Prolonged activation of the baroreflex abolishes obesity-induced hypertension

Prolonged electrical activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure in normotensive dogs. The main goal of this study was to assess the influence of prolonged baroreflex activation on arterial pressure and neurohormonal responses in 6 dogs with obesity-induced hypertension. After control measurements, the diet was supplemented with cooked beef fat for 6 weeks, whereas sodium intake was held constant. After 4 weeks of the high-fat diet, there were increments in body weight from 25.8+/-0.7 to 38.6+/-1.0 kg, mean arterial pressure from 97+/-2 to 110+/-3 mm Hg, heart rate from 67+/-3 to 91+/-4 bpm, and plasma norepinephrine concentration from 141+/-35 to 280+/-52 pg/mL. Plasma glucose and insulin concentrations were elevated, but increases in plasma renin activity during the initial weeks of the high-fat diet were not sustained. During week 5, baroreflex activation resulted in sustained reductions in mean arterial pressure, heart rate, and plasma norepinephrine concentration; at the end of week 5, these values were 87+/-2 mm Hg, 77+/-4 bpm, and 166+/-45 pg/mL, respectively. These suppressed values returned to week 4 levels during a 7-day recovery period after baroreflex activation. There were no changes in plasma glucose or insulin concentrations, or plasma renin activity during prolonged baroreflex activation. These findings indicate that baroreflex activation can chronically suppress the sympathoexcitation associated with obesity and abolish the attendant hypertension while having no effect on hyperinsulinemia or hyperglycemia.     

Prolonged activation of the baroreflex produces sustained hypotension

The role of baroreflexes in long-term control of arterial pressure is unresolved. To determine whether chronic activation of the baroreflex produces sustained hypotension, we developed a method for prolonged activation of the carotid baroreflex in conscious dogs. This was achieved by chronically implanting electrodes around both carotid sinuses and using an externally adjustable pulse generator to electrically activate the carotid baroreflex. Control values for mean arterial pressure (MAP) and heart rate were 93+/-3 mm Hg and 64+/-4 bpm, respectively. After control measurements, the carotid baroreflex was activated bilaterally for 7 days at a level that produced a prompt and substantial reduction in MAP, and for day 1 MAP was reduced to 75+/-4 mm Hg. Moreover, this hypotensive response was sustained throughout the entire 7 days of baroreflex activation (day 7, MAP=72+/-5 mm Hg). During prolonged baroreflex activation, heart rate decreased in parallel with MAP, although the changes were not as pronounced (day 7, heart rate=51+/-3 bpm). Prolonged baroreflex activation was also associated with approximately 35% reduction in plasma norepinephrine concentration (control=87+/-15 pg/mL). After baroreflex activation, hemodynamic measures and plasma levels of norepinephrine returned to control levels. Interestingly, despite the pronounced fall in MAP, plasma renin activity did not increase during prolonged baroreflex activation. These data indicate that prolonged baroreflex activation can lead to substantial reductions in MAP by suppressing the sympathetic nervous system. Furthermore, sustained sympathoinhibitory effects on renin secretion may play an important role in mediating the long-term hypotensive response.     

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.     

