Renal effects of atrial natriuretic factor during control of the renin-angiotensin system in anesthetized dogs

The contribution of the renin-angiotensin system to the natriuretic responses to intrarenal infusions of 1, 5, 25, and 125 pmol/kg/min synthetic rat atrial natriuretic peptide 101-126 was determined in one-kidney anesthetized dogs. In vehicle-treated dogs, atrial natriuretic peptide 101-126 increased fractional sodium excretion from 1.8 +/- 0.6% to a peak response of 5.1 +/- 0.9% during infusion of 25 pmol/kg/min. The peptide progressively decreased mean arterial pressure from 110 +/- 5 to 94 +/- 4 mm Hg, renal vascular resistance from 0.40 +/- 0.02 to 0.30 +/- 0.02 mm Hg/ml/min, and arterial plasma renin activity from 4.3 +/- 1.6 to 3.1 +/- 0.8 ng/ml/hr. When the renin-angiotensin system was blocked by 3 mg/kg i.v. enalaprilat, baseline pressure fell to 86 +/- 4 mm Hg, and subsequent infusions of atrial natriuretic peptide 101-126 did not affect fractional sodium excretion. The decreases in blood pressure (from 86 +/- 4 to 76 +/- 4 mm Hg) and in renal vascular resistance (from 0.27 +/- 0.03 to 0.23 +/- 0.02 mm Hg/ml/min) were also ameliorated compared with the control responses. Intravenous infusion of 2.5 ng/kg/min angiotensin II restored mean arterial pressure and potentiated the natriuretic and renal vascular responses to atrial natriuretic peptide 101-126. In two additional groups of anesthetized dogs, enalaprilat did not produce the profound hypotension and did not affect the natriuretic responses to atrial natriuretic peptide 101-126. When renal vascular resistance was elevated by intrarenal infusion of angiotensin II in enalaprilat-treated dogs, the natriuretic response was improved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic angiotensin II infusion decreases renal norepinephrine overflow in conscious dogs

Sympathetic nerve activity and in particular renal sympathetic nerve activity were monitored in six conscious dogs subjected to 6 days of intravenous angiotensin (ANG II) infusion (20 ng/kg/min). This was accomplished by measurement of both arterial and renal venous plasma catecholamine concentration. During the initial 4 hours of ANG II infusion, mean arterial pressure (MAP) increased 35 +/- 8 mm Hg from a control value of 101 +/- 4 mm Hg. Although there were no significant changes in arterial plasma norepinephrine (NE) concentration at this time (control = 148 +/- 40 pg/ml), arterial plasma epinephrine (E) concentration increased threefold (control 42 +/- 15 pg/ml). After 24 hours of ANG II infusion, MAP remained elevated (132 +/- 5 mm Hg), but plasma E concentration returned to control levels. From Days 2 through 6 of ANG II infusion, MAP was elevated approximately 40 mm Hg, but there were no chronic increases in either arterial plasma E or NE concentrations. In contrast to arterial plasma catecholamine concentration, renal vein plasma NE concentration (control = 216 +/- 27 pg/ml) actually decreased during both the acute (122 +/- 12 pg/ml) and chronic (103 +/- 26 pg/ml) phases of ANG II infusion. Moreover, renal NE overflow (renal venous plasma NE concentration-arterial plasma NE concentration X effective renal plasma flow), an index of renal sympathetic nerve activity, was depressed during the chronic phase of ANG II hypertension. These results, therefore, do not support the contention that the sympathetic nervous system mediates the hypertension produced by elevated plasma levels of ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressure natriuresis and control of arterial pressure during chronic norepinephrine infusion

