Rsr-13, an allosteric effector of hemoglobin, increases systemic
and iliac vascular resistance in rats.
Kunert, M. P., J. F. Liard, and D. J. Abraham.
Department of Physiology, Medical College of Wisconsin, Department
of Medicinal Chemistry, Virginia Commonwealth University
APStracts 3:0073H, 1996.
Tissue oxygen delivery in excess of metabolic demand may be a factor
in the development of high vascular resistance in experimental models
of volume-expanded hypertension. This hypothesis was previously
tested in rats with an exchange transfusion of red blood cells
treated with inositol hexaphosphate or an intravenous infusion of
RSR-4, both allosteric effectors of hemoglobin. The binding of these
drugs with hemoglobin effect a conformational change in the molecule
such that the affinity for oxygen is reduced. However, in both
preparations, the changes in vascular resistance could have been
nonspecific. The present studies used intravenous infusions of RSR-13
which did not share some of the same problematic characteristics of
the previous two. Conscious, instrumented rats (electromagnetic flow
probe on ascending aorta, or an iliac, mesenteric, or renal Doppler
flow probe) were studied for 6 hours after an infusion of RSR-13 (200
mg kg-1 in 15 minutes). This dose significantly increased arterial
P50 (the PO2 at which hemoglobin is 50% saturated) from 38+/-0.8 mmHg
to 58+/-1.4 mmHg at 1 hour after the start of the infusion. In the
third hour cardiac output fell significantly from a control value of
358+/-33 to 243+/-24 ml kg-1 min-1 and total peripheral resistance
significantly increased from 0.31+/-0.03 to 0.43+/-0.04 mmHg ml-1 kg
min. Both cardiac output and P50 returned toward control over the
next few hours. Neither cardiac output nor total peripheral
resistance changed in the group of rats receiving vehicle alone. In a
separate group of rats iliac flow decreased significantly to 60% of
control and iliac resistance increased to 160% of control. Iliac flow
increased significantly in the group of rats which received vehicle
only. Although the mechanism of these changes has not been
established, these results suggest that a decreased oxygen affinity
leads to an increased total peripheral resistance and regional
vascular resistance and support the hypothesis that oxygen plays a
role in the metabolic autoregulation of blood flow.
Received 14 March 1995; accepted in final form 24 January 1996.
APS Manuscript Number H247-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 14 February 96