Systemic and renal-specific sympathoinhibition in obesity hypertension

Chronic pressure-mediated baroreflex activation suppresses renal sympathetic nerve activity. Recent observations indicate that chronic electric activation of the carotid baroreflex produces sustained reductions in global sympathetic activity and arterial pressure. Thus, we investigated the effects of global and renal specific suppression of sympathetic activity in dogs with sympathetically mediated, obesity-induced hypertension by comparing the cardiovascular, renal, and neurohormonal responses to chronic baroreflex activation and bilateral surgical renal denervation. After control measurements, the diet was supplemented with beef fat, whereas sodium intake was held constant. After 4 weeks on the high-fat diet, when body weight had increased ≈50%, fat intake was reduced to a level that maintained this body weight. This weight increase was associated with an increase in mean arterial pressure from 100±2 to 117±3 mm Hg and heart rate from 86±3 to 130±4 bpm. The hypertension was associated with a marked increase in cumulative sodium balance despite an approximately 35% increase in glomerular filtration rate. The importance of increased tubular reabsorption to sodium retention was further reflected by ≈35% decrease in fractional sodium excretion. Subsequently, both chronic baroreflex activation (7 days) and renal denervation decreased plasma renin activity and abolished the hypertension. However, baroreflex activation also suppressed systemic sympathetic activity and tachycardia and reduced glomerular hyperfiltration while increasing fractional sodium excretion. In contrast, glomerular filtration rate increased further after renal denervation. Thus, by improving autonomic control of cardiac function and diminishing glomerular hyperfiltration, suppression of global sympathetic activity by baroreflex activation may have beneficial effects in obesity beyond simply attenuating hypertension.     

Renal responses to chronic suppression of central sympathetic outflow

Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated as hypertension therapy for patients with resistant hypertension. However, the chronic changes in renal function associated with natural suppression of sympathetic activity are largely unknown. In normotensive dogs, we investigated the integrative cardiovascular effects of chronic baroreflex activation (2 weeks) alone and in combination with the calcium channel blocker amlodipine, which is commonly used in the treatment of resistant hypertension. During baroreflex activation alone, there were sustained decreases in mean arterial pressure (17±1 mmHg) and plasma (norepinephrine; ≈35%), with no change in plasma renin activity. Despite low pressure, sodium balance was achieved because of decreased tubular reabsorption, because glomerular filtration rate and renal blood flow decreased 10% to 20%. After 2 weeks of amlodipine, arterial pressure was also reduced 17 mmHg, but with substantial increases in norepinephrine and plasma renin activity and no change in glomerular filtration rate. In the presence of amlodipine, baroreflex activation greatly attenuated neurohormonal activation, and pressure decreased even further (by 11±2 mmHg). Moreover, during amlodipine administration, the fall in glomerular filtration rate with baroreflex activation was abolished. These findings suggest that the chronic blood pressure-lowering effects of baroreflex activation are attributed, at least in part, to sustained inhibition of renal sympathetic nerve activity and attendant decreases in sodium reabsorption before the macula densa. Tubuloglomerular feedback constriction of the afferent arterioles may account for reduced glomerular filtration rate, a response abolished by amlodipine, which dilates the preglomerular vasculature.     

Captopril modifies the hemodynamic and neuroendocrine responses to sodium nitroprusside in hypertensive patients

To determine if clinically effective doses of the antihypertensive agent captopril affected the neuronal release of norepinephrine or baroreflex sensitivity, changes in plasma norepinephrine concentration and heart rate were related to the changes in mean arterial pressure seen during the intravenous infusion of stepwise incremental doses of sodium nitroprusside before and during captopril treatment in eight hypertensive men with normal or low plasma renin activity. At all times, significant linear correlations were found between the decrease in mean arterial pressure and the dose of sodium nitroprusside, the increase in heart rate and the decrease in mean arterial pressure, and the increase in plasma norepinephrine concentration and the decrease in mean arterial pressure. When the subjects were treated with captopril (25 mg t.i.d.) for 2 to 4 weeks, supine mean arterial pressure decreased from 130 to 114 mm Hg (-12%; p less than 0.05), heart rate did not change, supine and upright plasma renin activity increased, while supine plasma norepinephrine and epinephrine concentration decreased slightly. Therapy with captopril (25 mg t.i.d.) increased baroreflex sensitivity, as assessed by the slope of the regression line relating the increase in heart rate to the decrease in mean arterial pressure, and increased the responsiveness of the sympathetic nervous system, as assessed by the slope of the regression line relating the increase in plasma norepinephrine concentration to the decrease in mean arterial pressure. These increases were accompanied by a decrease in the slope of the regression line relating the decrease in mean arterial pressure to the dose of sodium nitroprusside and thus were associated with a decreased sensitivity to the vasodepressor effects of sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired cardiopulmonary baroreflex control of renal nerves in renal hypertension

