Modeling Hemodynamic Profiles by Telemetry in the Rat

Abstract

The newly developed radiotelemetry system offers a number of advantages for the measurement of blood pressure and heart rate in laboratory animals. However, no available statistical methods permit valid use of the many data gathered with this continuous recording of hemodynamic parameters. This study describes elaboration and testing of mathematical functions as applied to the measurement of the effects of drugs on blood pressure and heart rate in spontaneously hypertensive rats. We used parametric functions analogous to those for pharmacokinetic studies. Curve fitting is in fact the only approach that provides reasonable estimates of hemodynamic kinetic constants. Nonlinear functions were assessed by analyzing telemetric hemodynamic effects induced by three adenosine receptor agonists with different selectivity for the A ₁ or A _2a receptor. After acute administration in conscious rats, the A ₁ agonist 2-chloro- N ⁶ -cyclopentyladenosine induced dose-related hypotension (eg, 0.03 mg/kg; peak, −70 mm Hg; time to peak, 0.34 hour) and bradycardia (eg, 0.03 mg/kg; peak, −186 beats per minute [bpm]; time to peak, 0.38 hour). The A _2a agonist 2-hexynyl-5′- N -ethylcarboxamidoadenosine induced dose-related hypotension (eg, 0.003 mg/kg; peak, −36 mm Hg; time to peak, 0.32 hour) with reflex tachycardia (eg, 0.003 mg/kg; peak, 152 bpm; time to peak, 0.35 hour). The nonselective adenosine agonist 5′- N -ethylcarboxamidoadenosine (0.1 mg/kg) induced hypotension (peak, −75 mm Hg; time to peak, 2.2 hours) and bradycardia followed by tachycardia (first peak, −131 bpm; time to peak, 1.26 hours; second peak, 123 bpm; time to peak, 13.9 hours). With this model, other parameters, such as persistence (eg, half-life) or amount (eg, area under the curve) of the effects, can also be evaluated. Finally, the telemetry system permits precise characterization of the hemodynamic profile of different classes of cardiovascular drugs.