Author

John S. Smeda

Date of Award

3-1984

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. J.B. Forrest

Abstract

The alterations in renal vascular structure and function, and their role in the development and maintenance of hypertension were examined in Kyoto Wistar spontaneously hypertensive rats (SHR) and Wistar Kyoto normotensive controls (WKY). A study of the renal vascular bed in SHR with established hypertension and age matched normotensive WKY indicated that when the isolated kidney was perfused at a variety of flow rates, under maximally relaxed conditions, the renal vascular resistance (RVR) was similar between SHR and WKY. Consistent with the above finding, morphometric measurements of light and electron micrographs indicated that the lumen diameter of relaxed main renal, interlobar, arcuate and interlobular arteries, as well as the preglomerular arterioles was similar in SHR and WKY. The cross-sectional areas of total intima, endothelium, subendothelial space, internal elastic lamina and total adventitia, as well as the volume fraction of axons, nerve sheath cells, fibroblasts, collagen and fluid filled space within the adventitia were only modestly altered in SHR. However, with the exception of the preglomerular arterioles, the media of all the renal arterial classes of SHR exhibited an increase in smooth muscle cell (SMC) cross-sectional area and volume that was produced by SMC hypertrophy and/or hyperplasia, while the extracellular space surrounding the SHCs was increased in both arteriolar and pre-arteriolar vessels.

Based on these structural alterations, it was hypothesized that, if the mass of the arterial media is increased, contraction from the adventitial side would tend to push the media of the thicker hypertensive vessel into the lumen to a greater degree than the thinner walled WKY vessel. Under relaxed conditions, the RVR would be expected to be similar between SHR and WKY; however, during contraction RVR should be elevated to a greater degree in SHR than WKY. To test the above hypothesis, pharmacological studies were undertaken. Consistent with the model, at maximal relaxation the RVR was similar in SHR and WKY, while contraction of the renal vascular bed with infused norepinephrine (HE), BaCl₂ angiotensin II, or by stimulating the periarterial nerves produced a larger elevation of RVR in SHR. Aside from a modest increase in HE sensitivity within the renal vasculature of WKY, the contractile sensitivity to the various agents was not altered when SHR and WKY were compared. These studies indicated that the nerve mediated contractile responses within the renal vasculature were mediated by alpha₁ and dopamine receptors, and the proportion of the maximal response attributed to each receptor was similar in SHR and WKY.

Similar alterations, but of lesser magnitude, as those present in SHR with established hypertension were found to occur in prehypertensive SHR. The RVR at maximal relaxation was similar to that present in WKY, while the lumen diameter of the main renal, interlobar and cortical arteries was not modified between the two groups. All renal arteries of prehypertensive SHR that were studied exhibited an increase in the cross-sectional area ratio of arterial wall (intima + media) in relation to the lumen, and an increased number of SMC layers within the media. Consistent with the proposed model, when the renal vasculature of prehypertensive SHR was maximally contracted by infusing NE or by stimulating the periarterial nerves (under conditions where the presynaptic uptake of NE was blocked) the amplitude of RVR change was higher in prehypertensive SHR than WKY. As in SHR with established hypertension, the contractile sensitivity of the renal vasculature to NE was modestly increased in WKY.

To further test if such alterations occur independently of high blood pressure, hydralazine (an antihypertensive drug that crosses the placental barrier) was fed to female SHR prior to, and during, pregnancy, and subsequently to newborn rats from birth to 21 weeks of age. These animals were compared to similarly treated WKY and nontreated SHR and WKY controls. Treated SHR maintained normal blood pressure throughout the treatment period. The in utero and post-natal normalization of blood pressure in SHR had virtually no effect in altering the renal vascular wall thickness. Within most of the arteries studied, SHR with normalized blood pressure had similar cross-sectional quantities of media and SMC layers as were present in untreated SHR, and greater quantities than that present in either control or treated WKY. The withdrawal of hydralazine from 26 week old in utero and post-natally treated SHR resulted in the re-establishment of hypertension within two days of withdrawal to the levels that were present in control SHR.

These results suggest that the thickening of the renal vascular wall in SHR could be of etiological importance in the initiation and maintenance of high blood pressure in SHR, and that such changes are not a secondary modification produced by the elevation of blood pressure.

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