Geza Simon

Pressor and subpressor angiotensin II administration: Two experimental models of hypertension

Administered dose is an important determinant of the type of hypertension produced by angiotensin II. With chronic administration of pressor doses, there is salt and water retention and expansion of extracellular fluid volume, and the pressure-natriuresis curve is shifted to higher pressures. Important compensatory mechanisms, including resetting of baroreceptors, de novo synthesis of vasodilator prostaglandins, and atrial natriuretic factor release, are triggered by the acute rise of blood pressure. Histologic evidence for vascular injury confounds the interpretation of findings. When angiotensin II is administered in initially subpressor doses, the rise of blood pressure is gradual, there are no detectable changes in salt and water balance, and compensatory mechanisms do not seem to be activated. Autopotentiation of pressor and vasoconstrictor responses by angiotensin II is the characteristic feature of the early stages of hypertension induced by small doses of angiotensin II. Trophic stimulation of vascular tissue, in particular restructuring of extracellular matrix, precedes and may, therefore, be the mechanism responsible for the hemodynamic changes. The pressor and subpressor models of angiotensin II-induced hypertension draw attention to the relative importance of renal and extrarenal mechanisms in the pathogenesis of hypertension. The long-term administration of initially subpressor doses of angiotensin II mimics the development of human hypertension to a greater extent than does the administration of pressor doses.

Increased renal plasma flow in long‐term enalapril treatment of hypertension

The renal effects of long‐term antihypertensive treatment with enalapril were evaluated in 34 subjects (age, 53 yr; range, 27 to 65) with mild, uncomplicated hypertension. After receiving placebo for 4 wk, subjects were randomly assigned to groups receiving incremental doses of enalapril (10, 20, or 40 mg/day for 4 wk each) in a single morning dose or two divided doses, or of placebo. One subject who received enalapril developed acute renal failure by the end of the study. There was no evidence of glomerular or tubular damage in the other subjects; as measured by 24‐hr urinary protein excretion, urinary activity of N‐acetyl‐β‐D‐glucosaminidase, and uric acid clearance. During treatment with enalapril, renal plasma flow (measured with 131l‐iodohippurate sodium) and glomerular filtration rate increased by 12.1% and 6.8%. Changes in renal plasma flow correlated inversely with age and final mean arterial pressure and correlated positively with initial plasma renin activity of subjects. Except for an occasional idiosyncratic adverse reaction, enalapril is a safe and effective antihypertensive drug with the unique ability to increase renal function despite a fall in renal perfusion pressure.

Structural Vascular Changes in Hypertension Role of Angiotensin II, Dietary Sodium Supplementation, Blood Pressure, and Time

The dose and time dependence of angiotensin II (Ang II) induced hypertension and structural vascular changes and the effect of dietary sodium supplementation on these relationships were investigated. Male Sprague-Dawley rats were treated with 50, 100, or 200 ng . kg-1 . min-1 Ang II subcutaneously for 4 or 12 weeks on normal sodium diet (0.7% NaCl) or with 50 ng . kg-1 . min-1 Ang II SC for 12 weeks on high sodium diet (2% NaCl). Additional rats were sham-operated and fed normal sodium (control rats) or high sodium diet. Plasma Ang II level of rats receiving 100 ng . kg-1 . min-1 Ang II for 4 weeks was 26+/-5 pg/mL (mean+/-SEM, n=7) compared with 11+/-2 pg/mL (n=15) in control rats (P<0.03). Lumen and external diameters of small (50 to 100 microm OD) and intermediate-size (100 to 150 microm OD) resistance arteries were measured in maximally dilated, pump-perfused (55 to 60 mm Hg), in situ fixed mesenteric vascular beds of rats, and wall-to-lumen ratios (W/L) were calculated. Large mesenteric arteries of rats treated with 100 ng . kg-1 . min-1 Ang II for 12 weeks were examined to distinguish hypertrophy from hyperplasia of vascular muscle. Tail systolic blood pressure (BP) and W/L of resistance arteries of Ang II treated rats increased in a dose-dependent manner. Treatment with 50 ng . kg-1 . min-1 Ang II for 12 weeks had no significant effect on BP but produced the same increase in W/L (+10%, n=8, P<0.06) as 100 ng . kg-1 . min-1 Ang II for 4 weeks (+9%, n=18, P<0.05) (time dependence). A 2% NaCl diet for 12 weeks had no significant effect on either BP or W/L, but in combination with 50 ng . kg-1 . min-1 Ang II, it increased systolic BP by 31 mm Hg (P<0.01) and W/L of small resistance arteries by 28% (P<0.01) (synergism). In rats treated with 100 ng . kg-1 . min-1 Ang II for 12 weeks, arterial smooth muscle cell thickness was increased without a change in the number of cell layers (hypertrophy). There was a dissociation between the average BP load (the area under the weekly systolic BP curve) of Ang II treated rats and the W/L of their mesenteric resistance arteries. Ang II induced hypertension and structural vascular changes are dose- and time-dependent and synergistically enhanced by dietary sodium supplementation. Dissociation between BP and vascular structure in Ang II treated rats suggests that a direct trophic effect of Ang II may contribute to the development of structural vascular changes.

