5-HT receptors mediating contractions of the isolated human coronary artery
ABSTRACT We investigated contractile responses of the isolated human coronary artery to 5-hydroxytryptamine (5-HT), washed human platelets, sumatriptan and ergotamine. 5-HT (pD2: 6.8 ± 0.1, Emax: 47.7 ± 6.8 mN) and platelets (effect 14.4 ± 2.8 mN with 3 · 1010 platelets/1) caused contractile responses which were attenuated by ketanserin (1 μM). In the presence of ketanserin (1 μM), both rauwolscine (1 and 10 μM) and cyanopindolol (1 and 10 μM) caused concentration-dependent additional antagonism against contractions induced by low (⩽ 1 μM) concentrations of 5-HT. Sumatriptan-induced contractions (pD2: 6.2 ± 0.1; Emax: 10.7 ± 2.4 mN) were antagonized to a similar extent by both rauwolscine (1 μM) and cyanopindolol (1 μM) (pKB: 6.5 ± 0.1 and 6.4 ± 0.1, respectively) and also by metergoline (0.1 μM; pKB: 7.2 ± 0.1). The order of potency of antagonists against sumatriptan resembles the order reported for the human saphenous vein 5-HT1D-like receptor. No significant additional antagonism by cyanopindolol (1 μM) or rauwolscine (1 μM) against platelet-induced contractile responses was observed. Ergotamine caused potent contractile responses (pD2: 8.4 ± 0.3, Emax: 19.4 ± 2.4 mN). It is concluded that although 5-HT2 receptors predominantly mediate 5-HT-induced contractions, the 5-HT1-like receptor seems to play a role in coronary vasospasm caused by low concentrations of 5-HT.
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- "The relatively high intrinsic activity of 5-HT indicates that the 5-HT 2 receptor is the most important receptor in this preparation. Indeed, contraction to 5-HT is predominantly blocked by 5-HT 2 receptor antagonists whereas only a small proportion is blocked by 5-HT 1 receptor antagonists (Bax et al., 1993; Connor et al., 1989; Kaumann et al., 1994). Contraction to sumatriptan is blocked by non-selective 5-HT 1B/1D receptor antagonists (MaassenVanDenBrink et al., 2000; van den Broek et al., 2000), whereas the 5-HT 1B receptor antagonist SB224289 partially blocked this contraction (Chapter 8). "
ABSTRACT: Migraine is defined as an idiopathic, paroxysmal neurological disorder with moderate to severe attacks of unilateral, throbbing headache exacerbated by physical activity. The migraine attack is accompanied by associated features such as nausea, vomiting, photophobia and phonophobia (Headache Classification Committee of the International Headache Society, 1988). Since migraine is a common illness, it imposes a tremendous health burden on both patient and society (Solomon & Price, 1997). Prevalence rates of migraine vary geographically and its occurrence is dependent on age (most common from age 25-55 years), gender (three times more common in women than in man) and income (affecting lower socio-economic groups more, see Lipton & Stewart, 1997; Silberstein & Lipton, 1996). In about one third of patients (Rasmussen & Olesen, 1992), an aura may precede the migraine headache within one hour (migraine with aura), consisting of focal neurological (scintillating scotoma), sensory (pins or needle feeling or numbness) and/or motor (weakness or paralysis) symptoms. The majority of patients, however, do not present such symptoms (migraine without aura) (Ferrari, 1998). Migraine attacks per se are not necessarily an abnormal feature, considering that anyone may experience one or two migraine attacks in life. Migraine patients are therefore defined as individuals who have had at least two attacks with aura or at least five attacks without aura. To study migraine scientifically, the International Headache Society (IHS) provided some strict and uniform criteria to determine whether a patient is suffering from migraine (Headache Classification Committee of the International Headache Society, 1988) (see Table 1.1 for migraine with and without aura).
Article: SumatriptanDrugs 04/1994; 47(4). DOI:10.2165/00003495-199447040-00006 · 4.34 Impact Factor
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ABSTRACT: 1. Human epicardial coronary artery rings, freshly obtained from cardiac transplantation patients, commonly exhibited phasic contractile activity in vitro. This activity occurred either spontaneously or in response to vasoconstrictor stimulation. 2. Nifedipine pretreatment (1 nM-0.1 microM) reduced both types of phasic contractions in a concentration-dependent manner. At 0.1 microM nifedipine, spontaneous contractions were completely abolished, as were phasic contractions induced by U46619, endothelin-1 or 5-hydroxytryptamine (5-HT). 3. For U46619 (0.1-100 nM), the largest phasic contractions (amplitude peak to trough) occurred over the mid-range of concentrations used (1-10 nM). At higher concentrations (30-100 nM), phasic activity was reduced as the response reached a maximum. Estimated pEC50 values for the upper phasic and lower phasic curves were significantly different (8.71 +/- 0.13 versus 7.90 +/- 0.11; P < 0.05; n = 10). In the presence of nifidepine (0.1 microM), the purely tonic contraction curve to U46619 was similar to the lower phasic curve in the absence of nifedipine (pEC50 = 8.14 +/- 0.06, n = 10). Similar results were obtained for endothelin-1 (0.1-100 nM). 4. Responses to 5-HT (1 nM-3 microM) were more variable. The largest phasic contractions were spread unevenly throughout the concentration-response curve. In the presence of nifedipine (0.1 microM), the curve to 5-HT was significantly depressed in range but not sensitivity (pEC50) when compared with the phasic curves. 5. In conclusion, activation of dihydropyridine-sensitive voltage-operated Ca2+ channels mediated the phasic contractions commonly observed in human epicardial coronary arteries. These contractions amplified the contractile responses to low concentrations of vasoconstrictors. Inhibition of phasic activity by the Ca2+ channel antagonist, nifedipine, allowed the tonic vasoconstrictor profile of human isolated coronary artery to be determined which is important information for the accurate quantitative assessment of vasodilator responses in this tissue in vitro.British Journal of Pharmacology 12/1994; 113(4):1093-8. DOI:10.1111/j.1476-5381.1994.tb17108.x · 4.84 Impact Factor