Renal Artery Constriction Research Articles

Inhibition of lipoxygenase pathway reduces blood pressure in renovascular hypertensive rats

To assess the potential role of the lipoxygenase (LO) pathway in the vasculature in an angiotensin II (ANG II)-dependent model of hypertension, we investigated the effect of LO pathway inhibition on blood pressure in the two-kidney, one-clip (2K,1C) Goldblatt hypertensive rat. The development of renovascular hypertension in 2K,1C rats was attenuated by oral administration of phenidone (Phe, 60 mg.kg-1.day-1), a nonselective LO inhibitor, throughout the 3 wk of observation after renal artery constriction. In contrast, the same treatment protocol had no effect on the evolution of hypertension in the deoxycorticosterone acetate-salt rat, which is considered to be an ANG II-independent form of hypertension. The hypotensive effect of Phe was not associated with changes in plasma renin or aldosterone concentration (PRC and PAC, respectively). In vitro synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) by aortic segments was increased in 2K,1C hypertensive rats compared with sham-operated rats. In addition, the synthesis of 12-HETE was suppressed by the in vitro addition of Phe (10(-4) M) to aortic-segment incubates obtained from 2K,1C rats and sham-operated rats. Acute administration of Phe (30 or 60 mg/kg) in 2K,1C hypertensive rats produced a rapid and sustained decrease in mean blood pressure (MBP). This decrease in MBP was accompanied by a brisk rise in PRC and PAC. In contrast, bolus administration of indomethacin, a selective cyclooxygenase inhibitor, did not affect MBP, PRC, or PAC.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis

The aim was to compare the temporal sequence and structural relationship between perivascular and interstitial fibrosis and microscopic scarring seen in the left ventricle in response to either a transient or sustained stimulus to fibrosis. In 72 male Wistar rats (250-350 g) the transient stimulus model was based on the administration of isoprenaline (500 micrograms.kg-1) while the sustained stimulus model was produced by abdominal aortic banding with right renal artery constriction. Serial sections of myocardium were examined and compared at 4 and 12 weeks in each model and to corresponding controls. The collagen specific stain, Sirius Red F3BA, was used to determine collagen volume fraction and the fibrillar nature of the fibrous tissue response seen by light microscopy. Following isoprenaline a stable reparative fibrosis of the endomyocardium and increase in collagen volume fraction was seen without an interstitial or perivascular fibrosis of the non-involved myocardium. In unilateral renal ischemia, on the other hand, a progressive perivascular fibrosis was evident throughout the myocardium and from which fibrillar collagen extended into the extracellular space between muscle bundles creating an interstitial fibrosis; microscopic scarring of the endomyocardium became evident at 12 weeks. The reactive perivascular fibrosis of intramyocardial coronary arteries seen in renovascular hypertension is a progressive process that leads to an interstitial fibrosis and eventual microscopic scarring. In contrast, the endomyocardial scarring that follows isoprenaline induced myocyte necrosis is stable and intramural vessels in remote regions are not involved.

Left ventricular failure induced by long-term hypertension in rats.

