Response to Is Combined L- and T-Channel Blockade Better than L-Channel Blockade in Therapy?
We acknowledge and endorse the comments made by Godfraind1 that the response to Ca2+ channel blockers is multifactorial. However, our data indicate that regional differences in Ca2+ L- and T-channel abundance may be important additional mechanisms that account for differential responses to Ca2+ channel blockers. Data from our previous and ongoing studies suggest that the greater inhibition of constrictor responses in microvessels by combined L- and T-channel blockers compared with the L-channel blocker is independent of many of these alternate mechanisms.
Our studies focused on the inhibition of constrictor responses by Ca2+ channel blockers and, therefore, their ability to inhibit Ca2+ channel activation and/or to maintain an inactivated state. Both endothelin and depolarizing potassium solution responses were more effectively inhibited in microvessels by the combined L- and T-channel blockers than by the L-channel blockers. We have also observed these differences with phenylephrine constrictor responses, suggesting that the inhibition of Ca2+ channel activation (and/or maintenance of Ca2+ channel inactivation) by the combined L- and T-channel blocker is more effective in the microvessels. Our ongoing studies are evaluating the relative contribution of the L and T channels in this phenomenon.
Regarding other non-Ca2+ channel blocking effects of the Ca2+ channel blockers, we excluded endothelial influences, eg, NO production, by observing the phenomenon in endothelial denuded microvessels. Our ongoing studies are evaluating whether vascular disease states also influence the distribution of T versus L channels. These studies provide impetus for the further development of combined L- and T-channel blockers, because these agents may provide incremental benefits in the treatment of cardiovascular disorders.