MYOCARDIAL BETA-ADRENOCEPTOR AND VOLTAGE SENSITIVE CALCIUM-CHANNEL CHANGES IN A CANINE MODEL OF CHRONIC HEART-FAILURE

Effects of chronic heart failure upon receptor binding and cardiac function were studied in mongrel dogs. Heart failure was induced by three to seven, graded, sequential, intracoronary microembolizations performed 1 to 3 weeks apart. Depressed systolic and diastolic left ventricular function, reduced cardiac output, increased systemic vascular resistance, increased plasma norepinephrine concentration, left ventricular hypertrophy, and dilation were associated with the development of heart failure in this model. Three months after the last embolization, the density and affinity of myocardial beta adrenoceptors and voltage sensitive calcium channels were quantified by analyzing saturation isotherms of specific radioligand binding. [3H]Dihydroalprenolol and [3H]nitrendipine bound specifically and with high affinity to cardiac beta adrenoceptors and calcium channels, respectively. Scatchard transformation of the specific binding of these radioligands in membranes prepared following intracoronary embolization demonstrated a 47% decrease in the density of [3H]dihydroalprenolol binding sites (605 ± 20 fmol/mg, normal, vs. 323 ± 18 fmol/mg, failed; P<0.05) and a 20% decrease in [3H]nitredipine binding sites (371 ± 11 fmol/mg, normal, vs. 298 ± 17 fmol/mg, failed; P<0.05). The binding equilibrium dissociation constants for [3H]dihydroalprenolol and [3H]nitrendipine were not significantly different between normal and failed myocardium. There was no difference in the sialic acid content in the sarcolemmal membranes prepared from normal and failed dog hearts (31.07 ± 0.76 nmol/mg, normal, vs. 30.58 ± 5.25 nmol/mg, failed). This is inconsistent with the selective purification of membranes utilized in these radioligand binding studies. These data indicate that with left ventricular failure resulting from graded, sequential, intracoronary microembolization in dogs, there is an associated down-regulation of cardiac beta adrenoceptors and voltage sensitive calcium channels. Changes in beta adrenoceptors in this canine model of left ventricular failure parallel those reported in patients suffering from end-stage heart failure. © 1992.