The goal of this study was to quantitate changes in mean arterial pressure (MAP) and renal function during chronic increases in plasma levels of norepinephrine, and to determine the role of the renal pressure natriuresis mechanism in controlling sodium balance in norepinephrine hypertension. In six conscious dogs in which renal artery pressure (RAP) was allowed to increase during 7 days of norepinephrine infusion (0.2 micrograms/kg per min), sodium excretion (UNaV) rose from 66 +/- 3 to 112 +/- 15 mmol/day and MAP increased from 100 +/- 3 to 109 +/- 3 mmHg on the first day. On days 2-7, UNaV returned toward the control level while MAP averaged 108 +/- 2 mmHg. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) did not change significantly, averaging 85.9 +/- 4.0 and 235 +/- 17 ml/min, respectively, during 7 days of norepinephrine, compared to controls of 84.1 +/- 3.9 and 252 +/- 20 ml/min. When RAP was servo-controlled for 7 days during norepinephrine infusion, the natriuresis was abolished; UNaV averaged 76 +/- 8 during control, 77 +/- 13 during the first day of norepinephrine and 65 +/- 4 mmol/day during 7 days of norepinephrine. GFR and ERPF did not change significantly during norepinephrine infusion with RAP held constant. MAP did not reach a plateau but continued to rise from 102 +/- 3 to 137 +/- 3 mmHg after 7 days of norepinephrine and servo-control of RAP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic hypotensive effects of verapamil in angiotensin hypertension are steroid independent

This study was designed to examine the mechanisms that contribute to the chronic hypotensive effects of verapamil during angiotensin II-induced hypertension. Hypertension was induced in five dogs by continuous intravenous infusion of angiotensin II (5 ng/kg/min) for 17 days. On the sixth day of angiotensin II infusion when daily sodium balance was achieved, mean arterial pressure (control, 92 +/- 4 mm Hg), plasma aldosterone concentration (control, 5.2 +/- 0.9 ng/dl), and renal resistance (control, 0.28 +/- 0.01 mm Hg/ml/min) were increased 37 +/- 8 mm Hg, 13.6 +/- 5.0 ng/dl, and 0.20 +/- 0.05 mm Hg/ml/min, respectively. At this time there were no significant changes in glomerular filtration rate, effective renal plasma flow, net sodium and water balance, or extracellular fluid volume. Subsequently, when verapamil was infused (at 2 micrograms/kg/min) simultaneously with angiotensin II (days 7-13), there was a net loss of 55 +/- 10 meq sodium, a 7.0 +/- 0.7% fall in extracellular fluid volume, and approximately a 70% reduction in the chronic effects of angiotensin II on mean arterial pressure and renal resistance; in contrast, verapamil failed to attenuate the long-term aldosterone response to angiotensin II. Further, although glomerular filtration rate and effective renal plasma flow tended to increase during verapamil administration, there were no consistent chronic long-term changes in these renal indexes. In comparison with these responses in hypertensive dogs, when verapamil was infused for 7 days before the induction of angiotensin II hypertension, there were no significant changes in any measurements except mean arterial pressure, which fell 11 +/- 1 mm Hg. Thus, these data fail to support the hypothesis that the chronic stimulatory actions of angiotensin II on aldosterone secretion are dependent on a sustained increase in transmembranal calcium influx. Moreover, these data indicate that the pronounced long-term hypotensive effects of verapamil in angiotensin II hypertension are due to impairment of the direct renal actions of angiotensin II rather than the indirect sodium-retaining effects that are mediated via aldosterone secretion.     

Enhanced antinatriuresis in response to angiotensin II in essential hypertension

Angiotensin II regulates sodium homeostasis by modulating aldosterone secretion, renal vascular response, and tubular sodium reabsorption. We hypothesized that the antinatriuretic response to angiotensin II is enhanced in human essential hypertension. We therefore studied 48 white men with essential hypertension (defined by ambulatory blood pressure measurement) and 72 normotensive white control persons, and measured mean arterial pressure, sodium excretion, renal plasma flow, glomerular filtration rate, and aldosterone secretion in response to angiotensin II infusion (0.5 and 3.0 ng/kg/min). Hypertensive subjects exhibited a greater increase of mean arterial pressure (16.7+/-8.2 mm Hg v 13.4+/-7.1 mm Hg in normotensives, P < .05) and a greater decrease of renal plasma flow (-151.5+/-73.9 mL/ min v -112.6+/-68.0 mL/min in controls, P < .01) when 3.0 ng/kg/min angiotensin II was infused. The increase of glomerular filtration rate and serum aldosterone concentration was similar in both groups. Sodium excretion in response to 3.0 ng/kg/min angiotensin II was diminished in both groups (P < .01). However, the decrease in sodium excretion was more pronounced in hypertensives than in normotensives (-0.18+/-0.2 mmol/min v -0.09+/-0.2 mmol/min, P < .05), even if baseline mean arterial pressure and body mass index were taken into account (P < .05). We conclude that increased sodium retention in response to angiotensin II exists in subjects with essential hypertension, which is unrelated to changes in glomerular filtration rate and aldosterone concentration. Our data suggest a hyperresponsiveness to angiotensin II in essential hypertension that could lead to increased sodium retention.     

