Effects of chemical denervation with 6-hydroxydopamine on myocardial responsiveness to isoproterenol in rabbits.

Abstract

This study examined the hypothesis that chemical denervation with 6-hydroxydopamine (6-OHDA) would increase myocardial responsiveness to isoproterenol. Five days previously, 15 New Zealand white rabbits were given 60 mg/kg 6-OHDA intravenously. Fifteen control rabbits received vehicle. Hemodynamic, coronary blood flow (CBF), and cardiac output measurements were obtained before and during isoproterenol infusion (0.5 microgram/kg/min for 15 min). Norepinephrine tissue content, beta-adrenoceptor number (Bmax) and affinity (Kd), cyclic AMP content and cyclic AMP-phosphodiesterase (PDE) activity were measured in the subepicardium (EPI) and subendocardium (ENDO). Myocardial norepinephrine content was significantly decreased from 1263 +/- 292 (EPI) and 874 +/- 221 ng/g tissue (ENDO) in the control to 148 +/- 33 (EPI) and 90 +/- 45 ng/g tissue (ENDO) in the denervated group. There were no significant changes in cyclic AMP-PDE activity or Bmax and Kd of beta-adrenoceptors. Cyclic AMP content was similar at baseline, but controls had a significantly larger increase (123-155%) during isoproterenol infusion when compared to the denervated group (27-37%). The denervated animals showed a smaller increase in cardiac output during isoproterenol infusion (from 203 +/- 30 to 235 +/- 26 ml/min), when compared to the control animals (from 135 +/- 18 to 216 +/- 42 ml/min). Baseline CBF was significantly higher in the EPI but not ENDO of the denervated group (185 +/- 20 ml/100 g/min in EPI and 150 +/- 8 in ENDO) compared to the control group (108 +/- 13 in EPI and 133 +/- 17 in ENDO). The relative increase in CBF during isoproterenol infusion was smaller in the denervated group (44-45%) than the control group (107-109%). Isoproterenol infusions of 0.1 and 2.5 micrograms/kg/min showed similarly depressed coronary blood flow responses in denervated animals. Thus, the chemically denervated animals did not have beta-adrenoceptor upregulation, exhibited a lesser increase in cyclic AMP with isoproterenol, and had a reduced functional and coronary blood flow response to isoproterenol. This occurred without any significant change in beta-adrenoceptor number or affinity, or in cyclic AMP-phosphodiesterase activity, indicating there may be receptor uncoupling or other changes in the signal transduction pathway.