To determine whether the duration of hypertension is an essential component in the evolution of myocardial dysfunction, renal artery constriction was performed in male Fischer 344 rats at 4 months of age, and in vivo global cardiac performance of sham-operated and experimental animals was evaluated 8 months later. Systemic arterial blood pressure increased to 173 +/- 5 mm Hg 2 weeks after the arteries were clipped and remained elevated for the following 5 months. Blood pressure decreased over the remaining 3 months to a value not significantly different from control rats that were killed, 132 +/- 4 mm Hg. After 8 months of renovascular hypertension, we observed that the elevated level of systolic arterial pressure was accompanied by a distinct absence of left ventricular hypertrophy when measured at the ventricular weight level. Moreover, left ventricular end-diastolic pressure increased in hypertensive animals from 6.0 to 24.0 mm Hg while peak left ventricular pressure was identical to controls. In addition, peak +dP/dt and -dP/dt were depressed in hypertensive animals. Although stroke volume was unaltered, cardiac output in renal artery clipped animals was depressed by 34% while total peripheral resistance was elevated by 50%. Ventricular chamber remodeling in the hearts of hypertensive animals was evidenced as a 19% increase in the transverse and a 16% increase in the longitudinal axes of the left ventricle with a 27% diminution of wall thickness. Myocardial damage, in the form of myocyte loss and replacement fibrosis, increased in the hearts of hypertensive animals resulting in a ninefold augmentation in the volume fraction of collagen within the ventricular wall. These alterations in the architectural properties of chamber geometry coupled with the abnormalities in contractile performance resulted in a severe reduction in ejection fraction from 82% to 47% and a marked elevation in transmural diastolic and systolic stress in hypertensive animals. The gradient in stress across the ventricular wall, from epicardium to endocardium, revealed a direct correlation with the regional distribution of myocardial damage. In conclusion, the loading state of the myocardium, tissue injury, and myocardial fibrosis all appear to be critical determinants in the genesis of left ventricular failure in long-term pressure overload.

Reversal of hyperreactivity to bradykinin in renal hypertensive rats.

Increased blood pressure responsiveness to bradykinin in comparison with other vasodilator agents was demonstrated in rats with long-term one-kidney and two-kidney, one clip hypertension. In the present study, we analyzed the reactivity to intra-aortically injected bradykinin in unanesthetized one-kidney, one clip hypertensive rats during the control period and 1, 5, and 8 hours after reversal of hypertension after removal of the renal artery constriction. One and 5 hours after unclipping the renal artery, the mean blood pressure decreased markedly (from 195 +/- 7 to 124 +/- 8 and 145 +/- 9 mm Hg, respectively), whereas the hyperreactivity to bradykinin reverted only slightly, and the responses to nitroprusside remained unchanged. In another group of hypertensive rats examined 8 hours after unclipping (pressure decreased from 192 +/- 4 to 143 +/- 8 mm Hg), the hyperreactivity to bradykinin had partially reverted. Significantly larger doses of bradykinin were necessary to produce the same decrease in blood pressure when compared with the control period (16.4 +/- 2.0 vs. 7.2 +/- 1.2 ng). The same degree of reversal of hyperreactivity to bradykinin was observed when the blood pressure of hypertensive rats was reduced (from 207 +/- 8 to 143 +/- 5 mm Hg) during 1 hour by hydralazine injection. Complete reversibility of bradykinin hyperreactivity was produced by nitroprusside infusion (from 201 +/- 13 to 142 +/- 10 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Hypertension on Elasticity and Geometry of Aortic Tissue From Dogs

Inflation-extension experiments were carried out on segments of the descending thoracic aortas from 4 normotensive and 4 hypertensive dogs rendered hypertensive using either unilateral or bilateral renal artery constriction. Intravascular pressures up to 200 mm Hg and axial forces up to 200 g were used. The external diameter of the segment and the distance between two longitudinally spaced gage marks were recorded photographically at each pressure-force level combination. Dimensions in the underformed configuration were measured at the end of the inflation-extension experiment. Data were analyzed for changes in geometry and force-deformation response. Results indicate that: 1. Under sustained hypertension the wall thickness in the underformed configuration increases with a concurrent reduction in the in-situ longitudinal extension ratio. 2. This dual tissue response accomplishes substantial reductions in the circumferential and longitudinal stresses from the levels that would be reached at equivalent pressures in the absence of these geometric changes. 3. At comparable intravascular pressures the extensibility in the circumferential direction is slightly greater for the hypertensive aortas as compared to normals. However, the stress-extension ratio relationship in the circumferential direction is similar in the two groups. 4. The stress-extension ratio relationship in the longitudinal direction indicates that the hypertensive aorta is stiffer than its normotensive counterpart.