Polyuria, polydypsia, and hypertension produced by a six-day intravenous infusion of prostaglandin E1 in the conscious dog

The effects of a continuous intravenous infusion of prostaglandin E1 (PGE1) on mean arterial pressure (MAP), sodium and water balance, and plasma renin activity (PRA) were examined in 10 conscious dogs maintained on a 70 to 75 mEq/day sodium intake. In a crossover pattern, each dog received 6 days of intravenous PGE1 (0.1 micrograms/kg/min) and 6 days of intravenous diluent. When compared to diluent, intravenous PGE1 resulted in a mild sustained rise in MAP. By Day 6 the intravenous PGE1, MAP had increased from 98 +/- 4 to 112 +/- 5 mm Hg (mean +/- SE) (p less than 0.04). Concurrent with the MAP increase, PRA increased from 0.6 +/- 0.2 to 3.1 +/- 0.7 ng angiotensin I (AI)/ml/hr (p less than 0.03). To assess the role of the renin-angiotensin system in the maintenance of the systemic hypertension. AI converting-enzyme inhibitor was given to four dogs on Day 6 of both intravenous PGE1 and diluent. Only when the dogs were receiving PGE1 did the administration of converting-enzyme inhibitor result in a significant decrease in MAP (-19 +/- 5 mm Hg). In addition to increasing arterial pressure, the chronic infusion of PGE1 also produced changes in salt and water balance. When compared to diluent, PGE1 resulted in a twofold increase in both water intake and urine output, an increase in urinary sodium excretion (from 72 +/- 3 to 84 +/- 6 mEq/day, p less than 0.05, on Day 1), and a decrease in urine osmolality (from 942 +/- 82 to 586 +/- 61 mOsmol/kg H2O/day, p less than 0.05, on Day 1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of prolonged baroreflex activation on arterial pressure in angiotensin hypertension

Despite recent evidence indicating sustained activation of the baroreflex during chronic infusion of angiotensin II (Ang II), sinoaortic denervation does not exacerbate the severity of the hypertension. Therefore, to determine whether Ang II hypertension is relatively resistant to the blood pressure-lowering effects of the baroreflex, the carotid baroreflex was electrically activated bilaterally for 7 days in 5 dogs both in the presence and absence of a continuous infusion of Ang II (5 ng/kg per minute) producing high physiological plasma levels of the peptide. Under control conditions, basal values for mean arterial pressure (MAP) and plasma norepinephrine concentration (NE) were 93+/-1 mm Hg and 99+/-25 pg/mL, respectively. By day 7 of baroreflex activation, MAP and NE were reduced to 72+/-4 mm Hg (-21+/-3 mm Hg) and 56+/-15 pg/mL, respectively, but PRA was unchanged (control=0.41+/-0.06 ng ANG I/mL per hour). All values returned to basal levels by the end of a 7-day recovery period. After 7 days of Ang II infusion, MAP increased from 93+/-3 to 129+/-3 mm Hg, whereas NE fell from 117+/-15 to 86+/-23 pg/mL. During the next 7 days of baroreflex activation/Ang II infusion, further reductions in NE were not statistically significant, and on the final day of baroreflex activation, the reduction in MAP was only 5+/-1 mm Hg, compared with 21+/-3 mm Hg in the control normotensive state. These findings indicate that long-term baroreflex-mediated reductions in arterial pressure are markedly diminished, but not totally eliminated, in the presence of hypertension produced by chronic infusion of Ang II.     

Hemodynamic effects of amrinone in a canine model of massive pulmonary embolism.