What is critical renal artery stenosis?Implications for treatment

Renovascular disease due to progressive atherosclerotic renal artery stenosis is being diagnosed with increasing frequency in the elderly. At what degree of renal artery stenosis should intervention be recommended is not clear. To answer this question, unilateral or bilateral activation of the renin-angiotensin system or its absence were detected by captopril-stimulated renal vein renin measurements in 49 hypertensive patients, aged 63 years, with normal or near-normal renal function (serum creatinine concentration < or =2.0 mg/dL), and the information was matched against radiographic measurements of the extent of renal artery stenosis. With few exceptions, unilateral or bilateral hypersecretion of renin was associated with 80% or greater reduction of renal artery lumen diameter. In contrast, normal secretion or suppression of renin production in a kidney contralateral to an ischemic one was associated with either normal caliber renal artery or renal artery stenosis less than 80%. These findings suggest that renal artery stenosis less than 80% should be monitored rather than treated because improvement of renal function and amelioration of hypertension are not expected unless the renin-angiotensin system has been activated in the affected kidney. Renoprotection by early intervention is uncertain because progression of renal artery stenosis is unpredictable. Normal captopril-stimulated renal vein renin measurements in hypertensive patients obviate the need for further work-up or interventional therapy of renovascular disease.

Pathogenesis of structural vascular changes in hypertension.

The pathogenic role of angiotensin II (ANG II), dietary sodium chloride, sympathetic activation, obesity and aldosterone in the development of structural vascular changes (SVCs) in hypertension is considered from three perspectives (criteria): their utility in predicting hypertension and its complications (predictability); the effect of their inhibition or removal on the reversal of SVCs (reversibility); and their ability to induce SVCs in experimental animals (reproducibility). Only ANG II meets all three criteria. Importantly, ANG II increases preglomerular vascular resistance by inducing structural changes in renal cortical resistance arteries and arterioles. High salt intake, by dilating and thereby stiffening some arteries, may play a role in the development of systolic hypertension with aging, but does not produce structural changes in renal cortical resistance vessels. While high circulating levels of norepinephrine are associated with SVCs, the experimental evidence for the role of sympathetic nerve stimulation in the development of SVCs is inconclusive. Obesity is associated with hypertension, but is not known to be associated with SVCs. Salt-loading is required for aldosterone to produce SVCs, but vascular pathology in this experimental model differs from that in benign essential hypertension. The findings of this review indicate that SVCs in extra-renal sites by themselves do not lead to hypertension; structural changes in renal cortical arteries and arterioles that increase preglomerular vascular resistance are needed. Progressive trophic stimulation of preglomerular resistance vessels by itself may lead to hypertension. ANG II is prime candidate for such stimulus.

in Vivo Erythrocyte Sodium Concentration in Human Hypertension is Reduced, Not Increased

