mean arterial blood pressure, Pa02, PaC02 and pii + SEX in these rats was 114 + 11, 73 + 8, 32 + 1 mm Hi:and 7.45 + 0.017 respectively. A3 shown in Fig. 2,PGF2, produced a dose-depe;dent vasoconstriction of rat cerebral arterioles. Topical application of PGF2, had no effect on rat mean arterial blood pressure. Since PGF2, itself is not vavoactive in cerebral arterioles of the cat, we next determined whether PGF2, might influence the normal pial arteriolar dilator response to PGE2. In a separate series of 11 cats we tested the effect of 4 different increasing concentrations of PGE2 in the presence or absence of an equal, simultaneous concentration of PGF2,. Six of the cats received PGE2 plus PGF2, first and then only PGE2 while tineremaining animals first received PGE2 only and then PGE2 plus PGF2,. The control mean arterial blood pressure, Pa02, PaC02 and
DECEMBER
1983 VOL. 26 NO. 6
919
PROSTAGLANDINS
Fig. 1. The effect of PGF2a on the diameter of large and small cat cerebral arterioles. Linear regressionanalysis showed no relationship between increasing PGF2, concentrationand the diameter of large and small arterioles. A total of 23 large and 23 small arterioleswere analyzed in 6 cats.
[PGFza]- M
Fig. 2. The effect of PGF2, on the diameter of rat cerebral arterioles. Linear regressionanalysis showed that e.nincreasing PGF2, concentration was associated with a decrease in diameter. A total of 25 arterioles were analyzed in 6 rats. Unlike the oat data, only one control diameter category is reported since rats do not have larger pial arterioles. *IndicatesP < 0.01, oompared to control.
920
DECEMBER
1983 VOL. 26 NO. 6
PROSTAGLANDINS
CONTROL < 100 >I00
DIAMETER 63.7
2.3rm
174.5+4.4rm
flE
q E ANDF
r 8.5xIO’‘M
2.81dO’~M 8.5xIO*M
2.8~10%
Fig. 3. The effect of PGF2a on PGE2 induced dilation of large and small cat cerebralarterioles. Analysis by the paired t-test showed that PGF2, did not affect PGE2 induced dilation of large arteriolesbut did reduce PGE2 induced dilation of small arteriolesby an average of 3%. A total of 42 large arteriolesand 32 small arterioleswere studied in 11 cats. *indicatesP < 0.02, compared to PGE2 only.
pH + SE3\1 in these cats was 128 2 5, 98 + 3, 31 + 1, mm Q and 7.35 2 .Ol, respectively. In agreement with our previous report (21, figure 3 shows that PGE2 alone induces a dose dependentarteriolardilation. As shown in figure 3, the presence of PGF2, had no effect on the normal pial dilator response to PGE2 in large arterioles. For small arteriolesthe mean dilator response to each dose of PGE2 was decreased by 3% when PGF2, was present in an equal concentration(P < 0.02).
DECEMBER
1983
VOL.26N0.6
921
PROSTAGLANDINS
DISCUSSION Despite the fact that the cat brain has a large capacity to aynthesize PGF2, and PGF2, is a vaaoconatrictorin many species,the present experilnenta show that PGF2, alone is likely to have little or no direct vaaoactivityat in viva concentrationsin the cat cerebralmicrocirculation. Therefore,since our previoua studies have shown that PGI2 and PGD2 are pial arteriolardilators (4) it appears that the predominant effect of PGs on cerebral arteriolesin the cat is vasodilation. However the present results do show that PGF2, was able to reduce PGE2 induced dilation of small arteriolesby 3%. When the responsesto all dosea of PGE2 are combined, the average dilator response is 25%. Therefore a reductionto 22% dilation by t'nesimultaneouspresence of PGF2, is actuallya 12% decrease from the effect of PGE2 alone. Therefore under certain circumstancesPGF2, may play a role in reducing the dilator effect of other PGa on small arterioles. It is difficultto exactly compare our results with PGF2, in the cat with previous studies of the cerebrovaaculareffects of PGF2, in the , previous studies used an in vivo cat because, unlike our experiments arterial preparationwhich waa exposed to air. Nevertheless,Welch et al (10) found that concentrationsof lo-100 pg/ml were needed to cause a 17% decrease in oat pial arteriolardiameter in an open cranial preparation. These lo-100 pug/mlconcentrationsare 2-3 orders of magnitude greater than the PGF2, levels which we have found in quick frozen cat cortical tissue (6). Also, Kapp et al (1) reported that the minimum concentrationto cause constrictionof the tranaorallyexposed cat basilar artery was 0.1 - to 1 ~&ml. Examinationof the literatureon the systemic effects of PGF2, in cats also supportsthe concept that ?GFza has a limited direct effect on vascular tone. Kosa and Nakano (7) showed that IV injectionof 6 ,ug/Kg PGFza caused an increase in pulmonaryarterial pressure and a decrease in heart rate with subsequentfall in ayatemiopressure.Bilateral vagotomy abolishedall these effects except the increase in pulmonarypressure. This implies that the only direct effect of PGF2, on the cat vasculature is a constrictionof the pulmonaryvaaculature. More recently, Gillia et al (8) have reported that PGF2, administeredinto the lateral and third cerebral ventriclesof cats has no effect on heart rate or blood pressure whereas PGE2 increasedheart rate and blood pressure. There are no previouslypublishedreports on the in vivo cerebral arteriolareffects of PGF2, in rats, but our finding of cerebral vasoconstrictionis consistentwith the effects of systemicallyadminiatered PGF2, in rats. We have previouslyshown that in the rat IV PGF2, conatrictaskeletal muscle arteriolesand increasesblood pressure and pulse pressure (9). These effects of PGF2, were greater in intact apontaneoualyhypertensiverata (SHR) but not in SHR'a with pharmacologic blockade of their alpha-adrenergicreceptors,suggestinga sympathetic componentin the response to IV PGF2, in rata (9). Feurateinet al (10) have recently confirmed that PGF2, injected into the cerebroventricular ayatem in rata increases blood pressure by a peripheralsympathetic
922
DECEMBER
1983VOL.26 NO.6
PROSTAGLANDINS
mechanism. The fact that we did not observe any blood pressure effects with topical cortical administration with PGF2, in rats is consistent with the findings of Fourstein et al (10) that the central effect of PGF2, in rats is mediated by deeper brain structures. In summary, our finding that PGF2, is not vasoactive in the cat supports the concept that PGF2, is not a universal constrictor of the cerebral vasculature. Therefore, even though the cat cortex has a high capacity for PGF2, formation, any possible function of PGF2, in the cat cerebral circulation remains obscure.
ACKNOWLEDGEMENTS We thank Dr. J. Pike of the Upjohn Co. for generously providing prcstaglandins. The secretarial skills of Ms. Rebecca Harris and technical skills of Ms. Amy Richardson are gratefully acknowledged. This study was supported by NS-12587. REFERENCES
1)
Kapp, J.P., J.T. Robertson and R.P. White. Spasmogenic qualities of prostaglandin F2, in the cat. J. Neurosurg. 2: 173-175, 1376.
2)
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