Amrinone, an inotrope with vasodilating properties, is of potential use in managing the right ventricular failure and pulmonary vasoconstriction induced by massive pulmonary embolism (PE). Therefore, to determine the hemodynamic effects of amrinone in a canine model of massive PE, autologous blood clot was infused into ten dogs (eight treated and two control animals) in an amount sufficient to decrease mean systemic arterial pressure (MAP) by at least 25 percent. This resulted in an increase in mean pulmonary artery pressure (MPAP) from 13.4 +/- 3.7 mm Hg to 44.4 +/- 4.8 mm Hg (p less than 0.01), a decrease in MAP from 122 +/- 9.5 mm Hg to 35.6 +/- 9.8 mm Hg (p less than 0.01), and a decrease in cardiac output from 2.73 +/- 0.834 L/min to 1.22 +/- 0.61 L/min (p less than 0.01). Amrinone was administered in an initial bolus of 0.75 mg/kg followed by an infusion of 7.5 micrograms/kg/min, which resulted in significant hemodynamic improvement in all subjects, with a fall in MPAP to 35.3 +/- 5.1 mm Hg (p less than 0.01), an increase in MAP to 98.1 +/- 31.1 mm Hg (p less than 0.01), and an increase in cardiac output to 2.01 +/- 0.7 L/min (not significant) at 5 min. Cardiac output continued to increase to 2.56 +/- 0.16 L/min (p less than 0.01) at 35 min. We conclude that amrinone alleviated pulmonary hypertension, systemic hypotension, and low cardiac output in a canine model of massive PE.     

Effects of angiotensin inhibition and renal denervation in two-kidney, one clip hypertensive rats

Neural and angiotensin-mediated influences that alter hemodynamic and excretory behavior of the nonclipped kidney of two-kidney, one clip hypertensive rats were assessed by sequential acute surgical denervation of the nonclipped kidney and intravenous infusion of converting enzyme inhibitor (SQ 20881), 3 mg/kg X hr. Normal and two-kidney, one clip hypertensive rats (0.2-mm silver clip on the right renal artery 3-4 weeks before study) were prepared to allow study of each kidney. Mean arterial blood pressure of two-kidney, one clip hypertensive rats fell significantly from control values of 149 +/- 6 to 135 +/- 6 mm Hg after denervation of the nonclipped kidney. Despite this decrease in arterial pressure, the nonclipped kidney exhibited significant increases in glomerular filtration rate (from 1.00 +/- 0.08 to 1.24 +/- 0.08 ml/min), sodium excretion (from 88 +/- 39 to 777 +/- 207 nEq/min), fractional sodium excretion (from 0.06 +/- 0.02 to 0.54 +/- 0.14%), and urine flow rate (from 3.7 +/- 0.5 to 8.2 +/- 1.1 microliter/min). A significant decrease in glomerular filtration rate (from 1.12 +/- 0.07 to 0.85 +/- 0.08 ml/min) with no change in excretory function was observed for the clipped kidney following denervation of the nonclipped kidney. Intravenous addition of converting enzyme inhibitor significantly increased renal blood flow (from 7.0 +/- 1.3 to 10.6 +/- 1.5 ml/min) and sodium excretion (from 777 +/- 207 to 1384 +/- 425 nEq/min) for the nonclipped kidney; blood pressure decreased from 135 +/- 6 to 123 +/- 4 mm Hg, and renal vascular resistance decreased significantly (from 22 +/- 3 to 13 +/- 2 mm Hg X min/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal denervation decreases blood pressure in DOCA-treated miniature swine with established hypertension

The role of renal sympathetic nerve activity (RSNA) in the maintenance phase of essential hypertension has not yet been clearly defined. Renal function and mean arterial pressure (MAP) were studied in four Yucatan miniature swine (YMS) with established DOCA hypertension prior to and for 3 weeks after surgical renal denervation (RDX). During the first week post-RDX, MAP decreased from 141 /+- 6 to 121 +/- 3 mm Hg (P less than .05), while sodium balance increased from 0.32 +/- 0.05 to 0.95 +/- 0.14 mEq/kg/day (P less than .05). By 3 weeks post-RDX, MAP remained below normotensive levels while sodium balance returned to the pre-RDX value. There was no significant change in potassium or water balance after RDX. Thus, in DOCA-YMS the renal nerves are important in the maintenance of hypertension. The reduction in MAP with RDX in the absence of a natriuresis suggests a role for renal afferent nerve activity.     