The level of intracellular sodium concentration in hypertension is of theoretical interest. Using extensive in vitro manipulations, previous investigators have reported increased erythrocyte sodium content in human hypertension. In the present study, erythrocyte sodium (Nai) and potassium (Ki) concentrations were measured within seconds after venopuncture by centrifuging whole blood over oil to separate the erythrocytes from plasma. Labelled 125I-albumin and 57Co-EDTA were used to estimate plasma trapping. The presence of white cells and platelets in the cell pellets had no detectable effect on erythrocyte cation measurements. Twenty-eight white male hypertensives and 25 normotensive control subjects were studied. In hypertensive subjects, Nai was reduced and Ki was increased. Erythrocyte sodium and sodium: potassium ratio (Nai:Ki) of hypertensive subjects correlated inversely with their pressor responses to intravenous norepinephrine. The findings suggest increased erythrocyte Na, K-pump activity in human hypertension. Assuming that erythrocyte cation concentrations reflect those of vascular muscle, enhanced transmembrane sodium gradient does not preclude pressor hyper-responsiveness in hypertension.

Structural vascular changes in hypertension: Role of angiotensin II, dietary sodium supplementation, and sympathetic stimulation, alone and in combination in rats

Elevated circulating angiotensin (Ang) II levels, dietary sodium, and sympathetic stimulation are recurrent themes of hypertension research, but their in vivo interaction in physiologically meaningful doses has not been adequately investigated. In this study, the interaction of a subpressor dose of Ang II (50 ng · kg−1 · min−1 SC), 2% NaCl diet, and sympathetic stimulation in the form of overnight cold exposure was investigated in the development of hypertension and of structural vascular changes in male Sprague-Dawley rats. There were 8 experimental groups: sham operation and treatment (control), Ang II, 2% NaCl diet, cold exposure (5°C), Ang II plus 2% NaCl diet, Ang II plus cold exposure, cold exposure plus 2% NaCl diet, and Ang II plus 2% NaCl diet plus cold exposure (triple treatment). For each group, the duration of treatment was 12 weeks. Morphometric measurements of maximally dilated, in situ fixed, second-order (250 to 320 &mgr;m OD), intermediate-size (100 to 150 &mgr;m OD), and small (50 to 100 &mgr;m OD) mesenteric arteries were performed, and wall-to-lumen ratios (W/L) were calculated. During the 12-week study, the blood pressure (BP) load (the area under the systolic BP curve) of rats receiving the combined treatment of Ang II and 2% NaCl diet was increased (P <0.05), and that of rats receiving the combined treatment of cold exposure and 2% NaCl diet was decreased (P <0.05); there were no BP changes in the remaining groups of rats. The most pronounced changes among groups occurred in W/L of small resistance arteries. The W/L of small arteries increased in Ang II–treated (P <0.01) and in cold-stressed rats (P <0.01). The effect of Ang II was potentiated by the addition of a 2% NaCl diet. In contrast, the addition of 2% NaCl diet to cold stress reduced the W/L of small arteries (P <0.01). No other positive or negative synergism occurred among groups, including the rats receiving triple treatment. The findings confirm the potentiation of the hypertensinogenic and vascular trophic effects of Ang II by a high-sodium diet but do not provide evidence for synergism between Ang II and sympathetic stimulation. The finding of hypotension and reduced W/L of small resistance arteries in rats receiving the combined treatment of cold stress and high-sodium diet is unique because there are few known nonpharmacological vascular “hypotrophic” stimuli. The ultimate test of the hypertensinogenic potential of pressor stimuli alone or in combination is their long-term administration in physiologically meaningful doses to experimental animals.