Effects of Nifedipine on Renal Cortical and Medullary Blood Flow in Two-Kidney, One-Clip Renovascular Hypertension in Rabbits

The effects of nifedipine, a calcium antagonist, on blood pressure and renal regional blood flow were investigated in two-kidney, one-clip renovascular hypertensive rabbits. At 1 week after left renal artery constriction, in the constricted group, systemic blood pressure (BP) significantly rose with the elevation of plasma renin activity (PRA). In both kidneys, renal vascular resistance (RVR on the constricted group was significantly increased as compared to that in the control group. In the clipped kidney, total renal blood flow (RBF) and renal cortical blood flow (RCBF) of the constricted group were significantly decreased, while renal medullary blood flow (RMBF) remained at the control value. In the nonclipped kidney, RBF and RCBF of the constricted group did not significantly change, and RMBF was significantly increased as compared to that of the control group. After administration of nifedipine for 1 week (1.0 mg/kg/day), BP in the constricted group was decreased to the control level and PRA in both groups was increased. The percent change of BP in the constricted group was significantly decreased and the percent change of PRA in the constricted group was significantly increased as compared to those in the control group. Nifedipine increased RBF, RCBF and RMBF and decreased RVR of both kidneys in each group. In the nonclipped kidney, the percent change of RBF, RCBF and RMBF of the constricted group was significantly increased and the percent change of RVR was significantly decreased as compared to those of the control group. In the clipped kidney, only the percent change of RBF of the constricted group was significantly lower than that in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional and biochemical analyses of isolated rat hearts in renal and reversed renal hypertension

The present study evaluates cardiac function, plasma renin activity (PRA) and left ventricular (LV) myosin isoenzymes in untreated two-kidney, one-clip Goldblatt hypertensive rats (2KIC) and in 2KIC treated with felodipine and metoprolol. Normotensive rats (NCR) and another group of 2KIC, in which the renal artery constriction was removed (UC-2KIC), were also investigated. Cardiac performance was assessed by means of a working heart perfusion device, allowing also for measurements of myocardial oxygen consumption. Following antihypertensive therapy and unclipping, blood pressure became close to normotensive levels. PRA remained equally elevated in treated and untreated 2KIC, but became practically normalized after unclipping. Relative LV weight in 2KIC increased 74% above that in NCR but in treated 2KIC increased by only 20%. In UC-2KIC LV hypertrophy became reversed, LV weight/body being about the same as in treated 2KIC. In treated 2KIC, coronary resistance at maximal dilatation was significantly reduced, implying prevention of hypertensive, structural coronary vascular changes, and optimal LV function was improved markedly in the lower range of perfusion pressures compared with untreated 2KIC. When, however, the hearts were challenged at a high pumping resistance (perfusion pressure), LV function was similar in untreated and treated 2KIC. Myocardial oxygen consumption for given levels of stroke work was significantly lower in treated than in untreated 2KIC. The myosin isoenzyme pattern in the LV of 2KIC was shifted, with significantly higher amounts of VM-3 than in NCR. This shift was normalized by antihypertensive therapy or by unclipping. In conclusion, antihypertensive therapy with felodipine and metoprolol prevents the development of coronary vascular and left ventricular hypertrophy in 2KIC. This may contribute to enhance cardiac performance at low aortic pressure. The lack of improvement in optimal cardiac performance (at high aortic pressure) implies that the hypertensive state per se, rather than extent of pressure elevation, cardiac hypertrophy, or changes of LV isoenzymes, determines the reduced cardiac function in renal hypertensive rats (Friberg & Nordborg 1986).