Chronic hyperinsulinemia and blood pressure. Interaction with catecholamines?

Although hyperinsulinemia and increased adrenergic activity have been postulated to be important factors in obesity-associated hypertension, a cause and effect relation between insulin, catecholamines, and hypertension has not been established. The aim of this study was to determine whether chronic hyperinsulinemia, comparable with that found in obese hypertensive patients, causes hypertension in normal dogs, increases plasma catecholamines, or potentiates the blood pressure effects of norepinephrine. In six normal dogs, insulin infusion (1.0 milliunits/kg/min) for 7 days, with euglycemia maintained, increased fasting insulin fourfold to sixfold. However, mean arterial pressure did not increase, averaging 99 +/- 2 mm Hg during the control period and 91 +/- 3 mm Hg during the 7 days of insulin infusion. Insulin did not alter plasma norepinephrine or epinephrine, which averaged 171 +/- 27 and 71 +/- 14 pg/ml, respectively, during the control period and 188 +/- 29 and 45 +/- 12 pg/ml during the 7 days of insulin infusion. In six dogs, norepinephrine was infused (0.2 microgram/kg/min) for 7 days to raise plasma norepinephrine to 2,940 +/- 103 pg/ml. Insulin infusion (1.0 milliunits/kg/min) for 7 days during simultaneous infusion of norepinephrine did not further increase mean arterial pressure, which averaged 101 +/- 3 during norepinephrine and 98 +/- 2 mm Hg during insulin plus norepinephrine infusion. Thus, chronic hyperinsulinemia did not increase mean arterial pressure or plasma catecholamines and did not potentiate the blood pressure actions of norepinephrine. These observations provide no evidence that chronic hyperinsulinemia or interactions between insulin and plasma catecholamines cause hypertension in normal dogs.     

Renal function curve in patients with secondary forms of hypertension

The causative mechanisms of hypertension were investigated by studying the renal function (pressure-natriuresis) curve in patients with primary aldosteronism (n = 6) and renovascular hypertension (n = 6). Before and after radical operation (removal of adenoma in primary aldosteronism and percutaneous transluminal angioplasty in renovascular hypertension), dietary NaCl intake was altered from 10 to 13 g/day in Week 1 to 1 to 3 g/day in Week 2. Mean arterial pressure (MAP) and urinary sodium excretion were measured on the last 3 days of each week. By restricting sodium intake before operation, MAP was reduced from 122 +/- 7 to 113 +/- 7 mm Hg (p less than 0.025) in primary aldosteronism but not in renovascular hypertension (130 +/- 6 to 128 +/- 5 mm Hg). The renal function curve was drawn by plotting urinary sodium excretion on the ordinate and MAP on the abscissa before and after operation. The slope of the curve was analyzed between the plotted points, and each curve was extrapolated to zero sodium excretion as an estimate of the degree of shift of the curve along the MAP axis. Before, as compared with after operation, the extrapolated x-intercept of the curve was shifted rightward in both primary aldosteronism (111 +/- 7 vs 87 +/- 4 mm Hg; p less than 0.025) and renovascular hypertension (128 +/- 5 vs 95 +/- 2 mm Hg; p less than 0.025) and the slope was depressed in primary aldosteronism (16 +/- 1 vs 40 +/- 17 [mEq/day]/mm Hg; p less than 0.025) but not in renovascular hypertension (130 +/- 75 vs 40 +/- 13 [mEq/day]/mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of the blood pressure and renal hemodynamic effects of captopril

This study was designed to investigate the mechanisms of captopril's chronic effect on arterial pressure and renal function. In dogs maintained on high sodium intake (250 mEq/day), 6 days of captopril infusion caused no change in arterial pressure, renal hemodynamics, sodium excretion or plasma aldosterone concentration. Infusion of captopril for 7 days also caused no significant changes in arterial pressure or renal function in dogs made hypertensive by chronic infusion of angiotensin II and high sodium intake, a model of hypertension in which plasma renin activity is undetectable and prostaglandin and bradykinin formation may be elevated. In dogs maintained on low sodium intake, chronic infusion of captopril decreased arterial pressure and plasma aldosterone concentration markedly while increasing effective renal plasma flow. Infusion of aldosterone (200 μg/day) for 8 days during captopril infusion restored plasma aldosterone concentration but did not significantly change arterial pressure or renal function, indicating that decreased plasma aldosterone concentration did not play a major role in the hypotensive and renal effects of captopril. However, angiotensin II infusion (10 ng/kg/min) for 8 days during captopril infusion restored arterial pressure, plasma aldosterone concentration and renal function toward control levels. These data suggest that the effects of captopril on arterial pressure, renal hemodynamics and electrolyte excretion are mediated primarily by decreased angiotensin II formation.     

