PubMed1997
1. Evidence that nitric oxide (NO) bioactivity is altered in chronic hypertension is conflicting, possibly as a result of heterogeneity in both the nature of the dysfunction and in the disease process itself. The brain is particularly vulnerable to the vascular complications of chronic hypertension, and the aim of this study was to assess whether differences in the cerebrovascular responsiveness to the NO synthase (NOS) inhibitors, NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), and to the NO donor 3-morpholinosydnonimine (SIN-1) might indicate one possible source of these complications. 2. Conscious spontaneously hypertensive (SHR) and WKY rats, were treated with L-NAME (30 mg kg-1, i.v.), 7-NI (25 mg kg-1, i.p.), (0.54 or 1.8 mg kg-1 h-1, continuous i.v. infusion) or saline (i.v.), 20 min before the measurement of local cerebral blood flow (LCBF) by the fully quantitative [14C]-iodoantipyrine autoradiographic technique. 3. With the exception of mean arterial blood pressure (MABP), there were no significant differences in physiological parameters between SHR and WKY rats within any of the treatment groups, or between treatment groups. L-NAME treatment increased MABP by 27% in WKY and 18% in SHR groups, whilst 7-NI had no significant effect in either group. Following the lower dose of SIN-1 infusion, MABP was decreased to a similar extent in both groups (around -20%). There was no significant difference in MABP between groups following the higher dose of SIN-1, but this represented a decrease of -41% in SHR and -21% in WKY rats. 4. With the exception of one brain region (nucleus accumbens), there were no significant differences in basal LCBF between WKY and SHR. L-NAME produced similar decreases in LCBF in both groups, ranging between -10 and -40%. The effect of 7-NI upon LCBF was more pronounced in the SHR (ranging from -34 to -57%) compared with the WKY (ranging from -14 to -43%), and in seven out of the thirteen brain areas examined there were significant differences in LCBF. 5. Following the lower dose of SIN-1, in the WKY 8 out of the 13 brain areas examined showed significant increases in blood flow compared to the saline treated animals. In contrast, only 2 brain areas showed significant increases in flow in the SHR. In the rest of the brain areas examined the effects of SIN-1 upon LCBF were less marked than in the WKY. 6. Infusion of the higher dose of SIN-1 resulted in further significant increases in LCBF in the WKY group (ranging between +30% and +74% compared to saline-treated animals), but no significant effects upon LCBF were found in the SHR. As a result, there were significant differences in LCBF between SIN-1-treated WKY and SHR in six brain areas. In most brain areas examined, cerebral blood flow in SHR following the higher dose of SIN-1 was less than that measured with the lower dose of SIN-1. 7. Despite comparable reductions in MABP (approximately 20%) in both groups, calculated cerebrovascular resistance (CVR) confirmed that the vasodilator effects of the lower dose of SIN-1 were significantly more pronounced throughout the brain in the WKY (ranging between -3% and -50%; median = -38%) when compared to the SHR (ranging between -10% and -36%; median = -26%). In the animals treated with the higher dose of SIN-1, CVR changes were broadly similar in both groups (median = -45% in WKY and -42% in SHR), but with the reduction in MABP in SHR being twice that found in WKY, this is in keeping with an attenuated blood flow response to SIN-1 in the SHR. 8. The results of this study indicate that NO-dependent vasodilator capacity is reduced in the cerebrovasculature of SHR. In addition, the equal responsiveness to a non-specific NOS inhibitor but an enhanced effectiveness of a specific neuronal NO inhibitor upon LCBF in the SHR could be consistent with an upregulation of the neuronal NO system.