CEREBROVASCULAR EFFECTS OF NITRIC-OXIDE MANIPULATION IN SPONTANEOUSLYHYPERTENSIVE RATS

1 Evidence that nitric oxide (NO) bioactivity is altered in chronic hy pertension is conflicting, possibly as a result of heterogeneity in bo th the nature of the dysfunction and in the disease process itself. Th e brain is particularly Vulnerable to the vascular complications of ch ronic hypertension, and the aim of this study was to assess whether di fferences in the cerebrovascular responsiveness to the NO synthase (NO S) inhibitors, N-G-nitro-L-arginine methyl ester (L-NAME) and 7-nitroi ndazole (7-NI), and to the NO donor 3-morpholinosydnonimine (SIN-1) mi ght indicate one possible source of these complications. 2 Conscious s pontaneously hypertensive (SHR) and WKY rats, were treated with L-NAME (30 mg kg(-1), i.v.), 7-NI (25 mg kg(-1), i.p.), SIN-1 (0.54 or 1.8 m g kg(-1) h(-1), continuous i.v. infusion) or saline (i.v.), 20 min bef ore the measurement of local cerebral blood how (LCBF) by the fully qu antitative [C-14]-iodoantipyrine autoradiographic technique. 3 With th e exception of mean arterial blood pressure (MABP), there were no sign ificant differences in physiological parameters between SHR and WKY ra ts within any of the treatment groups, or between treatment groups. L- NAME treatment increased MABP by 27% in WKY and 18% in SHR groups, whi lst 7-NI had no significant effect in either group. Following the lowe r dose of SIN-1 infusion, MABP was decreased to a similar extent in bo th groups (around -20%). There was no significant difference in MABP b etween 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 dif ferences in basal LCBF between WKY and SHR. L-NAME produced similar de creases in LCBF in both groups, ranging between -10 and -40%. The effe ct 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 seve n out of the thirteen brain areas examined there were significant diff erences 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 mar ked than in the WKY. 6 Infusion of the higher dose of SIN-1 resulted i n further significant increases in LCBF in the WKY group (ranging betw een +30% and +74% compared to saline-treated animals), but no signific ant effects upon LCBF were found in the SHR. As a result, there were s ignificant differences in LCBF between SIN-1-treated WKY and SHR in si x brain areas. In most brain areas examined, cerebral blood how in SHR following the higher dose of SIN-1 was less than that measured with t he lower dose of SIN-1. 7 Despite comparable reductions in MABP (-20%) in both groups, calculated cerebrovascular resistance (CVR) confirmed that the vasodilator effects of the lower dose of SIN-1 were signific antly more pronounced throughout the brain in the WKY (ranging between -3% and -50%; median = -38%) when compared to the SHR (ranging betwee n -10% and -36%; median = -26%). In the animals treated with the highe r dose of SIN-1, CVR changes were broadly similar in both groups (medi an = -45% in WKY and -42% in SHR), but with the reduction in MABP in S HR being twice that found in WKY, this is in keeping with an attenuate d 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 cer ebrovasculature of SHR. In addition, the equal responsiveness to a non -specific NOS inhibitor but an enhanced effectiveness of a specific ne uronal NO inhibitor upon LCBF in the SHR could be consistent with an u pregulation of the neuronal NO system.