Preservation of renal function by angiotensin during chronic adrenergic stimulation

The purpose of the present study was to determine the role of angiotensin II (Ang II) in mediating renal responses to chronic intrarenal norepinephrine infusion. Norepinephrine was continuously infused for 5 days into the renal artery of unilaterally nephrectomized dogs at progressively higher daily infusion rates: 0.05, 0.10, 0.20, 0.30, and 0.40 micrograms/kg/min. In three additional groups of dogs, norepinephrine infusion was repeated during chronic intravenous captopril administration to fix plasma Ang II concentration at 1) low levels (no Ang II infused), 2) high levels in the renal circulation (Ang II infused intrarenally at a rate of 1 ng/kg/min), and 3) high levels in the systemic circulation (Ang II infused intravenously at a rate of 5 ng/kg/min). In the control group of animals with intact renin-angiotensin systems, there were progressive increments in mean arterial pressure (from 96 +/- 4 to 141 +/- 6 mm Hg) and plasma renin activity (from 0.4 +/- 0.1 to 10.9 +/- 4.5 ng angiotensin I/ml/hr) and concomitant reductions in glomerular filtration rate and renal plasma flow to approximately 40% of control during the 5-day norepinephrine infusion period. In marked contrast, when captopril was infused chronically without Ang II, mean arterial pressure was 20-25 mm Hg less than that under control conditions, and the renal hemodynamic effects of norepinephrine were greatly exaggerated; by day 3 of norepinephrine infusion, both glomerular filtration rate (16 +/- 2% of control) and renal plasma flow (12 +/- 4% of control) were considerably lower than values in control animals (86 +/- 4% and 80 +/- 8% of control, respectively). Similarly, when a high level of Ang II was localized in the renal circulation during captopril administration, mean arterial pressure was depressed, and again there were pronounced renal responses to norepinephrine. Conversely, when Ang II was infused intravenously during captopril administration, mean arterial pressure was not reduced, and the glomerular filtration rate and renal plasma flow responses to norepinephrine were similar to those that occurred under control conditions. These findings indicate that the renin-angiotensin system prevents exaggerated renal vascular responses to chronic norepinephrine stimulation by preserving renal perfusion pressure.     

Control of arterial pressure by angiotensin II and nitric oxide at the onset of diabetes

We have reported that the induction of diabetes in N(omega)-nitro-L-orginine methyl ester (L-NAME)-infused rats causes significant hypertension that is associated with increased plasma renin activity. This study tested the role of angiotensin II (Ang II) by clamping it chronically at baseline levels. The clamp consisted of an intravenous infusion of enalapril (10 mg/kg/d), which decreased mean arterial pressure (MAP) by approximately 20 mm Hg after 3 days, and adding chronic Ang II at 4 ng/kg/min, which restored MAP to normal. Chronic L-NAME infusion increased MAP to 127 +/- 1 and 132 +/- 2 mm Hg in normal and clamped rats, respectively, and induction of diabetes (streptozotocin) increased MAP progressively in normal rats to 161 +/- 8 mm Hg by day 12, whereas MAP in the clamped rats decreased progressively to 98 +/- 5 mm Hg by day 12. In non-L-NAME rats, MAP averaged 95 +/- 1 and 91 +/- 1 mm Hg for normal and clamped groups, respectively, before diabetes, and MAP was 10 to 13 mm Hg lower in the clamped versus normal rats midway through the diabetic period. This suggests that Ang II is important for maintaining blood pressure at the onset of diabetes, possibly to compensate for renal volume losses. Angiotensin II also is required for the hypertension caused by induction of diabetes in rats with chronic blockade of nitric oxide synthesis, but whether this is due to increased volume sensitivity in L-NAME-treated, vasoconstricted rats remains to be determined.     

