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.

Tissue harmonic imaging for standard left ventricular measurements: fundamentally flawed?

Tissue harmonic imaging (THI) is a B mode imaging technique that improves echocardiographic image quality by reducing superficial artefact. The modality increases image signal-to-noise ratio at the expense of reduced axial resolution. While the qualitative improvements of harmonic echocardiographic imaging are widely accepted, the degree to which this is translated into improved quantitative measurements and whether THI-derived measurements result in systematic bias continue to be areas of uncertainty. This review examines differences between THI and fundamental imaging-derived measurements from a theoretical, tissue phantom and clinical perspective.

The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon.

OBJECTIVES: The aim of the study was to assess the angiographic and clinical benefits of the calcium T-channel blocker, mibefradil, in the coronary slow flow phenomenon (CSFP). BACKGROUND: The CSFP is characterized by delayed vessel opacification on angiography (Thrombolysis In Myocardial Infarction [TIMI]-2 flow) in the absence of obstructive epicardial coronary disease and is often associated with recurrent chest pain. METHODS: A total of 10 CSFP patients (46 +/- 9 years) underwent angiography before and 30 min after 50 mg mibefradil; off-line blinded analysis of angiographic data included comparisons of epicardial vessel diameter, TIMI flow grade and TIMI frame count. We also performed a randomized, double-blind, placebo-controlled, cross-over study to examine the long-term efficacy of mibefradil 100 mg/day on the frequency of total angina, prolonged angina (i.e., persisting >20 min) episodes, and sublingual nitrate consumption, during consecutive one-month treatment periods in 20 patients (age 51 +/- 12 years) with the CSFP. RESULTS: Without changing epicardial vessel diameter or rate-pressure product, mibefradil reduced the number of vessels exhibiting TIMI-2 flow from 18 to 5; furthermore, mibefradil significantly improved the TIMI frame count only in those vessels exhibiting TIMI-2 flow (28 +/- 18%, p < 0.005). Compared with placebo, mibefradil significantly reduced total angina frequency by 56% (p < 0.001), prolonged episodes of angina by 74% (p < 0.001), and sublingual nitrate consumption by 59% (p < 0.01); furthermore, mibefradil improved physical quality of life as assessed by the Health Outcome Study Short Form-36. CONCLUSIONS: These angiographic and clinical improvements produced by mibefradil support a microspastic pathogenesis of the CSFP.