A comparison of the effects of the calcium entry blockers, verapamil, diltiazem and flunarizine against contractions of the rat isolated aorta and portal vein

1 The effectiveness of the calcium antagonist, 1,4-dihydropyridine nisoldipine, as an inhibitor of contraction and 4'Ca entry evoked by noradrenaline in rat aorta has been investigated and correlated with binding characteristics in intact artery. 2 Contractions evoked by noradrenaline were concentration-dependently depressed by nisoldipine (0.3-300 nM). About 60% of the response was resistant to inhibition, while KCI-induced contractions could be completely blocked. Noradrenaline-induced contractions were also less sensitive to nisoldipine inhibition than were KCl-induced contractions. (1-1O0pM noradrenaline) was comparable in amplitude to the effect of 25 mm KCl solution. 8 It is concluded that in rat aorta, noradrenaline activates voltage-operated calcium channels that contain the specific, voltage-sensitive binding sites for calcium antagonistic dihydropyridines. The existence of a fraction of noradrenaline-stimulated '"Ca entry that is resistant to nisoldipine blockade suggests that another Ca2 + entry pathway is also opened by the agonist.

Section: Resultssupporting

confidence: 91%

Characterization in rat aorta of the binding sites responsible for blockade of noradrenaline‐evoked calcium entry by nisoldipine

Morel

Godfraind

1991

“…Clearly, those vascular contractions which are mediated by release of intracellular Ca2+ should be insensitive to calcium entry blockade, unless release processes are triggered by influx of extracellular Ca2 + Previous studies have demonstrated that EGTA-resistant responses of the rat aorta are indeed resistant to verapamil, supporting the suggestion that these responses are mediated by intracellular Ca2+ (Heaslip & Rahwan, 1983;Marriott, 1988). Nevertheless, it is not certain that the relative contribution of Ca2+ from an intracellular source ultimately determines the verapamil sensitivity of sustained NA-induced contractions elicited in the presence of Ca2", since in the rat aorta, intracellular Ca2" is only transiently involved during the early part of NA-induced contractions (Yamashita et al, 1977).…”

Section: Mechanisms Ofpo2-dependent Modifications In Verapamil Sensitmentioning

confidence: 74%

“…Vascular contractility has also been shown to be reduced by verapamil through mechanisms independent of calcium entry blockade (Raddino et al, 1987), but these actions are associated with the use of higher concentrations (> 10 gM) than those utilised in the present study (Triggle, 1982). However, in the rat aorta the effects of selective blockade of Ca2+ entry processes by verapamil need not be identical to those of extracellular Ca2+ withdrawal, since different pathways for activated Ca2+ entry do not appear to be equally sensitive to verapamil (Marriott, 1988).…”

Section: Mechanisms Ofpo2-dependent Modifications In Verapamil Sensitmentioning

confidence: 99%

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

Marriott

1989

Self Cite

1 Noradrenaline (NA; ED9Q) 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 (30min) 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 (70h) 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% 02 caused a 36.5 + 3.1% (n = 42) reduction of NA-induced contractions, whereas prolonged exposure to 21% 02 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% 02, 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%°2 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 (10nM-10uM) produced similar concentration-dependent reductions of NA-induced contractions elicited during control conditions or acute hypoxia; under these conditions, 1 gIM verapamil caused a 34.1 + 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 pm, caused a 59.2 + 2.7% (n = 18) reduction of these responses. Verapamil (10 nM-10 MM) 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 JM 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 JM 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.

“…Contractions induced by high concentrations of noradrenaline are also biphasic: the early fast component of contraction depends upon release of intracellular Ca2", while the slowly developing sustained phase of contraction depends upon influx of extracellular Ca2+ (Marriott, 1988). Accordingly, under Ca2'-free conditions, a smaller contraction may be induced in the rat aorta by noradrenaline and this must be mediated by intracellular Ca2'-release from internal stores (Noguera & D'Ocon, 1992, 1993.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of the cardiovascular activity of laudanosine: comparison with papaverine and other benzylisoquinolines

Chuliá

Ivorra

Lugnier

et al. 1994

1 The activity of (± )-laudanosine, a benzyltetrahydroisoquinoline alkaloid, was methoxamine (3-3001igkg-, i.v.) in normotensive pithed rats was shifted to the right by (±)-laudanosine, 3 and 6mgkg-'. 3 (± )-Laudanosine inhibited in a concentration-dependent manner the contractile responses evoked by noradrenaline (NA 1 jiM), depolarizing solution (KCI 80 mM) or depolarizing solution plus phentolamine (10 jAM) in rat isolated aorta. The alkaloid appeared to be more potent against NA-induced contractions.4 In Ca2"-free solution, (±)-laudanosine (100 jM) inhibited the contraction evoked by NA and did not modify the phasic contractile response evoked by caffeine. The alkaloid did not modify the refilling of the intracellular Ca2+-stores sensitive to NA or caffeine. (±)-Laudanosine inhibited [3H]-prazosin binding to cortical membranes and also inhibited [3H]-(+)-cis-diltiazem but with a lower potency. [3H~nitrendipine binding was not affected by laudanosine. 6 (±)-Laudanosine does not have a significant effect on the different forms of PDEs isolated from bovine aorta. In contrast, compounds structurally related to this alkaloid such as papaverine and its derivatives, had a non-selective or more specific inhibitory effect on these PDE forms. These differences can be explained on the basis of their structural features: the planarity of the isoquinoline ring (papaverine) facilitates the interaction with receptor sites, and the different position of the benzyl group does not modify the activity unless this position leads to the presence of a chiral centre (laudanosine). 7 These results suggest that (±)-laudanosine has a selective activity as an ax-adrenoceptor blocker. Its lack of action on different PDE forms provides us with information about a group of benzylisoquinolines that with small structural changes show a different effect on PDE-forms isolated from vascular smooth muscle.