Cationic amino acid transport in the renal medulla and blood pressure regulation

Previous studies have indicated that NO synthesis in isolated inner medullary collecting duct cells is reduced by cationic amino acids that compete with L-arginine for cellular uptake. In the present study, we investigated the effects of chronic renal medullary infusion of cationic amino acids on renal NO concentration and mean arterial pressure (MAP) in Sprague-Dawley rats. Renal medullary infusion of L-ornithine (50 microg/kg per min) or L-lysine (50 microg/kg per min) markedly decreased NO in the medulla (vehicle, 124 +/- 11 nmol/L; L-ornithine, 45 +/- 4 nmol/L; L-lysine, 42 +/- 6 nmol/L) and increased MAP (vehicle, 111 +/- 7 mm Hg; L-ornithine, 143 +/- 6 mm Hg; L-lysine, 148 +/- 3 mm Hg) after 5 days of infusion. In contrast, intravenous infusion of the same dose of L-ornithine or L-lysine for 5 days increased plasma concentration to levels similar to those observed with intramedullary infusion but did not change NO in the medulla or alter MAP. Furthermore, the NO-suppressing and hypertensive effects of medullary interstitial infusion of L-ornithine (50 microg/kg per min) were attenuated by simultaneous infusion of L-arginine (500 microg/kg per min; NO, 97 +/- 10 nmol/L; MAP, 124 +/- 3 mm Hg). A 5-day infusion of an antisense oligonucleotide against CAT-1 (18-mer, 8.3 nmol/h) significantly decreased CAT-1 protein in the medulla, decreased NO in the medulla (scrambled oligo, 124 +/- 10 nmol/L; antisense oligo, 67 +/- 11 nmol/L), and increased MAP (scrambled oligo, 113 +/- 2 mm Hg; antisense oligo, 130 +/- 2 mm Hg). These results suggest that uptake of L-arginine by cationic amino acid transport systems in the renal medulla plays an important role in the regulation of medullary NO and MAP in rats.     

Thromboxane mediation of the pressor response to infused angiotensin II

The role of thromboxane A2(Tx) in mediating the pressor response to angiotensin II (AII) was studied in anesthetized rats. Intravenous AII (500 ng/kg/min) increased mean arterial pressure (MAP) by 35 +/- 3 mm Hg and increased the excretion of prostaglandin PGE2, the metabolites of prostacyclin (6kPGF1 alpha) and Tx (TxB2) (P less than .05). A similar pressor infusion of the alpha 1-adrenoreceptor agonist phenylephrine (PE) increased the excretion of PGE2 and 6kPGF1 alpha but not TxB2. The increases in MAP and prostaglandin excretion produced by AII were reversed by the AII-receptor antagonist saralasin (10 micrograms/kg/min) while those produced by PE were reversed by the alpha-adrenoreceptor antagonist phenoxybenzamine (250 micrograms/kg). The Tx receptor antagonist, SQ-29,548 (8 mg/kg) attenuated (P less than .0001) the AII-induced rise in MAP (13 +/- 1 mm Hg) but did not modify the pressor response to PE. The Tx synthetase inhibitor, UK-38,485 (50 mg/kg/d) given for 3 days, reduced basal TxB2 excretion by 75% and also attenuated (P less than .001) the AII-induced rise in MAP (11 +/- 2 mm Hg). However, when given 40 min before the AII infusion, UK-38,485 did not attenuate the pressor response. In separate groups of rats, the log dose-response curve for bolus intravenous injection of AII was shifted to the right by SQ-29,548 while that for PE was unaffected. In conclusion: 1) AII releases Tx; 2) Tx release is not secondary to hypertension; and 3) Tx can mediate up to two-thirds of the short-term pressor response to high-dose AII infusion.     

