Research ArticlesA Signal Transduction Pharmacodynamic Model of the Kinetics of the Parasympathomimetic Activity of Low-Dose Scopolamine and Atropine in Rats
Section snippets
INTRODUCTION
Sequences of cardiac interbeat intervals show spontaneous quasi-periodic fluctuations. This heart rate variability (HRV) is caused by the interaction of multiple regulatory influences on the sinus node, with most effects due to neural drive. HRV is decreased in various pathological states such as myocardial infarction1 and congestive heart failure.2 Prognosis of patients with low HRV following myocardial infarction is poor.3,4 This finding led to a clinical approach of elevating HRV by
Animals
Male Sabra rats weighing 300–350 g were housed separately in plastic cages and were maintained in a 12-h light/dark cycle with food and water available ad libitum. The project adhered to the principles of Laboratory Animal Care (NIH publication no. 85-23, revised 1985).
Transmitter Implantation
To minimize stress involved with data collection, a telemetric monitoring system was implanted in the peritoneal cavity while the animals were anesthetized [by intraperitoneal (ip) injection of 50 mg/kg ketamine and 10 mg/kg
Pharmacokinetics
The concentration versus time data of scopolamine followed the two-compartment open PK model with a rapid distribution phase (t1/2 alpha = 2 min) succeeded by a relatively short elimination phase (t1/2 beta = 18 min). The concentration versus time profile of atropine also followed the two-compartment model, but with much longer elimination phase (t1/2 beta = 52 min). The major PK parameters of both drugs are summarized in Table 1.
Pharmacodynamics
The temporal cumulative approach enabled the quantification of the HF
DISCUSSION
HRV is caused by the interaction of multiple regulatory influences on the sinus node, with most effects due to neural drive, and the HRV tachogram reflects the sum of all the different interactions. PSA is a well-established technique for frequency domain analysis of HRV that enables the division of the entire variability into separate frequencies and the identification of the effect of the interacting components.4,24 Thus, PSA provides the means to noninvasively determine neural drive by
ACKNOWLEDGEMENTS
The authors thank Dr. Joshua Backon for his valuable suggestions. Prof. A. Hoffman is affiliated with the David R. Bloom Center of Pharmacy. This work is part of the Ph.D. dissertation of I. Perlstein.
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