２腎性Ｇｏｌｄｂｌａｔｔ型高血圧犬におけるＭＫ‐０５２１の連続経口投与による降圧作用

MK-0521 and captopril were orally administered to acute (6 to 8 days after unilateral renal artery constriction) and chronic (2 to 2.5 months after the constriction) 2-kidney Goldblatt hypertensive dogs for 7 to 21 days. MK-0521 lowered the blood pressure to similar extents in the acute and chronic stages of hypertension. The antihypertensive effect of MK-0521 was dose-dependent and persistent even after its cessation. Captopril also produced an antihypertensive effect, although the effect in the chronic stage of hypertension was less prominent than that in the acute stage of hypertension. MK-0521 was more inhibitory on the renin-angiotensin system than captopril. In the acute stage of hypertension, the dogs treated with MK-0521 had increased angiotensin converting enzyme (ACE) activity, while they had decreased plasma angiotensin II level and elevated plasma angiotensin I level and plasma renin activity. These results clarified the inhibitory effect of MK-0521 on ACE. In contrast, in the chronic stage of hypertension, MK-0521 showed no depression of plasma angiotensin II. There were no significant changes in daily urinary volume, and renal clearances of sodium, potassium and creatinine. These results suggest that the major mechanism of the antihypertensive effect of MK-0521 in 2-kidney Goldblatt hypertensive dogs is an inhibition of the ACE. In addition, the different effects in the acute and chronic hypertensive dogs suggest that some differences exist in the mechanisms of maintaining blood pressure between the two stages of 2-kidney Goldblatt hypertensive dogs.

Effects of caffeine on the vascular smooth muscles isolated from two-kidney, one-clip renovascular hypertension in rabbits.

To examine the intracellular calcium content of the vascular smooth muscle in the chronic phase of renovascular hypertension, the effects of caffeine on isolated aortic, renal and iliac arterial strips were evaluated in two-kidney, one-clip renovascular hypertension in rabbits. 10 weeks after left renal artery constriction in the constricted group, systemic blood pressure (BP) was significantly higher than in the control group, but plasma renin activity was similar to the control value. The amplitude of caffeine-induced contraction of various vascular strips in the constricted group gradually increased and, at 10 weeks, this was higher in the constricted group than in the control group. In the constricted group, sodium loading produced BP elevation and increased the amplitude of caffeine-induced contraction, whereas sodium constriction decreased BP and the amplitude. In the control group, altered sodium intake did not affect BP and the amplitude of caffeine-induced contraction. These results suggest that in the chronic phase of renovascular hypertension, the increased caffeine-sensitive intracellular calcium store on vascular smooth muscle, which is increased by sodium loading and is decreased by sodium restriction, may contribute to the maintenance of hypertension.

Naloxone attenuates development of hypertension in two-kidney one-clip Goldblatt rats.

The present experiments were designed to determine if an opiate antagonist affects blood pressure in two-kidney one-clip Goldblatt rats. Male Sprague-Dawley rats were divided into three groups. Group 1 received an infusion of saline intraperitoneally via an osmotic pump and left renal artery constriction (RAC). In group 2, rats were treated the same as group 1, except that they received an intraperitoneal infusion of naloxone (100 micrograms/h). Group 3 received the same infusion of naloxone without RAC. Naloxone-infused Goldblatt rats showed a significantly lower systolic blood pressure (SBP) than saline-infused Goldblatt rats (132 +/- 7 vs. 160 +/- 9 mmHg at day 14), but a higher SBP than control (132 +/- 7 vs. 106 +/- 1 mmHg). Infusion of naloxone did not significantly change SBP in normotensive rats. Renal renin activity in the clipped kidney was higher than in the nonclipped kidney in groups 1 and 2. Plasma renin activity (PRA) in both groups of Goldblatt rats was higher than in group 3, but no significant difference was found between the two groups of Goldblatt rats (groups 1 and 2). Naloxone (1.5 microM) did not affect the basal secretion of renin by isolated cortical slices from untreated rats. The present data demonstrate that naloxone significantly attenuates the development of hypertension in two-kidney one-clip rats. The attenuation of blood pressure was not associated with the changes in PRA, renal renin activity, or plasma aldosterone concentrations. The data support the hypothesis that the endogenous opioid system may be involved in the development of renovascular hypertension.

Haemodynamic regulation of renal prostaglandin and renin release.