A comparison of synthetic rat and human atrial natriuretic factor in conscious dogs

The renal and hypotensive responses to intravenous infusions of 10, 50, 100, and 200 pmol/kg/min of synthetic rat atrial natriuretic factor (Arg101-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile110-Asp-Arg-Ile-G ly-Ala-Gln-Ser-Gly -Leu-Gly120-Cys-Asn-Ser-Phe-Arg-Tyr; disulfide bond between cysteines) were compared with those produced by synthetic human atrial natriuretic factor (Met110) in five conscious dogs. Increasing doses of rat or human atrial natriuretic factor lowered mean arterial pressure in a dose-related manner. At 200 pmol/kg/min, the maximally effective dose for both peptides, mean arterial pressure was reduced from 116 +/- 4 to 96 +/- 5 mm Hg and from 117 +/- 5 to 100 +/- 3 mm Hg (p less than 0.01), respectively. Neither peptide affected heart rate. Fractional sodium excretion increased from 0.69 +/- 0.22 to 3.95 +/- 1.23% and from 0.69 +/- 0.16 to 4.62 +/- 0.72% during infusions of 200 pmol/kg/min of rat and human atrial natriuretic factor, respectively. Urine volume and fractional chloride excretion rose during infusions of rat or human atrial natriuretic factor in a manner that resembled the elevation in sodium excretion. The stimulation of fractional potassium excretion by both rat and human peptides was more variable and not as clearly dose-dependent. Glomerular filtration rate was enhanced by both rat and human atrial natriuretic factor, while neither peptide significantly changed renal plasma flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Levels of renal and extrarenal sympathetic drive in angiotensin II-induced hypertension

We examined the contribution of the renal nerves to mean arterial pressure (MAP) during 5-week chronic infusion of angiotensin II (Ang II; 50 ng/kg per minute SC) in conscious rabbits. Basal MAP was 68+/-1 mm Hg, and the maximum depressor response to ganglion blockade was -20+/-2 mm Hg. MAP increased by 25+/-2 mm Hg after 1 week and remained stable over the next 4 weeks. Depressor responses to pentolinium (6 mg/kg IV) were similar to control during the first week of hypertension but thereafter became increasingly greater in Ang II-treated rabbits but not vehicle-treated rabbits. After 5 weeks, the fall in MAP was 54% greater in Ang II- than in vehicle-treated rabbits (-34+/-2 versus -22+/-2 mm Hg), but renal sympathetic nerve activity was similar in both groups. Renal denervation produced a small fall in MAP in all of the vehicle-treated rabbits after 4 days (-6+/-2 mm Hg; P=0.01), but there was no consistent effect in hypertensive rabbits. The depressor response to ganglion blockade was enhanced in vehicle-treated but not Ang II-treated rabbits. The finding that renal sympathetic nerve activity is not altered by Ang II hypertension nor is the hypertension altered by renal denervation suggests that renal sympathetic nerves do not contribute to the hypertension. The greater depressor effect of acute ganglion blockade in hypertensive rabbits suggests that the sympathetic nervous system exerts increased vasoconstriction in the peripheral vasculature in Ang II-induced hypertension.     

Pressure natriuresis in rats during blockade of the L-arginine/nitric oxide pathway.

The natriuretic response was studied in anesthetized rats during the intravenous infusion of L-arginine analogues to inhibit the production of endothelium-derived nitric oxide. In an initial experimental series, rats were administered saline vehicle or vehicle containing 300 mumol/kg body wt N omega-monomethyl-L-arginine, N omega-nitro-L-arginine methyl ester, N omega-monomethyl-D-arginine, or L-arginine. Infusion of the competitive inhibitors N omega-monomethyl-L-arginine and N omega-nitro-L-arginine methyl ester significantly increased mean arterial pressure to 155 +/- 3 and 145 +/- 5 mm Hg, respectively, compared with a mean arterial pressure of 118 +/- 3 mm Hg determined in the vehicle control group. Sodium excretion averaged 3.27 +/- 1.08 and 2.52 +/- 0.78 mu eq/min in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated rats, respectively, and each was significantly higher than the basal sodium excretion of 0.20 +/- 0.05 mu eq/min in the vehicle-treated control animals. Plasma renin activity was significantly lower in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated groups than in the vehicle-treated group. Neither L-arginine nor N omega-monomethyl-D-arginine administration significantly altered any of the measured variables compared with vehicle alone. In a second experimental series, an adjustable snare was placed around the suprarenal aorta for the purpose of controlling renal perfusion pressure independently of increases in the systemic mean arterial pressure initiated by infusion of N omega-nitro-L-arginine methyl ester (75 mumol/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)