We recently reported that arterial baroreflex control of renal nerve traffic is impaired in renal hypertensive rabbits. The purpose of this study was to determine if vagal cardiopulmonary baroreflex control of renal nerve traffic is also impaired. Experiments were performed in 10 hypertensive (mean arterial pressure +/- SE in conscious state, 110 +/- 3 mm Hg) and 10 normotensive (79 +/- 1 mm Hg) chloralose-anesthetized rabbits. Responses to graded blood volume expansion (+5, +10, +15 ml/kg) with dextran in saline were recorded with all baroreflexes intact, after sinoaortic baroreceptor denervation, and after vagotomy. With arterial and cardiopulmonary baroreflexes intact, volume expansion resulted in decreases in renal nerve traffic of -12 +/- 2%/mm Hg increase in left atrial pressure in normotensive rabbits, but of only -5 +/- 2%/mm Hg in the hypertensive rabbits (P less than 0.05). This difference is particularly striking in view of the larger maximum increases in arterial (25 +/- 7 vs. 12 +/- 3 mm Hg) and left atrial pressure (9 +/- 1 vs. 6 +/- 1 mm Hg) during volume expansion in hypertensive vs. normotensive rabbits. After sinoaortic baroreceptor denervation, the responses of normotensive rabbits were preserved (-11 +/- 3%/mm Hg), while those of hypertensive rabbits were impaired further (-2 +/- 1%/mm Hg). Vagotomy abolished responses of renal nerves to volume expansion in both groups. These data demonstrate striking impairment of vagal cardiopulmonary baroreflex control of renal nerve traffic in renal hypertension. Even though arterial baroreflexes have been shown to be abnormal in renal hypertension, they still may partially compensate for markedly impaired cardiopulmonary baroreflex control of the renal nerves.     

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.     

Neurohumoral and hemodynamic effects of lower body negative pressure in patients with congestive heart failure

Baroreflex modulation of forearm vascular resistance (FVR) has been reported to be abnormal in patients with congestive heart failure (CHF). However, the neurohumoral mechanisms for this impairment are not defined. We assessed the responses of arterial pressure, FVR, plasma norepinephrine, and plasma renin activity to lower body negative pressure in 29 patients with compensated CHF (New York Heart Association class III and IV) and in 11 normal age-matched control subjects. Baseline mean arterial pressure (83 +/- 2 vs 84 +/- 2 mm Hg) and mean arterial pressure during LBNP (-10, -20, and -40 mm Hg) were not significantly different in the two groups. Basal FVR (43.7 +/- 4 vs 27 +/- 2 units), plasma norepinephrine (605 +/- 81 vs 155 +/- 8 pg/ml), and plasma renin activity (8.3 +/- 1.7 vs 1.2 +/- 0.2 ng/ml/hr) were significantly (p less than 0.01) higher in patients with CHF. The relative increases in FVR responses during LBNP of -10, -20, and -40 mm Hg (10 +/- 4% vs 70 +/- 12%, 17 +/- 6% vs 106 +/- 21%, and 24 +/- 9% vs 152 +/- 28%) were markedly attenuated in patients with CHF compared to control subjects. Plasma norepinephrine and plasma renin activity responses during LBNP were also attenuated in patients with heart failure. Our results suggest that baroreflex control of FVR and plasma norepinephrine and plasma renin activity is impaired in CHF because of the inability of the cardiopulmonary baroreceptors to alter sympathetic outflow.     

