Differential effects of calcium antagonists and Bay K 8644 on contractile responses to exogenous noradrenaline and adrenergic nerve stimulation in the rabbit ear artery

Abstract

1. The effects of three calcium antagonists (nifedipine, verapamil, diltiazem) and the calcium agonist Bay K 8644 were compared on contractile responses of similar amplitude elicited by noradrenaline (NA) and electrical nerve stimulation (ENS) in the rabbit isolated ear artery. 2. Contractions induced by both NA (3 x 10(-7) M) and ENS (10 Hz, 10s) were almost exclusively mediated by alpha 1-adrenoceptors, since 10(-7) M prazosin abolished (NA) or almost abolished (ENS) the responses, and prazosin was more than three orders of magnitude more potent than rauwolscine on both types of response. 3. ENS-induced contractions were considerably less inhibited by nifedipine, verapamil and diltiazem than were those elicited by NA. Bay K 8644 enhanced responses to NA more than those to ENS. 4. The inhibitory effect of nifedipine and Ca2+ deprivation on NA-induced contractions decreased with increasing NA concentration. Reduction of the NA response by prazosin or phenoxybenzamine increased the nifedipine inhibition. 5. Reduction of the ENS-induced contractions by prazosin or phenoxybenzamine, or by use of a lower stimulation frequency did not increase the inhibitory effect of nifedipine. 6. In conclusion, the differential effects of the calcium antagonists on NA- and ENS-induced contractions were not related to differences in alpha-adrenoceptor subtype (alpha 1/alpha 2), receptor reserve or response amplitude, but may rather reflect temporal and spatial differences in alpha-adrenoceptor activation between the responses.

Vasoconstrictor stimulus determines the functional contribution of myoendothelial feedback to mesenteric arterial tone

“…). However, in our experiments, as in rabbit ear artery (Skärby & Högestätt, ), there was no apparent role for ATP in nerve‐evoked increases in tone and so the decreased reliance of VOCCs with increasing frequency of stimulation may be explained by reports that responses to high concentrations of noradrenaline are less dependent on VOCCs, as reported in rabbit aorta and pulmonary artery (Casteels et al . ; van Breemen et al .…”

“…). Also, voltage‐independent contractions to sympathetic nerve stimulation at frequencies above 5 Hz were previously described rabbit isolated ileocolic, saphenous and ear arteries (Skärby & Högestätt, ; Bulloch et al . ).…”

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Moreover, NRF2 allows the cancer cells to escape death by cooperating with other pathways playing a role in apoptosis regulation. For instance, the tumor suppressor p53 inhibits NRF2 signaling by down regulating the expression of NRF2 target genes such as x-CT, NQO1, and GST1 and triggers cell cycle arrest and apoptosis [196][197][198]. Under mild cellular stress conditions, the p21 protein, a major p53 target, binds to the DLG motif and prevents KEAP1-mediated NRF2 proteasomal degradation, activating the antioxidant response [199].…”