To examine the relationship between renal release of the prostaglandins E2 (PGE2) and I2 (PGI2) and renin during autoregulatory vasodilation, experiments were performed in anaesthetized dogs with denervated kidneys. Autoregulatory vasodilation was induced by reducing renal arterial pressure (RAP) or by raising ureteral pressure in steps. During progressive renal arterial constriction, PGE2 and PGI2 release reached maximal values (10.6 +/- 1.7 for PGE2 and 6.6 +/- 1.1 pmol min-1 for PGI2 release) at RAP of 70-80 mmHg, associated with almost no increase in renin release. By further reduction of RAP, prostaglandin release was not significantly altered, whereas renin release reached maximal values (18.7 +/- 2.4 micrograms AI min-1) when autoregulatory vasodilation was complete at RAP below 55-60 mmHg. During progressive elevation of ureteral pressure, the release of PGE2, PGI2 and renin increased in concert in a curvilinear fashion, reaching maximal values at a ureteral pressure of 85 mmHg. There was no further increase during ureteral occlusion and the plateau values averaged 23.6 +/- 3.7 pmol min-1 for PGE2, 8.0 +/- 1.6 pmol min-1 for PGI2 and 16.6 +/- 3.4 micrograms AI min-1 for renin. We conclude that vascular dilation enhances both prostaglandin and renin release. During reduction of RAP, preglomerular arteries are dilated at higher RAP than are afferent arterioles. Release of prostaglandins synthetized in arteries consequently occurs at higher RAP than release of renin, which is not enhanced until afferent arterioles ultimately dilate at RAP approaching 60 mmHg. In contrast, elevation of ureteral pressure provides nearly uniform enhancement of prostaglandin and renin release, indicating a more uniform dilation of the whole preglomerular vascular tree.

Effects of hypertension and its reversal on canine arterial wall properties.

Segments of carotid, femoral, saphenous, and left circumflex coronary arteries were obtained from control, renal hypertensive, and nephrectomized hypertensive dogs for in vitro study of mechanical properties. Hypertension was produced in two-kidney dogs by unilateral renal artery constriction. After 3 months, the compromised kidney was removed in half of the dogs. Mean arterial pressure was significantly elevated in the hypertensive dogs after 3 months (127 +/- 2 vs 94 +/- 1 mm Hg for controls) and partially returned toward normal 3 months after nephrectomy (105 +/- 2 mm Hg). Pressure-diameter relations were determined under conditions of maximum active and passive smooth muscle activation. Contiguous segments were used for the determination of water and connective tissue content. Hypertension was associated with increased passive arterial wall stiffness at most sites, with a partial return toward normal after nephrectomy. Maximum responses to smooth muscle activation (active stress and constriction response) were augmented in arteries from hypertensive dogs and partially returned toward normal in the nephrectomized hypertensive group. The elastin content of these arteries was unchanged, while collagen content was nonuniformly decreased in renal hypertensive dogs. Small decreases were found in the radius-wall thickness ratio of some arteries. No significant mechanical changes occurred in the saphenous artery. The largest hypertension-related changes were found in the coronary arteries, which also exhibited the smallest recovery toward normal properties after nephrectomy. Considerable regional variability of changes in arterial wall in renal hypertensive and nephrectomized hypertensive dogs was found. Incomplete resolution of the hypertension and arterial wall changes by nephrectomy was found in this animal model.

A new constrictor device for external induction of a long-term stable and irreversible renal artery stenosis in the dog.

A new externally adjustable constrictor device for renal artery stenosis in the dog is described. The constrictor combines hydraulic and mechanical characteristics, and is connected to the exterior of the animal by a thin catheter. Applying hydraulic pressure via the catheter causes the plunger in the device to compress the renal artery to any desired degree of stenosis. A mechanical catch prevents backward movement of the plunger, thus ensuring a stable, irreversible renal artery constriction. This constrictor was implanted in 13 dogs, together with an electromagnetic blood flow sensor around a renal artery. In twelve dogs the constriction procedure was performed 3-12 weeks after implantation, and in all 12 cases the intended degree of stenosis [defined as percentage renal blood flow reduction (RBF)] was achieved within a range of 10%. In 5 dogs the long-term stability of the stenosis was studied and the RBF reduction appeared to be stable up to at least 6 weeks after constriction. In conclusion, the presented constrictor device is easily externally adjustable, and allows induction of a stable renal artery stenosis of various degrees in the conscious dog.

