Related Experiment Videos
Selectivity of omega-conotoxin GVIA for n-type calcium channels in rat isolated small mesenteric arteries
S L Whorlow1, J A Angus, C E Wright
1Department of Pharmacology, University of Melbourne, Victoria, Australia.
Abstract:
1. The selectivity of omega-conotoxin GVIA (omega-CTX) for prejunctional N-type voltage-operated calcium channels (VOCC) was examined in rat isolated small mesenteric arteries mounted in a Mulvany-Halpern myograph. Contractile responses to perivascular nerve stimulation, noradrenaline (NA) and potassium (K+) were obtained before and after treatment with omega-CTX. The effects of omega-CTX were compared with those of felodipine, an L-type VOCC blocker. 2. Omega-CTX (3 nmol/L-10 mu mol/L) inhibited contractions to electrical field stimulation by up to 94%, compared with the corresponding time control group. Felodipine (0.1 mu mol/L) had little effect on the contractions to electrical stimulation compared with the vehicle-treated vessels. 3. Concentration-response curves to exogenous NA (0.1 mu mol/L) and contractions to a submaximal concentration of K+ (50 mmol/L) were unaffected by omega-CTX (3 nmol/L-10 mu mol/L). In contrast, the maximum contraction to NA in vessels exposed to felodipine (0.1 mu mol/L) was reduced by 37%, and the contraction to K+ (62 mmol/L) was reduced by 84% compared with vehicle-treated arteries. 4. The results indicate that even at concentrations up to 10 mu mol/L (10 000-fold higher than required to inhibit prejunctional N-type VOCC), omega-CTX inhibits only neurotransmitter release. Its effects are clearly different to felodipine as omega-CTX has no effect on post-junctional alpha1-adrenoceptor-mediated vasoconstriction or direct smooth muscle depolarization considered to be mediated by L-type VOCC. Therefore, at least at the vascular neuroeffector junction, omega-CTX appears to be highly selective for N-type VOCC with no effect on L-type VOCC.
Insights
Omega-conotoxin GVIA selectively blocks prejunctional N-type voltage-operated calcium channels (VOCC) in mesenteric arteries, inhibiting neurotransmitter release without affecting smooth muscle contraction mediated by L-type VOCC.
Area of Science:
- Pharmacology
- Neuroscience
- Cardiovascular Physiology
Background:
- Voltage-operated calcium channels (VOCC) play critical roles in neurotransmission and smooth muscle contraction.
- N-type VOCC are implicated in neurotransmitter release at the vascular neuroeffector junction.
- L-type VOCC mediate smooth muscle depolarization and vasoconstriction.
Purpose of the Study:
- To investigate the selectivity of omega-conotoxin GVIA (omega-CTX) for prejunctional N-type VOCC.
- To compare the effects of omega-CTX with felodipine, an L-type VOCC blocker, on vascular responses.
- To determine the impact of omega-CTX on neurotransmitter release versus direct smooth muscle activation.
Main Methods:
- Rat isolated small mesenteric arteries were mounted in a Mulvany-Halpern myograph.
- Contractile responses to perivascular nerve stimulation, noradrenaline, and potassium were measured.
- Vessels were treated with varying concentrations of omega-CTX or felodipine.
Main Results:
- Omega-CTX (3 nmol/L–10 μmol/L) inhibited nerve stimulation-induced contractions by up to 94%.
- Omega-CTX did not affect contractions to exogenous noradrenaline or potassium.
- Felodipine significantly reduced contractions to noradrenaline and potassium, but had minimal effect on nerve stimulation-induced contractions.
Conclusions:
- Omega-conotoxin GVIA demonstrates high selectivity for prejunctional N-type VOCC.
- Omega-CTX inhibits neurotransmitter release without affecting post-junctional L-type VOCC-mediated responses.
- These findings distinguish omega-CTX from L-type VOCC blockers like felodipine in vascular preparations.