The obese Zucker rat shows microvascular remodeling and rarefaction in skeletal muscle before any elevation of blood pressure has occurred, and rarefaction still occurs if the increase in blood pressure is prevented by treatment with hydralazine, a direct-acting smooth muscle relaxant [31]. Rarefaction in this situation, therefore, is not a consequence of hypertension. Thus, it seems likely that microvascular abnormalities in obesity can both result from and contribute to hypertension, and a “vicious

cycle” may exist in which the Tamoxifen molecular weight microcirculation maintains or even amplifies an initial increase in blood pressure [71]. However, according to the Borst-Guyton concept, chronic hypertension can occur only if renal function is abnormal with a shift this website in the renal pressure–natriuresis relationship [17]. In the absence of the latter, increased peripheral resistance only temporarily raises blood pressure, to be followed by an increase in renal sodium excretion restoring blood pressure towards normal. Importantly, therefore, subtle renal microvascular disease [52] as well as a reduced number of nephrons [67] may reconcile the Borst-Guyton concept with the putative role of vessel rarefaction in the etiology of high blood pressure [17,24]. This may also explain the observed salt sensitivity of blood pressure in insulin-resistant subjects [32]. In agreement with a

central role for generalized microvascular dysfunction as a link between salt sensitivity, insulin resistance, and hypertension, recent data suggest an association between ADP ribosylation factor salt sensitivity and microvascular dysfunction independent of hypertensive status. More importantly, microvascular function, at least statistically, largely explained associations of salt sensitivity with both insulin resistance and

elevated blood pressure [24]. In summary, microvascular dysfunction, by affecting peripheral vascular resistance and renal function, may initiate the pathogenic sequence and subsequently maintain or amplify the initial increase in blood pressure. It may also explain salt-sensitivity of blood pressure, associated with insulin resistance. Recent evidence indicates that insulin delivery to the skeletal muscle interstitium is the rate-limiting step in insulin-stimulated glucose uptake by skeletal muscle, and is much slower in obese, insulin-resistant subjects than in normal subjects [6]. Interestingly, insulin acts on the vasculature at different levels, which may potentially regulate its own delivery to muscle interstitium [6,14,97]: (A) relaxation of resistance arteries/arterioles to increase total blood flow; (B) relaxation of precapillary arterioles to increase the microvascular exchange surface perfused within skeletal muscle (microvascular/capillary recruitment); (C) influencing vasomotion of pre-capillary arterioles; and (D) the TET of insulin.