Properties of the macula densa mechanism for renin release in the dog.

To study the macula densa mechanism for renin release, both the macula densa and the haemodynamic mechanisms were activated in anaesthetized dogs with denervated kidneys, either by renal arterial constriction to a renal arterial pressure (RAP) of 52 +/- 2 mmHg or by ureteral occlusion to a ureteral pressure of 95-105 mmHg, 20-25 mmHg below RAP. Renal arterial constriction increased renin release from 0.3 +/- 0.2 to 16 +/- 4 micrograms AI min-1. At low RAP, renin release was subsequently reduced to 7 +/- 3 micrograms AI min-1 when sodium excretion was raised far above control values by plasma volume expansion and acetazolamide infusion. Ethacrynic acid (3 mg kg-1 body wt.) restored renin release to pre-expansion values, and a large dose (25 mg kg-1 body wt.) prevented renin release from falling even after unclamping the artery. During ureteral occlusion with stopped glomerular filtration, plasma volume expansion, acetazolamide and ethacrynic acid infusion did not alter renin release. On the other hand, beta-adrenergic stimulation by isoproterenol raised renin release equally (by 30-40 micrograms AI min-1) before and after plasma volume expansion, during both renal arterial constriction and ureteral occlusion. Indomethacin (10 mg kg-1 body wt.) abolished renin release induced by ethacrynic acid infusion and ureteral occlusion. We conclude that the macula densa mechanism for renin release is inactivated by high NaCl reabsorption during plasma volume expansion and acetazolamide infusion, reactivated by inhibition of NaCl reabsorption with ethacrynic acid and completely inhibited by indomethacin. The degree of activation does not influence the renin release induced by beta-adrenergic stimulation.

Role of sodium and renal prostaglandin E2 in the maintenance of hypertension in the chronic phase of two-kidney one-clip renovascular hypertension in rabbits.

To study the role of sodium and renal prostaglandin E2 in the chronic phase of two-kidney one-clip renovascular hypertension, urinary excretion rates of sodium and prostaglandin E2 were measured in rabbits with hypertension induced by left renal artery constriction during alteration in sodium intake. The arterial blood pressure, the increasing rate of body weight and sodium balance during alteration in sodium intake were directly proportional to the amount of sodium intake in the hypertensive rabbits, but not in the control ones. Plasma renin activity and plasma aldosterone concentration, which had no significant difference between hypertensive and control rabbits, were inversely proportional to the amount of sodium intake in both rabbits. Urinary excretion rates of sodium in the clipped kidneys of the hypertensive rabbits were significantly lower than the control values in all dietary regimens (p less than 0.01). Urinary excretion rates of sodium in the nonclipped kidneys were not significantly higher and in the total kidneys were significantly lower than the corresponding control values during sodium load (p less than 0.01). Urinary excretion rates of prostaglandin E2 were inversely proportional to the amount of sodium intake in both groups. Urinary excretion rates of prostaglandin E2 in the clipped kidneys were significantly lower than the control values in all dietary regimens (p less than 0.001). Urinary excretion rates of prostaglandin E2 in the nonclipped kidneys were significantly higher during sodium restriction (p less than 0.01) but not during sodium load than the control values. Furthermore, urinary excretion rates of prostaglandin E2 in the total kidneys were significantly lower than the control values in all dietary regimens (p less than 0.01). These results suggest that two-kidney one-clip renovascular hypertension in rabbits seems to be partly sodium-dependent in the chronic phase because the nonclipped kidney fails to excrete sodium sufficiently. There may also be disorders of renal prostaglandin E2 metabolism influencing these disorders of sodium in the nonclipped kidneys.

