Spontaneously Hypertensive Rats

We studied the local renin-angiotensin system in the microcirculation of cremaster muscle in spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. We used intravital microscopy in an original preparation of cremaster isolated from its normal blood supply and externally perfused with physiological solution, thus allowing the exclusion of circulating converting enzyme, circulating renin, and circulating angiotensinogen. We classified arterioles studied as second-, third-, and fourth-order, with mean diameters, respectively, of 67±6, 35±2, and 17±1 jwn in WKY controls and 61±5, 34±2, and 16±1 /im in SHR. No difference between WKY controls and SHR was found for arteriolar vasoconstrictions in response to topical administration of 0.01 to 1 nmol/mL angiotensin II. Conversely, in response to 0.01 to 1 nmol/mL angiotensin I, significantly more arteriolar vasoconstriction was found in SHR cremaster muscle. In both strains, responses to angiotensin I were significantly inhibited by 10 nmol/mL of the angiotensin-converting enzyme inhibitor lisinopril. When angiotensinogen-rich, renin-free plasma containing 2.3 nmol/mL angiotensinogen was administered, almost no vasoconstriction was found in WKY controls, but significant constrictions were observed in SHR (23±4%, 30±5%, and 41 ±4% for second-, third-, and fourth-order It is now well recognized that the renin-angiotensin system (RAS) is not only an endocrine system but that some of its components are generated or activated in several tissues. By studying isolated large arteries and endothelial cell cultures as well as by whole-organ perfusion, several authors have shown the presence of different components of the local RAS in the vasculature. The possibility that angiotensin II (Ang II) may be locally formed within the vasculature led some authors to test the hypothesis that local RAS and especially local angiotensin-converting enzyme (ACE) activity can be different in hypertensive states. Indeed, an increase in vascular ACE concentration or activity was found in both experimental and genetic hypertensive rat models" as well as an increase in aortic ACE mRNA levels in two-kidney, one clip hypertensive rats. All these studies involved RAS or ACE activity in large arteries. However, it is well known that the microcirculation is an important site for pressure reguReceived September 27, 1993; accepted in revised form March 30, 1994. From the Laboratoire de Biophysique (E.V., X.H.) and INSERM U141 (E.V.), Hopital F. Widal, Paris, France. Correspondence to Dr Vicaut, Laboratoire de Biophysique, Hopital F. Widal, 200 rue du Fg. St-Denis, 75010 Paris, France. © 1994 American Heart Association, Inc. arterioles, respectively). In SHR, vasoconstriction in response to angiotensinogen-rich, renin-free plasma was dose dependent, was inhibited by lisinopril, and was not found 24 hours after bilateral nephrectomy. Topical administration of 1.2 Aig/mL renin did not induce arteriolar vasoconstriction in either WKY or SHR cremaster muscle. We conclude that in the skeletal muscle microcirculation, (1) local angiotensinconverting enzyme activity in arterioles is higher in SHR than in their normotensive controls and is consequently an important target site for angiotensin-converting enzyme inhibitors; (2) the enzymatic cascade constituted by local renin and local angiotensin-converting enzyme is able to produce significant vasoconstriction in the presence of angiotensinogen in SHR but not in their normotensive controls; (3) the bulk of vascular renin responsible for this vasoconstriction in response to angiotensinogen in SHR is likely derived from the uptake of circulating renin of renal origin; and (4) no evidence exists in either WKY rats or SHR for the presence of local angiotensinogen, which can induce arteriolar constriction in the presence of renin. (Hypertension. 1994;24:70-76.)