Effects of an Angiotensin-Converting Enzyme Inhibitor, a Calcium Antagonist, and an Endothelin Receptor Antagonist on Renal Afferent Arteriolar Structure

Abstract

Narrowed afferent arteriolar diameter in young, spontaneously hypertensive rats (SHR) may be a contributor to later development of high blood pressure. Thus, treatment that causes dilation of the afferent arterioles in SHR may inhibit the redevelopment of high blood pressure when treatment is withdrawn. We treated SHR with an ACE inhibitor (cilazapril, 5 to 10 mg/kg per day, high; 1 mg/kg per day, low), a calcium antagonist (mibefradil, 20 to 30 mg/kg per day), and an endothelin receptor antagonist (bosentan, 100 mg/kg per day) from age 4 to 20 weeks. Untreated SHR and Wistar-Kyoto rats were also investigated. At 20 weeks, the rats were killed, and morphology of the afferent arterioles was studied. Other SHR (untreated, high cilazapril, low cilazapril, mibefradil) were treated in exactly the same way and then followed to 32 weeks without treatment. The morphometric studies showed that cilazapril increased the lumen diameter in the afferent arterioles and decreased the media-lumen ratio in a dose-dependent manner. On withdrawal of cilazapril treatment, the reduction in blood pressure persisted. Mibefradil tended to increase afferent arteriolar diameter, whereas it did not alter media-lumen ratio. The persistent effect on blood pressure was only moderate after withdrawal of mibefradil. Bosentan had no effect on renal afferent arteriolar structure or blood pressure. In conclusion, cilazapril was more effective than mibefradil in altering afferent arteriolar structure and caused the most persistent effect on blood pressure after treatment withdrawal. The association of increased afferent arteriolar diameter and lower blood pressure level after withdrawal of treatment may suggest a pathogenic role for afferent arteriolar diameter in the development of high blood pressure in SHR.

Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism

“…The observation that ACE inhibitors can prevent arteriolopathy is consistent with other studies that suggest that this group of drugs can reduce SMC proliferation and collagen (18,25). Because a low-salt diet will activate the renin-angiotensin system, we also examined the effect of enalapril and losartan on the arteriolopathy induced by oxonic acid in the setting of a normal-salt diet.…”

Treatment of Young Subjects at High Familial Risk of Future Hypertension With an Angiotensin-Receptor Blocker

“…The result contrasts with the strong animal data, 8,9 and comparison with these suggests that the discrepancy could be attributable to our subjects being too old (mean age 29 years) or that treatment duration was too short. The animal evidence on which the study is based shows that the persistent effect is most pronounced if the inhibition of the renin-angiotensin system is made in prepubertal animals 8,[22][23][24][25] ; for ethical reasons such studies are hardly feasible in humans. Another possible reason for the lack of persistent effect is that the animal studies show that the effect is related to renal mechanisms.…”

Chloride-Dominant Salt Sensitivity in the Stroke-Prone Spontaneously Hypertensive Rat

“…In the SHR, and presumably also in the SHRSP, hypertension is likely caused by a genetically determined narrowing of the renal afferent arteriole 29 -31 that is susceptible to physiological 32 and pharmacological modulation. 33,34 In the SHR, pharmacological inhibition of the angiotensin converting enzyme dose-dependently attenuates hypertension and the narrowing of the renal afferent arteriole, 33,34 the extent of narrowing varying directly with the severity of pharmacologically attenuated hypertension. 33 Even in the normal rat, Cl Ϫ selectively loaded either in the diet 13,14 or in the isolated perfused kidney 35 induces renal vasoconstriction and amplifies that induced by angiotensin II, 14,36 likely by constricting the renal afferent arteriole 37 such that glomerular filtration rate is reduced.…”

“…33,34 In the SHR, pharmacological inhibition of the angiotensin converting enzyme dose-dependently attenuates hypertension and the narrowing of the renal afferent arteriole, 33,34 the extent of narrowing varying directly with the severity of pharmacologically attenuated hypertension. 33 Even in the normal rat, Cl Ϫ selectively loaded either in the diet 13,14 or in the isolated perfused kidney 35 induces renal vasoconstriction and amplifies that induced by angiotensin II, 14,36 likely by constricting the renal afferent arteriole 37 such that glomerular filtration rate is reduced. 35 An increased delivery of Cl Ϫ to the macula densa of the thick ascending limb of the renal tubule, as presumably occurred with the chlorureses currently induced in the SHRSP, elicits dose-dependent constriction of the renal afferent arteriole as part of the normal tubuloglomerular feedback (TGF) response.…”