Atrial natriuretic factor in dogs with one-kidney, one-clip Goldblatt hypertension.

The temporal changes in the plasma concentration of immunoreactive atrial natriuretic factor (ANF) were studied in dogs (n = 5) before and after renal artery constriction to produce one-kidney, one-clip renovascular hypertension. Three days after renal artery constriction, circulating ANF increased from 34 +/- 7 to 344 +/- 129 pg/ml (P less than 0.05) in association with a 38-mmHg elevation of mean arterial pressure and increases in plasma renin and aldosterone levels. Plasma renin and aldosterone remained elevated for 9 days after renal artery constriction. Arterial pressure stabilized at this elevated level of 35-40 mmHg above base line for the duration of the 4 wk after renal artery constriction. Right atrial filling pressure did not change significantly (P greater than 0.05) after constriction of the renal artery. This observation suggests that volume expansion with right atrial distention is not the only stimulus for release of ANF in these hypertensive dogs. Plasma ANF remained significantly elevated above base-line levels for 7 days postconstriction even though a twofold decrease from the maximal response of 344 +/- 129 pg/ml on day 3 to 168 +/- 48 pg/ml on day 7 was observed during this same time interval. Plasma ANF continued to decrease toward prehypertensive levels throughout the remainder of the established phase of the hypertension lasting an additional 21 days of observation. The mechanisms for this observed pattern of plasma ANF are unclear but may involve changes in left atrial distention and stretch as a stimulus for hormone secretion with progression of the hypertension.

Oral calcium treatment lowers blood pressure in renovascular hypertensive rats by suppressing the renin-angiotensin system.

The effects of calcium supplementation on blood pressure and its mechanisms were investigated in two-kidney, one clip renovascular hypertensive rats. Two series of experiments were performed: one was begun just after renal artery constriction, the other after the onset of hypertension. Calcium supplementation significantly attenuated the development of hypertension (systolic blood pressure: 183 +/- 8 vs 130 +/- 2 mm Hg) and was found to abate existing renovascular hypertension (systolic blood pressure: from 183 +/- 8 to 151 +/- 4 mm Hg). Calcium treatment did not cause significant alterations in fluid intake, urine volume, or urinary sodium excretion in either study. However, increased plasma renin activity and plasma aldosterone concentration were suppressed to the basal levels at the end of 3 weeks of calcium treatment (14 +/- 3 vs 8 +/- 2 ng angiotensin I/ml/hr; 530 +/- 50 vs 380 +/- 40 pg/ml). Blood pressure of calcium-treated renovascular hypertensive rats responded poorly to blockade of the renin-angiotensin system with captopril injection and angiotensin II analogue (saralasin) infusion. Further, in rats with chronic established renovascular hypertension, calcium treatment attenuated the enhanced pressor response to norepinephrine, but not to angiotensin II. These results suggest that the blood pressure-lowering actions of calcium supplementation are related primarily to suppression of renin secretion and secondarily to alteration of pressor response to norepinephrine in two-kidney, one clip renovascular hypertensive rats.

De novo intrarenal formation of angiotensin II during control and enhanced renin secretion.