Subpressor angiotensin II is a bifunctional growth factor of vascular muscle in rats

Objective: The proposition that angiotensin II in subpressor doses stimulates vascular growth in vivo was tested. Design: Young adult, male Sprague—Dawley rats received angiotensin II, 200ng/kg per min intraperitoneally by osmotic minipump, for 24 h or 7—10 days. Sham-infused rats served as controls. Methods: Protein (35S-methionine) synthesis in aortic media, portal vein, bladder wall and diaphragm; proteoglycan (35S-sulfate) synthesis in aorta and bladder and synthesis of DNA (3H-thymidine) in aortic media were all measured ex vivo in the rat. Results: The systolic blood pressure of angiotensin ll-treated rats was unchanged at 24 h and increased at 7—10 days. At 24 h in angiotensin ll-treated rats the protein synthesis in aortic media, portal vein and bladder wall but not in the diaphragm was increased, indicating that the hypertrophic effect of angiotensin II was independent of the arterial pressure. The rate of 35S-methionine washout from angiotensin II- and sham-treated aorta was the same. At 24 h there was also an increase in proteoglycans synthesis of the aorta and bladder wall of angiotensin ll-treated rats. In contrast to protein synthesis, the incorporation of 3H-thymidine into aortic muscle DNA was reduced in angiotensin ll-treated rats at 24 h, suggesting the inhibition of DNA synthesis. At 7—10 days angiotensin II administration the protein synthesis of aortic media returned to baseline, and DNA synthesis was bimodal: in 53% of rats (n = 10) inhibition continued, and in 26% (n = 5) it was increased by two- to threefold. Conclusions: The present findings confirm in vivo the bifunctionality of the trophic vascular action of angiotensin II. Vascular hypertrophy may play a role in the slow pressor action of angiotensin II.

Development of structural vascular changes with subpressor angiotensin II administration in rats

We investigated whether the slow pressor action of small doses of angiotensin II (ANG II) administered to rats was accompanied by the development of structural vascular changes. Male Sprague-Dawley rats (350 to 400 g) were given ANG II intraperitoneally, 200 ng/kg/min, for 7 to 10 days or 6 weeks, or 100 ng/kg/min for 6 weeks. Sham-treated rats were controls. Lumen and external diameters of arterioles (30 to 60 microns) and small (61 to 120 microns) and intermediate-size (121 to 220 microns) arteries were measured in maximally dilated, pump-perfused (55 to 60 mm Hg), in situ fixed mesenteric and renal vascular beds, and wall-to-lumen ratios were calculated. Systolic blood pressure and vessel dimensions were unchanged in rats receiving ANG II for 7 to 10 days. Systolic blood pressures rose (P < .001) in rats treated with 200 or 100 ng/kg/min ANG II for 6 weeks but were significantly different from those of controls only in rats receiving the higher dose (P < .01). In rats treated with 200 and 100 ng/kg/min ANG II for 6 weeks, wall-to-lumen ratios of mesenteric and renal arteries were increased 23% and 9% (P < .001) and 13% and 6% (P < .01), respectively. With the higher dose of ANG II, the increase of wall-to-lumen ratios of mesenteric arteries was greater than that of renal arteries (P < .005). Initially subpressor doses of ANG II, when applied long enough, may lead to the development of structural vascular changes. There may be significant regional differences in the extent of structural vascular changes induced by ANG II.

Development of structural vascular changes in salt-fed rats*

The hypothesis that long-term administration of a physiologically relevant high salt diet to rats leads to the development of structural vascular changes that predispose to hypertension was tested. Adult male Sprague-Dawley rats were fed 2% NaCl diet for 3 or 6 months; rats fed 0.7% NaCl diet were controls. Then, the systemic circulation of the rats was perfusion-fixed at 100 mm Hg. The junction of the mesentery and small intestine, the renal cortex, and segments of left carotid artery, thoracic aorta, and second order mesenteric arteries were embedded in paraffin or epoxy for morphometric measurements. The average monthly tail systolic blood pressure (BP) of salt-fed rats at 3 and 6 months were unchanged. The following morphometric changes in salt-fed rats were observed: 1) dilatation of the carotid artery at 3 months (P <.05); 2) dilatation and reduced wall-to-lumen ratio of the second order mesenteric artery (P <.01); 3) increased wall-to-lumen ratio of small mesenteric resistance arteries (P <.01); 4) reduced wall-to-lumen ratio of renal cortical resistance arteries at 6 months (P <. 05); and 5) unchanged structure of aorta. The long-term administration of a high salt diet leads to structural vascular changes in normotensive rats. There are important regional and segmental variations in the long-term adaptation of arteries to a high salt diet.