Background and Purpose
Animal models which have been generated to investigate the pathophysiology of hypertensive vascular injury generally require surgical or pharmacological intervention or depend upon the constitutive expression of endogenous genes. A novel inbred rat model with inducible hypertension has recently been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter 1 . The transgene is expressed primarily in the liver and is rendered inducible by xenobiotics such as indole-3 carbinol (I3C). The purpose of this study was to examine the effects of a temporally regulated period of inducible hypertension upon neocortical perfusion in this transgenic model, and to compare the effects with hypertension induced by chronic nitric oxide synthase (NOS) inhibition.
Methods
Adult rats from the established transgenic line TGR(Cyp1a1Ren2) on a Fischer F344 background, were taken at random and fed for 14 days with either standard powdered food (n=10) or food supplemented with I3C (n=10) as described previously 1 . Two groups of non-transgenic Fischer rats were injected (i.p.) with L-NAME (75 mg.kg-1; n=10) or saline (n=10) once daily for 14 consecutive days. On the day of the experiment (day 15) neocortical cerebral blood flow (LCBF) and glucose utilization (LCMRglu) were measured in equal numbers from each treatment group, using [14C]-iodoantipyrine and [14C]-2-deoxyglucose quantitative autoradiography respectively. Mean arterial blood pressure (MABP) and blood gases were measured in each animal. Data (mean ± s.e.m.) were analysed using t-test with Bonferroni correction (p<0.05) and region-specific LCBF/ LCMRglu ratios were analysed using Mann-Whitney U-test (p<0.05).
Results
With the exception of MABP, there were no significant differences in physiological parameters between any of the groups. MABP in transgenic rats fed with I3C (175 ± 3 mmHg) was significantly increased from control levels (136 ± 3 mmHg) and similar significant increases were found following chronic L-NAME (135 ± 2 to 181 ± 5 mmHg). Neither LCMRglu nor LCBF were significantly different from control in L-NAME treated rats. In contrast, whilst the were no significant changes LCMRglu in I3C-fed transgenic rats, LCBF was significantly increased in all 6 cortical areas examined. The largest increase (80%) was in frontal cortex (from 101 ± 2 to 181 ± 7 ml.100 g−1.min−1) and the smallest (18%) in cingulate cortex (from 141 ± 3 to 167 ± 6 ml.100 g−1.min−1). These increases in LCBF in the absence of any change in LCMRglu resulted in a significant increase in cortical flow metabolism ratios (P<0.004, Mann-Whitney), indicating a relative hyperaemia.
Conclusions
Although both models were found to induce similar levels of hypertension, evidence of cerebrovascular dysfunction was found only in the inducible transgenic model. This model will facilitate studies of the cellular and genetic mechanisms underlying hypertension-induced vascular injury and repair, and may provide a basis for the identification of novel therapeutic targets for vascular disease.