In previous studies it has not been possible to determine net intrarenal formation of angiotensin II (ANG II) from arteriovenous ANG II concentrations because of the high intrarenal ANG II degradation rates (DR). This study was designed to determine ANG II-DR and to estimate net intrarenal ANG II formation during normal and enhanced renin secretion rate (RSR). In anesthetized dogs, plasma renin activity and ANG II were measured in arterial and renal venous blood by radioimmunoassay during four periods: control, renal arterial constriction (RAC), angiotensin converting enzyme (ACE) inhibition (MK 422), and MK 422 plus systemic arterial ANG II infusion. ANG II-DR was determined in each dog from the arterial-renal venous ANG II concentration difference during the period of ANG II infusion in the presence of ACE inhibition; this value was used to estimate net ANG II formation by predicting the amount of arterially delivered ANG II that escaped degradation. The average percent ANG II-DR calculated during ANG II infusion (range of 0.05 to 0.20 microgram/min) was 89 +/- 2%. In response to RAC, RSR increased from 11 +/- 3 to 24 +/- 5 ng ANG I X h-1 X min-1 X g-1. Arterial ANG II (67 +/- 11 pg/ml) and renal venous ANG II (29 +/- 6 pg/ml) increased to 133 +/- 18 and 61 +/- 10 pg/ml, respectively. Net intrarenal ANG II formation increased from 44 +/- 11 to 83 +/- 13 pg X min-1 X g-1 after renal arterial constriction. There was a significant relationship between the change in RSR and the change in ANG II formation rate.(ABSTRACT TRUNCATED AT 250 WORDS)

The area postrema in deoxycorticosterone-salt hypertension in rats.

Ablation of the area postrema in rats prevents sustained hypertension during angiotensin II infusion and after unilateral renal artery constriction (two-kidney, one clip hypertension). The current experiment was performed to determine whether an intact area postrema is required for hypertension development in a low renin model of experimental hypertension in rats. In 11 rats, the area postrema was destroyed using electrical current; the extent and specificity of each lesion was confirmed later by blind histological analysis. In 12 rats, sham operations were performed. All rats were uninephrectomized and drank saline. During once-weekly injections of deoxycorticosterone pivalate (5 mg/wk) for 4 weeks, sham-operated rats (n = 10) showed a significant increase in mean arterial pressure (Days 6-28) and saline intake (Days 12-28), but no significant increase in sodium or water retention. Deoxycorticosterone-treated rats with area postrema ablation (n = 9) exhibited no change in arterial pressure, sodium retention, or water retention, but a significant increase in saline intake (Days 17-28). Plasma renin activity was equally suppressed in both groups of rats. The depressor response to ganglion blockade with hexamethonium (20 mg/kg i.v.) was significantly increased during the 2nd, 3rd, and 4th weeks of steroid treatment in sham-operated, but not area postrema-ablated, rats. Four rats (2 sham-operated; 2 ablated) showed no change in any variable over 28 days in the absence of steroid treatment. It is concluded that the area postrema may be important in some non-angiotensin-dependent forms of experimental hypertension, possibly by affecting neurogenic control mechanisms.

Atrial natriuretic factor during development and reversal of one-kidney, one clip hypertension.

Atrial natriuretic factor (ANF) was studied in rat plasma and atria 1, 2, 4, 6, and 8 weeks after constriction of the left renal artery and removal of the contralateral kidney. Plasma ANF was elevated at all periods of investigation. A positive correlation was observed between plasma ANF and blood pressure (r = 0.56, p less than 0.001). The total atrial ANF content (microgram/atrium) in one-kidney, one clip (1K1C) rats was lower during Weeks 1 and 2, but only in the left atrium. Lower ANF concentrations (microgram/mg protein) were also evident in the left atrium at Weeks 1, 2, and 8, and in the right atrium at Week 8. A negative correlation between ANF in plasma and in the left atrium was discerned (r = 0.43, p less than 0.01). Blood pressure (184 +/- 4 vs 114 +/- 4 mm Hg), body weight, and plasma ANF were also examined in 1K1C rats and their normotensive controls before and after unclipping. Blood pressure was normalized 6 hours after unclipping. Plasma ANF declined in 1K1C rats within 6 hours after clip removal, but it was still higher than in the controls. Plasma ANF was similar in both groups on Days 9 and 13 after unclipping. There were no differences in atrial ANF between hypertensive and normotensive animals 13 days after unclipping. The high levels of plasma ANF observed in 1K1C rats probably are secondary to increased intra-atrial pressure caused by the dual mechanism of expanded plasma volume and high blood pressure.