>Also, what do you think might be the significance of increased superoxide production in the venules of SHR and hypertensive Dahl-S? Could this have an effect on permeability (via reducing basal NO activity)?
Thank you for the compliment, we have enjoyed these studies. We have not measured the level of superoxide production in the rat skeletal muscle arterioles, therefore I cannot answer your question directly (regarding arcade vs transverse arterioles). In the Dahl mesentery we did find a positive correlation between superoxide production and arteriolar tone (determined by way of papaverine dilations), and it had a correlation coefficient of r=0.86 (Hypertension'97, 30:1682). There exists a similar correlation in SHR.
I am glad you ask about the significance of the elevated superoxide production in venules we encountered in SHR and Dahl hypertensive rats. This question goes to the very heart of the thinking about hypertension. There is today a very deeply rooted belief that blood pressure needs to be treated (i.e. reduced) in hypertensives. But it has been very difficult to obtain convincing evidence that the blood pressure causes the disease "Hypertension" with atherosclerosis, stroke and many other complications. The documentation of oxygen free radicals, as prposed in our report, is a much more important issue in this respect, since it provides a reasonable hypothesis regarding two directly related questions: why is the blood pressure elevated (by superoxide production, NO anihilation und underproduction) and why is there lesion formation (by oxidative injury)? Our results show that the mechanism for oxygen free radical production in the Dahl and SHR form of hypertension and in human essential hypertensives involves oxidases (XO, NADPH, and possibly others). They are induced by an adrenal stimulus, which is why they can be detected in all blood vessels, not just the arterioles. There are older studies which have documented that venules in hypertension have altered compliance, at least qualitatively in line with the observation of enhanced oxygen free radical production. The enhanced free radical production is to me a much more reasonable hypothesis for the pathogenesis of hypertension than the pressure hypothesis. It is also much more stimulating hypothesis, since it will suggest many new treatment modalities as we better understand the mechanisms for free radical production in the hypertensives. You don't need to treat in hypertensive the arteriolar tone only, you need to reduce oxygen free radical production in ALL segments of the circulation. A longwinded answer to your short question.
Regarding permeability: Please keep in mind that many of the classical inflammatory pathways (e.g. leukocyte attachment to the postcapillary endothelium) are blocked by glucocorticoids in the SHR (described in several earlier reports) and also in the Dahl (unpublished results). There is an abnormality of macromolecular transport (e.g. albumin) but no major edema formation, as you know. I don't think that the combination of oxygen free radical production in the presence of glucocorticoids have been examined in great detail.