TY - JOUR

T1 - Nitric oxide-induced headache may arise from extracerebral arteries as judged from tolerance to isosorbide-5-mononitrate

AU - Christiansen, Ingelise

AU - Iversen, Helle Klingenberg

AU - Olesen, Jes

AU - Tfelt-Hansen, Peer

PY - 2008/8

Y1 - 2008/8

N2 - Long-term exposure to organic nitrates influences different sections of the vascular bed heterogeneously. Continuous dosage of nitrates leads to the development of tolerance both to the vascular effects and to the unwanted adverse effect, headache. Human data on the development of tolerance in different cranial arteries over more than 24 h are lacking. We compared the vascular changes of the middle cerebral, superficial temporal and radial arteries during oral administration of isosorbide-5-mononitrate (5-ISMN) 30 mg three times daily for 7 days in 11 healthy subjects in a double-blind, randomised, placebo controlled cross-over design. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and the diameters of the temporal and radial arteries were measured with high frequency ultrasound. Headache recordings were compared to the observed vascular changes over time. Tolerance was complete within 24 h in the middle cerebral artery whilst in the superficial temporal and the radial arteries, tolerance was only partial and developed much more slowly, i.e. after 7 days correlating with the disappearance of NO-induced headache. The present study thus demonstrated the important differences in the time profiles of appearance of nitrate tolerance in arteries of different vascular beds in man. If vasodilatation is the cause of NO-induced headache the results point to extracerebral arteries as the locus of nociception. Due to a variety of other possible pain-inducing effects of nitric oxide our results do not exclude cerebral arteries.

AB - Long-term exposure to organic nitrates influences different sections of the vascular bed heterogeneously. Continuous dosage of nitrates leads to the development of tolerance both to the vascular effects and to the unwanted adverse effect, headache. Human data on the development of tolerance in different cranial arteries over more than 24 h are lacking. We compared the vascular changes of the middle cerebral, superficial temporal and radial arteries during oral administration of isosorbide-5-mononitrate (5-ISMN) 30 mg three times daily for 7 days in 11 healthy subjects in a double-blind, randomised, placebo controlled cross-over design. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and the diameters of the temporal and radial arteries were measured with high frequency ultrasound. Headache recordings were compared to the observed vascular changes over time. Tolerance was complete within 24 h in the middle cerebral artery whilst in the superficial temporal and the radial arteries, tolerance was only partial and developed much more slowly, i.e. after 7 days correlating with the disappearance of NO-induced headache. The present study thus demonstrated the important differences in the time profiles of appearance of nitrate tolerance in arteries of different vascular beds in man. If vasodilatation is the cause of NO-induced headache the results point to extracerebral arteries as the locus of nociception. Due to a variety of other possible pain-inducing effects of nitric oxide our results do not exclude cerebral arteries.

KW - Adult

KW - Blood Pressure

KW - Cross-Over Studies

KW - Double-Blind Method

KW - Drug Tolerance

KW - Female

KW - Headache

KW - Heart Rate

KW - Humans

KW - Isosorbide Dinitrate

KW - Male

KW - Middle Aged

KW - Middle Cerebral Artery

KW - Nitric Oxide Donors

KW - Severity of Illness Index

KW - Time Factors

KW - Ultrasonography, Doppler, Transcranial

U2 - 10.1007/s10194-008-0043-9

DO - 10.1007/s10194-008-0043-9

M3 - Journal article

C2 - 18521538

VL - 9

SP - 215

EP - 220

JO - Journal of Headache and Pain

JF - Journal of Headache and Pain

SN - 1129-2369

IS - 4

ER -