MICROGRAVITY-INDUCED ORTHOSTATIC INTOLERANCE:
AN ARTERIAL MICROVASCULAR MECHANISM
Michael D. Delp, Departments of Health and Kinesiology and Medical Physiology, and the
Cardiovascular Research Institute, Texas A&M University, College Station, TX 77843.
INTRODUCTION
It appears that the precision with which the cardiovascular system tightly regulates
arterial pressure and cerebral perfusion during orthostasis is due in part to it's capacity to
appropriately adapt to the prevailing mechanical environment, which on Earth is largely
determined by the head-to-foot hydrostatic pressure gradient created by 1G. Consequently, when
the head-to-foot gravitational vector is removed during spaceflight, there is a cephalad fluid shift
and a putative elimination of arterial pressure gradients. There is little evidence to suggest that
cardiovascular function is compromised in microgravity or that cardiovascular adaptations to this
new environment are inappropriate. However, adaptive responses to a weightless environment
do appear inappropriate upon return to 1G. These "maladaptations" of the cardiovascular system
are manifest primarily as orthostatic intolerance and reduced aerobic capacity.
Studies of humans following spaceflight and bedrest indicate that one of the predominant
mechanisms underlying orthostatic intolerance is hypotension resulting from an inability to
adequately elevate total peripheral resistance (TPR) (Arbeille et al. Acta Astronautica 36, 1996;
Buckey et al., JAP 81, 1996; Mulvagh et al. J Clin Pharm 31, 1991; Vernikos et al. J Clin Pharm
31, 1991). Although this inadequate elevation of TPR could originate from both neural and
vascular alterations, there is evidence in humans to suggest a peripheral vascular mechanism
(Schmid et al. Hypogravic and Hypodynamic Environments, p. 211-223 (SP-269) 1971;
Shoemaker et al. JAP 84, 1998; Whitson et al. JAP 79, 1995). Additionally, there is indirect
evidence in humans to suggest that alterations in autoregulatory control of cerebrovascular tone
may serve to attenuate brain perfusion during orthostasis (Zhang et al. JAP 83, 1997). In order to
further study these phenomenon, the hindlimb unloaded (HU) rat has been used as a model to
study weightlessness because, like that in humans, HU elicits a headward fluid shift and
cardiovascular deconditioning characterized by orthostatic hypotension and a diminished
capacity to elevate TPR. The purpose of these studies was to determine whether HU alters the
structure and contractile function of resistance arteries from skeletal muscle, visceral tissue, and
the cerebrum.
CURRENT STATUS OF RESEARCH
Methods: HU rats were placed in a head-down position by elevating the hindlimbs to an
approximate spinal angle of 40-45° from horizontal; this was maintained for 2 wk. At the end of
the experimental period, resistance arteries were isolated from the gastrocnemius and soleus
muscles, mesentery, spleen and brain (basilar artery). The vessels were cannulated with
micropipettes and pressurized. To assess vasomotor responsiveness of skeletal muscle arterioles,
concentration-response relationships to several vasoconstrictors (norepinephrine and KCl) and
vasodilators (isoproterenol, adenosine, acetylcholine and sodium nitroprusside) were determined.
To examine vascular structure, isolated resistance arteries were pressurized, bathed in Ca2+-free
buffer solution, fixed, embedded in paraffin, and sectioned. Media layer cross-sectional area,
outer and inner media perimeter, and media wall thickness were determined from the vessel
cross-sections.
2
Results: HU resulted in an increased basilar artery media (smooth muscle) wall thickness and a
decreased luminal cross-sectional area (Figure 1); the increase in medial cross-sectional area and
wall thickness resulted from smooth muscle hypertrophy (Wilkerson et al. JAP 87, 1999). There
was no effect of HU on the structure of mesenteric or splenic resistance arteries. Conversely,
HU resulted in a thinning of the medial layer in gastrocnemius feed arteries and arterioles
(Figure 2; Delp et al. AJP-HCP 278, 2000). The functional consequence of this smooth muscle
atrophy was a diminished myogenic and agonist-induced vasoconstrictor responsiveness (Delp
JAP 86, 1999).
Figure 1. Basilar artery from
control (A) and HU (B) rat.
Figure 2. Feed artery (A, B) and first-order arteriole
(C, D) from control (A, C) and HU (B, D) rat.
Conclusion: In several vascular beds of the HU rat, such as that in the hindlimb musculature and
brain, the fluid shift alters the mechanical forces acting upon resistance arteries and induces a
remodeling of arterial structure (Delp et al. AJP-HCP; Wilkerson et al. JAP). These structural
alterations, in turn, profoundly affect arterial function, so that vasoconstrictor responsiveness is
diminished in the hindlimb circulation (Delp JAP; McDonald et al. JAP 72, 1992) and enhanced
in the cerebral circulation (Geary et al. JAP 85, 1998). Others have also reported vasoconstrictor
responsiveness is diminished in the splanchnic circulation (Looft-Wilson & Gisolfi JAP 88,
2000; Overton & Tipton JAP 68, 1990), but this alteration is not the result of an arterial
structural remodeling, presumably because these vascular beds are located at or near the
hydrostatic indifference point of the rat. There is evidence to suggest that the diminished
constrictor responsiveness of visceral arteries result from an up-regulation of inducible nitric
oxide synthase activity (Vaziri et al. JAP 89, 2000). If vascular alterations similar to those in the
HU rat occur in humans during spaceflight, this could explain the compromised ability to elevate
TPR during the assumption of an upright posture upon return to Earth.
FUTURE PLANS: Determine further the functional consequences of smooth muscle
hypertrophy in cerebral resistance arteries and the mechanisms of diminished splanchnic
vasoconstriction.
INDEX TERMS: cardiovascular; hindlimb unloading; unweighting; simulated microgravity