Augmented contraction of the human isolated coronary artery by sumatriptan: a possible role for endogenous thromboxane

• Published in: British journal of pharmacology 1996-11, Vol.119 (5), p.855-862
• Main Authors: MaassenVanDenBrink, Antoinette, Bax, Willem A., Ferrari, Michel D., Zijlstra, Freek J., Bos, Egbert, Saxena, Pramod R.
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 5‐HT1D receptor; Adolescent; Adult; Arteries - drug effects; Arteries - physiology; aspirin; Biological and medical sciences; Child; Child, Preschool; Coronary Vessels - drug effects; Coronary Vessels - physiology; Drug toxicity and drugs side effects treatment; endothelin‐1; Female; human coronary artery; Humans; In Vitro Techniques; Infant; Male; Medical sciences; Middle Aged; migraine; Pharmacology. Drug treatments; Potassium - pharmacology; Prostaglandin Endoperoxides, Synthetic - pharmacology; Substance P - pharmacology; sumatriptan; Sumatriptan - pharmacology; thromboxane A2; Thromboxane A2 - analogs & derivatives; Thromboxane A2 - biosynthesis; Thromboxane A2 - pharmacology; Thromboxane A2 - physiology; Toxicity: cardiovascular system; Vasoconstrictor Agents - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15751.x

1 The antimigraine drug, sumatriptan, contracts the human coronary artery and, in some patients, elicits chest symptoms (e.g. pressure and pain), particularly after subcutaneous administration. We studied the effects of the thromboxane A2 (TxA2) analogue, U46619 and endothelin‐1 on contractile responses to sumatriptan in the human isolated coronary artery as well as the role of endogenously produced TxA2 and endothelin‐1 in contractions evoked by sumatriptan. 2 In the presence of U46619 (1 and 3 nM), mean concentration‐response curves to sumatriptan in the human coronary artery were shifted vertically due to the initial contraction by U46619, but when this initial contraction was subtracted from the response to sumatriptan, no significant augmentation was observed. However, analysis of the degree of augmentation in individual arterial segments revealed that the augmentation was variable and related inversely to the Emax of sumatriptan in the absence of U46619 (r = 0.78 and 0.81 for 1 and 3 nM, respectively; P < 0.05). 3 Treatment with the TxA2 receptor antagonist, SQ30741 (100 nM), or incubation of vessel segments with aspirin (10 μm), significantly reduced responses to sumatriptan; in aspirin‐treated vessel segments, SQ30741 failed to decrease further the contractions to sumatriptan. The decrease in Emax of sumatriptan by both SQ30741 and aspirin correlated significantly with the Emax of sumatriptan without SQ30741 (r = 0.74; P < 0.01) or aspirin (r = 0.94; P < 0.01). In aspirin‐treated vessel segments, responses to sumatriptan were significantly augmented in the presence of U46619 (3 nM; P < 0.05). 4 The specificity of SQ30741 was demonstrated by its ability to antagonize coronary artery contractions to U46619 (pA2: 7.54 ± 0.30), but not endothelin‐1. Similarly, incubation with aspirin (10 μm) did not affect contractile responses to endothelin‐1, but significantly reduced TxA2 production in coronary artery segments as judged by a decrease in thromboxane B2 (TxB2) from 4.77 ± 0.98 to 1.38 ± 0.36 ng g−1 2h−1. 5 Endothelin‐1 (1 nM) did not significantly augment contractions to sumatriptan; there was also no relationship between the degree of augmentation and the control Emax of sumatriptan in the absence of endothelin‐1. Furthermore, unlike SQ30741 or aspirin, a high concentration (100 nM) of the nonselective ETA/ETB receptor antagonist, SB 209670, failed to affect contractile responses to sumatriptan. However, SB 209670 potently antagonized coronary artery