Regional cerebral blood flow and arterial blood volume and their reactivity to hypercapnia in hypertensive and normotensive rats

Abstract

Chronic hypertension induces cerebrovascular remodeling, changing the inner diameter and elasticity of arterial vessels. To examine cerebrovascular morphologic changes and vasodilatory impairment in early-stage hypertension, we measured baseline (normocapnic) cerebral arterial blood volume (CBV(a)) and cerebral blood flow (CBF) as well as hypercapnia-induced dynamic vascular responses in animal models. All experiments were performed with young (3 to 4 month old) spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) under ∼1% isoflurane anesthesia at 9.4 Tesla. Baseline regional CBF values were similar in both animal groups, whereas SHR had significantly lower CBV(a) values, especially in the hippocampus area. As CBF is maintained by adjusting arterial diameters within the autoregulatory blood pressure range, CBV(a) is likely more sensitive than CBF for detecting hypertensive-mediated alterations. Unexpectedly, hypercapnia-induced CBF and blood-oxygenation-level-dependent (BOLD) response were significantly higher in SHR as compared with WKY, and the CBF reactivity was highly correlated with the BOLD reactivity in both groups. The higher reactivity in early-stage hypertensive animals indicates no significant vascular remodeling occurred. At later stages of hypertension, the reduced vascular reactivity is expected. Thus, CBF and CBV(a) mapping may provide novel insights into regional cerebrovascular impairment in hypertension and its progression as hypertension advances.

Figure 1

Anatomic T₂-weighted images (A) and quantified cerebral blood flow (CBF) (B) and cerebral arterial blood volume (CBV_a) (C) maps from Wistar–Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Data from one representative animal for each group are shown. The volume of hyperintense ventricles increased in SHR. Overall, both animal models had similar CBF values, whereas SHR demonstrated smaller CBV_a values than WKY. Five regions of interest were chosen in both hemispheres, but overlaid on one hemisphere in the anatomic images; sensory cortex—orange; motor cortex—blue; caudate putaman—red; thalamus—purple; hippocampus—green.

Figure 2

Baseline cerebral blood flow (CBF) (A) and cerebral arterial blood volume (CBV_a) (B) of five regions of interest (ROIs) under the normocapnic condition. All 12 animal data for each group were averaged. Spontaneously hypertensive rats (SHR) had slightly lower CBF values as compared with Wistar–Kyoto rats (WKY), whereas CBV_a values were signtificantly lower in most areas, particularly in the hippocampus (*P<0.05, **P<0.01). Error bars: s.e.m. (n=12); CPU, caudate putamen; Th, thalamus; Hip, hippocampus.

Figure 3

End-tidal CO₂ (EtCO₂) responses to CO₂ stimulation. All animal data were averaged. Inhalation of ∼4% CO₂ in a gas mixture of air with 30% oxygen began at time 0 and continued for 30 seconds; however, there was a delay owing to a long gas delivery system to the animal inside the magnet. In all animals, dynamic end-tidal CO₂ responses were quite similar. Error bars: s.e.m. SHR, spontaneously hypertensive rats; WKY, Wistar–Kyoto rats.

Figure 4

Group-averaged blood-oxygenation-level-dependent (BOLD) (left), relative cerebral blood flow (rCBF) (middle) and cerebral arterial blood volume (ΔCBV_a) (right) responses of the sensory (upper) and the hippocampus area (lower) to CO₂ stimulation. The dynamics of BOLD and ΔCBF were similar, but their peak response was much higher for spontaneously hypertensive rats (SHR). The ΔCBV_a responses in SHR appeared to have a slightly shorter time-to-peak and faster return with similar amplitude of signal changes. Error bars: s.e.m.. WKY, Wistar–Kyoto rats.

Figure 5

Blood-oxygenation-level-dependent (BOLD) (A), relative cerebral blood flow (rCBF) change (B), relative cerebral arterial blood volume (rCBV_a) change (C), ΔCBF (D) and ΔCBV_a (E) during CO₂ stimulation. Hypercapnia-induced BOLD and rCBF responses in spontaneously hypertensive rats (SHR) were significantly higher than those in Wistar–Kyoto (WKY) rats in all regions examined (*P<0.05). ΔCBV_a responses between both groups were similar, whereas relative CBV_a responses appeared higher for hypertensive animals. Error bars: s.e.m.; CPU, caudate putamen; Th, thalamus; Hip, hippocampus.

Figure 6

Relationship between the hypercapnia-induced blood-oxygenation-level-dependent (BOLD) response and relative cerebral blood flow (rCBF) changes. This graph includes data from all five regions of interest (ROIs) (different symbols) in all of the animals. Blood-oxygenation-level-dependent responses were linearly correlated with rCBF changes in both spontaneously hypertensive rats (SHR) (red symbols) and Wistar–Kyoto rats (WKY) (blue symbols). This indicates that BOLD is a good index of CBF reactivity, as no oxygen consumption is expected.