Evaluation of ultra-early and dose-dependent edema and ultrastructural changes in the myocyte during anti-hypertensive drug delivery in the spontaneously hypertensive rat model

BACKGROUND: Quantifying dose-dependent ultra-early edema and ultrastructural changes in the myocyte after drug delivery is important for the development of new mixed calcium channel blockers (CCBs). MATERIALS AND METHODS: Arterial cannulation was used to measure mean arterial pressure in real time; simultaneously, magnetic resonance imaging proton density mapping was used to quantify edema 5–55 min after the delivery of L-type CCBs, T- and L-type CCBs, and solvent to a spontaneously hypertensive rat model. Transmission electron microscopy was used to show ultrastructural changes in the myocyte. RESULTS: Analysis of variance showed significant differences among the three groups in mean arterial pressure reduction (F = 246.36, P = 5.75E(-25)), ultra-early level of edema (ULE) (F = 175.49, P = 5.62E(-22)), and dose-dependent level of edema (DLE) (F = 199.48, P = 4.28E(-23)). Compared with the solvent’s mean arterial pressure reduction (2.65±6.56±1.64), ULE (1.16±0.09±0.02), and DLE (0.0010±0.0001±0.0000), post hoc tests showed that T- and L-type CCBs had better mean arterial pressure reduction (90.67±11.58±2.90, P = 1.06E(-24) vs. 68.34±15.19±3.80, P = 1.76E(-12)), lower ULE (1.53±0.14±0.04, P = 4.74E(-9) vs. 2.08±0.18±0.04, P = 2.68E(-22)), and lower DLE (0.0025±0.0004±0.0001, P = 1.14E(-11) vs. 0.0047±0.0008±0.0002, P = 2.10E(-11)) than L- type CCBs. Transmission electron microscopy showed that T- and L-type CCBs caused fewer ultrastructural changes in the myocytes after drug delivery than L-type CCBs. CONCLUSION: T- and L-type CCBs produced less ultra-early and dose-dependent edema, fewer ultrastructural changes in the myocyte, and a greater antihypertensive effect. Proton density mapping combined with arterial cannulation and transmission electron microscopy allowed for quantification of ultra-early and dose-dependent edema, antihypertensive efficacy, and ultrastructural changes in the myocyte. This is important for the evaluation of induced vasodilatory edema.