The effects of verapamil upon noradrenaline‐induced contraction of the rat isolated aorta following acute and prolonged alterations in PO2

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Abstract
1 Noradrenaline (NA; ED90) caused a contraction of the rat aorta which could be separated into two components, a rapid response mediated by release of intracellular Ca2+ and a more slowly developing contraction which relied principally upon Ca2+ influx. 2 Exposure to acute (30 min) hypoxia has been previously shown to reduce the NA-induced contraction (by 28.0 ± 2.7%, n = 168) which recovered completely upon re-oxygenation (recovery response). In the present study, prolonged exposure to hypoxia (70 h) caused a more pronounced reduction (39.7 ± 3.0%, n = 90) of the NA-induced contraction, but, re-oxygenation then produced incomplete recovery to 77.9 ± 3.9% (n = 90) of the control response. 3 Prolonged exposure to 95% O2 caused a 36.5 ± 3.1% (n = 42) reduction of NA-induced contractions, whereas prolonged exposure to 21% O2 only caused a small (12.6 + 3.4%, n = 6) depression of these responses. 4 The component of the NA-induced contraction mediated by release of intracellular Ca2+ is 39.8 ± 1.3% (n = 83) of the NA contraction in Ca-containing Krebs solution and was previously found to be unaffected by acute hypoxia. However, following prolonged exposure to either hypoxia or 21% O2, this component only reached 30.7 ± 2.2% (n = 32) or 28.3 ± 0.9% (n = 6) of the control response, respectively. Prolonged exposure to 95% O2 caused a more pronounced reduction of this component of contraction which then reached 19.1 ± 2.1% (n = 12) of the control response. 5 Verapamil (10 nM-10 μm) produced similar concentration-dependent reductions of NA-induced contractions elicited during control conditions or acute hypoxia; under these conditions, 1 μm verapamil caused a 34.1 μ 6.9% (n = 6) and a 41.8 ± 2.9% (n = 18) reduction of these responses respectively. However, recovery responses caused by re-oxygenation of tissues exposed to acute hypoxia were more sensitive to verapamil which, at a concentration of 1 μm, caused a 59.2 ± 2.7% (n = 18) reduction of these responses. Verapamil (10 nM-10 μm) also caused similar pronounced concentration-dependent reductions of contractions elicited during prolonged exposure to normoxia or hyperoxia and of recovery responses obtained following re-oxygenation of tissues exposed to prolonged hypoxia; 1 μm verapamil caused a 62.5 ± 1.1% (n = 6), 77.2 ± 3.8% (n = 12) and a 68.0 ± 4.3% (n = 12) reduction of these responses respectively. In contrast, contractions elicited during prolonged hypoxia were less sensitive to verapamil which at a concentration of 1 μm only caused a 16.2 ± 2.2% (n = 12) reduction of these responses. 6 The present study indicates that prolonged exposure of the rat aorta to either hypoxic or oxygenated conditions causes attenuation of NA-induced contraction. However, these effects are also accompanied by changes in tissue Ca2+ handling which differ under each condition and might account for the observed modifications in tissue sensitivity to the calcium-entry blocker verapamil.