A model of orthostatic hypotension in the conscious monkey using lower body negative pressure.
BACKGROUND
Methods most commonly used for detecting susceptibility to orthostatic hypotension in humans include head-up tilt and the application of lower body negative pressure (LBNP). The objective of this study was to evaluate the use of LBNP for detecting drug-induced changes in susceptibility to orthostatic hypotension in conscious monkeys (Macaca fascicularis).


METHODS
Orthostatic responses were produced using an airtight chamber, which sealed around the stomach (umbilical area) and enclosed the lower body, to which were applied successive decrements of 10 mmHg chamber pressure every 5 min until the orthostatic response was observed. Cardiovascular measurements, involving arterial pressures, heart rate, and left ventricular pressures were recorded. The hypotensive agents prazosin and minoxidil were administered to evaluate the ability of the procedure to detect drug-induced changes in the susceptibility to orthostatic hypotension.


RESULTS
A rapid decrease in systolic arterial pressure of >20 mmHg occurring within a 30 s time period was determined to be the best indicator of an orthostatic response. The application of LBNP produced an orthostatic response in all monkeys and on all occasions (100% response). The onset, rate and magnitude of the decrease in systolic blood pressure were also consistent for each monkey. Prazosin (>or=0.16 mg/kg, iv) produced an increase in the susceptibility to the orthostatic response, whereas minoxidil (10 mg/kg, po) had no effect. These results are consistent with previous findings in humans, where similar decreases in arterial pressures occur following the administration of prazosin and minoxidil, whereas increased susceptibility to orthostatic hypotension only occurs with prazosin.


CONCLUSIONS
The results of this study demonstrate that the application of the LBNP is a reliable method for producing an orthostatic hypotensive response in conscious monkeys. In addition, the use of positive (prazosin) and negative (minoxidil) controls demonstrated that the use of LBNP is a valid method for evaluating the effect of drug treatment on susceptibility to orthostatic hypotension.
Murphy
Dennis J
DJ
Department of Safety Pharmacology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA. dennis.j.murphy@gsk.com
Renninger
Jonathan P
JP
Ju
Haisong
H
D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007024:Hypotension, Orthostatic / Q000139:chemically induced* / Q000503:physiopathology*; D008150:Lower Body Negative Pressure; D008252:Macaca fascicularis; D008297:Male; D008914:Minoxidil / Q000633:toxicity; D011224:Prazosin / Q000633:toxicity; D015203:Reproducibility of Results
D000959:Antihypertensive Agents; D008914:Minoxidil; D011224:Prazosin