Related Experiment Videos
Factors affecting rabbit mesenteric artery smooth muscle sensitivity to calcium antagonists
K D Meisheri1, G P Sage, L A Cipkus-Dubray
1Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan.
Abstract:
The sensitivity of rabbit isolated superior mesenteric artery to Ca++ antagonists was examined under various conditions. Relaxation dose-response curves for D600 or nifedipine were generated, and IC50 values were calculated. In the first series of experiments, D600 or nifedipine IC50 was found to be 20-25-fold greater for norepinephrine (NE, 5 microM) contraction than for 80 nM K+ contraction. Even when the tissues were depolarized with 80 mM K+ before NE contraction, D600 or nifedipine IC50 still remained significantly greater compared with 80 mM K+ alone and remained closer to that during NE alone. Also a protocol was designed to study NE-induced phasic contraction in EGTA-physiological salt solution (a functional indicator of intracellular Ca++ release) as well as NE-induced sustained contraction after readdition of Ca++. The effects of varying [K+]ex (0-80 nM range) on NE-induced [Ca++]i release as well as on the D600 IC50 for NE contraction was studied. Increasing [K+]ex was found to enhance NE-sensitive [Ca++]i release and lower the D600 IC50 for NE contraction. Thus, conditions causing an increase in the ability of NE to cause [Ca++]i release were associated with an increase in the sensitivity of NE contraction to D600. These data provide functional evidence that the receptor-agonist sensitive Ca++ influx process in vascular smooth muscle is not solely regulated by changes in membrane potential. Additional mechanisms, such as a modulatory role of [Ca++]i release, in this process are implicated.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Calcium channel blockers like D600 and nifedipine show altered sensitivity in rabbit arteries depending on the contraction method. Norepinephrine-induced contractions are less sensitive to these drugs than potassium-induced ones, suggesting complex calcium regulation in vascular smooth muscle.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Smooth Muscle Biology
Background:
- Calcium ions (Ca++) play a critical role in vascular smooth muscle contraction.
- Calcium channel antagonists are used to treat cardiovascular conditions by affecting Ca++ influx.
- The precise mechanisms regulating Ca++ entry in response to receptor agonists are not fully understood.
Purpose of the Study:
- To investigate the sensitivity of rabbit isolated superior mesenteric artery to Ca++ antagonists (D600, nifedipine) under different contractile conditions.
- To explore the relationship between norepinephrine (NE)-induced Ca++ release and the efficacy of Ca++ antagonists.
Main Methods:
- Generation of relaxation dose-response curves for D600 and nifedipine.
- Calculation of IC50 values for contractions induced by norepinephrine (NE) and potassium (K+).
- Investigation of NE-induced contractions in solutions with varying extracellular K+ concentrations and EGTA to assess intracellular Ca++ release.
Main Results:
- D600 and nifedipine IC50 values were significantly higher for norepinephrine-induced contractions compared to K+-induced contractions.
- Even with prior depolarization, NE-induced contractions remained less sensitive to antagonists than K+-induced contractions.
- Increased extracellular K+ enhanced NE-sensitive intracellular Ca++ release and decreased the D600 IC50 for NE contraction.
Conclusions:
- Vascular smooth muscle Ca++ influx, triggered by receptor agonists like NE, is not solely dependent on membrane potential changes.
- Intracellular Ca++ release appears to modulate the sensitivity of NE-induced contractions to Ca++ channel blockers.
- These findings suggest complex regulatory mechanisms beyond simple membrane potential shifts govern receptor-operated calcium channels.