Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries

Christina Rostrup Kruuse; Saurabh Gupta; Elisabeth Nilsson; Lars Kruse; Lars Edvinsson

doi:10.1016/j.ejphar.2011.10.037

Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries

Christina Rostrup Kruuse, Saurabh Gupta, Elisabeth Nilsson, Lars Kruse, Lars Edvinsson

Institut for Klinisk Medicin

13 Citationer (Scopus)

Abstract

Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment. The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extra-luminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P=0.03) and 10% (tadalafil, P=0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3mg/kg);1mg/kg sildenafil inducing 60 ± 14% (P=0.04) and vehicle (DMSO) 13 ± 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects.

Originalsprog	Engelsk
Tidsskrift	European Journal of Pharmacology
Vol/bind	674
Udgave nummer	2-3
Sider (fra-til)	345-51
Antal sider	7
ISSN	0014-2999
DOI	https://doi.org/10.1016/j.ejphar.2011.10.037
Status	Udgivet - 14 jan. 2012

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10.1016/j.ejphar.2011.10.037

Citationsformater

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title = "Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries",

abstract = "Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment. The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extra-luminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P=0.03) and 10% (tadalafil, P=0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3mg/kg);1mg/kg sildenafil inducing 60 ± 14% (P=0.04) and vehicle (DMSO) 13 ± 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects.",

keywords = "Animals, Blood Pressure, Carbolines, Cyclic Nucleotide Phosphodiesterases, Type 5, Gene Expression Regulation, Enzymologic, In Vitro Techniques, Male, Middle Cerebral Artery, Morpholines, Phosphodiesterase 5 Inhibitors, Piperazines, Purines, Pyrazoles, Pyrimidines, Rats, Rats, Sprague-Dawley, Sulfones, Vasodilator Agents",

author = "Kruuse, {Christina Rostrup} and Saurabh Gupta and Elisabeth Nilsson and Lars Kruse and Lars Edvinsson",

year = "2012",

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doi = "10.1016/j.ejphar.2011.10.037",

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T1 - Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries

AU - Kruuse, Christina Rostrup

AU - Gupta, Saurabh

AU - Nilsson, Elisabeth

AU - Kruse, Lars

AU - Edvinsson, Lars

PY - 2012/1/14

Y1 - 2012/1/14

N2 - Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment. The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extra-luminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P=0.03) and 10% (tadalafil, P=0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3mg/kg);1mg/kg sildenafil inducing 60 ± 14% (P=0.04) and vehicle (DMSO) 13 ± 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects.

AB - Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment. The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extra-luminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P=0.03) and 10% (tadalafil, P=0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3mg/kg);1mg/kg sildenafil inducing 60 ± 14% (P=0.04) and vehicle (DMSO) 13 ± 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects.

KW - Animals

KW - Blood Pressure

KW - Carbolines

KW - Cyclic Nucleotide Phosphodiesterases, Type 5

KW - Gene Expression Regulation, Enzymologic

KW - In Vitro Techniques

KW - Male

KW - Middle Cerebral Artery

KW - Morpholines

KW - Phosphodiesterase 5 Inhibitors

KW - Piperazines

KW - Purines

KW - Pyrazoles

KW - Pyrimidines

KW - Rats

KW - Rats, Sprague-Dawley

KW - Sulfones

KW - Vasodilator Agents

U2 - 10.1016/j.ejphar.2011.10.037

DO - 10.1016/j.ejphar.2011.10.037

M3 - Journal article

C2 - 22094063

SN - 0014-2999

VL - 674

SP - 345

EP - 351

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 2-3

ER -

Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries

Abstract

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