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.