Heterogeneity of L- and T-channels in the vasculature: rationale for the efficacy of combined L- and T-blockade.
Clinical studies suggest that T-type Ca(2+) channel blockade may have incremental benefits over conventional L-channel blockade, particularly in microvascular disorders. This study examined functional vasomotor differences in L- and T-channel blockade between large and small vessels and compared the abundance of the L- and T-type channels in these vessels. The inhibition of endothelin-1 and potassium-induced vascular contractile responses by L-channel blockers (verapamil and nifedipine) was compared with combined L- and T-channel blockers (mibefradil and efonidipine) in large (rat aorta) and small (rat mesenteric and human subcutaneous) vessels using wire myography. All 4 of the Ca(2+) channel blockers inhibited contractile responses to a similar extent in large rat vessels; however, in rat microvessels, the combined L- and T-channel blockers produced significantly greater inhibition of contraction than L-channel blockers alone. The significance of this differential T-channel effect in microvessels was further supported by the following: (1) a greater abundance of T-channels compared with L-channels in microvessels but not in large vessels; (2) demonstration of divergent Ca(2+) channel blocker responses in human microvessels; (3) incremental inhibition of constrictor responses with combined L- and T-Ca(2+) channel blockers despite maximal L-channel blockade; (4) the use of structurally diverse Ca(2+) channel blockers with varied affinity for L- and T-channels; (5) the use of pharmacodynamically and therapeutically appropriate Ca(2+) channel blocker concentrations; (6) confirmation of contractile agonist independent responses; and (7) exclusion of an endothelium-dependent mechanism. We propose that T-type channels play an important role in regulating contractile responses in the microvasculature and, therefore, are a potential therapeutic target.
Ball
Christine J
CJ
Cardiology Research Laboratory, Queen Elizabeth Hospital, University of Adelaide, 28 Woodville Rd, Woodville South, SA 5011, Australia.
Wilson
David P
DP
Turner
Stuart P
SP
Saint
David A
DA
Beltrame
John F
JF
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D020748:Mibefradil / Q000494:pharmacology; D055806:Microvessels / Q000187:drug effects* / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050151:Subcutaneous Fat / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D020748:Mibefradil; C066425:efonidipine; D011189:Potassium Chloride; D014700:Verapamil; D009543:Nifedipine