Direct versus indirect pressor and vasoconstrictor actions of angiotensin in conscious dogs

To determine the importance of the direct and the indirect pressor and vasoconstrictor actions of angiotensin II (ANG II), experiments were conducted in conscious dogs 2 to 8 weeks after instrumentation with aortic catheters and aortic electromagnetic flow probes to measure arterial pressure and cardiac output. Total peripheral resistance was calculated by an on-line digital computer. Pretreatment with propranolol eliminated complicating inotropic effects of norepinephrine, released by the indirect actions of ANG II. The pressor and vasoconstrictor responses after ganglionic blockade, in either the presence or absence of arterial baroreceptor nerves, were considered to be the direct effects of ANG II. In conscious dogs, systemically administered ANG II (32 ng/kg bolus) increased mean arterial pressure by 38 +/- 3 mm Hg, total peripheral resistance by 37 +/- 2 mm Hg/L/minute, and decreased heart rate by 15 +/- 2 beats/minute. After arterial baroreceptor denervation, administration of ANG II increased mean arterial pressure by 88 +/- 7 mm Hg, total peripheral resistance by 54 +/- 4 mm Hg/L/minute, and heart rate by 12 +/- 2 beats/minute. After arterial baroreceptor denervation and ganglionic blockade with hexamethonium, administration of ANG II increased mean arterial pressure by 53 +/- 8 mm Hg, total peripheral resistance by 27 +/- 3 mm Hg/L/minute, and left heart rate unchanged. These results indicate that in the conscious dog without baroreflex buffering nearly one-half of the pressor and vasoconstrictor actions of angiotensin are not direct, but are mediated by the autonomic nervous system.     

Control of arterial pressure and renal function during chronic renin inhibition

The aim of this study was to determine whether the renin inhibitor CP-71362 (Pfizer Central Research, Groton, Connecticut, USA) is capable of inducing sustained reductions in arterial pressure in sodium-depleted dogs and to examine the changes in renal function associated with chronic renin inhibition. In addition, we also examined the chronic effects on renal function and blood pressure of the angiotensin converting enzyme (ACE) inhibitor enalaprilat. Infusion of CP-71362 (1.1 micrograms/kg per min, intravenously) for 7 days decreased mean arterial pressure from 87 +/- 3 to 75 +/- 2 mmHg, while causing no significant changes in sodium excretion, the glomerular filtration rate, or effective renal plasma flow. Plasma renin activity was suppressed to undetectable levels throughout the 7 days of CP-71362 infusion. Infusion of enalaprilat (4 mg/kg per day) for 7 days in sodium-depleted dogs decreased mean arterial pressure (from 85 +/- 2 to 64 +/- 3 mmHg) and renal vascular resistance, and increased effective renal plasma flow and sodium excretion, but caused no significant changes in the glomerular filtration rate. Thus CP-71362 is a potent inhibitor of dog plasma renin, and we observed no waning of this inhibitory effect of CP-71362's hypotensive actions over 7 days. The mechanisms responsible for the differences in the blood pressure and renal responses to CP-71362 and ACE inhibition are not clear, but may be dose-related or due to differences in the distribution of these compounds to various tissues, including the kidney.     

Role of the renal nerves in one-kidney, one clip hypertension in rats

The effects of renal denervation on the onset and maintenance of one-kidney, one clip Goldblatt (1K1C) hypertension were determined. Renal denervation was performed at the time of 1K1C surgery, and was repeated at 3-week intervals to prevent renal nerve regeneration. Denervation delayed the onset of 1K1C hypertension by about 5 weeks, but the final hypertensive state was unaltered. Mean arterial pressure (MAP) averaged 196 +/- 11.4 mm Hg in six rats at 9 weeks after 1K1C surgery and 194 +/- 11.3 mm Hg in eight renal-denervated rats at this time. The delay in the development of 1K1C hypertension following renal denervation could not be explained by interference with renin release. This delay in the development of hypertension could be prevented, however, in renal-denervated 1K1C rats by substituting saline for the drinking water. Two weeks after 1K1C surgery and a high sodium diet, MAP averaged 164 +/- 6.4 mm Hg in eight rats rats with intact renal nerves and 173 +/- 4.8 mm Hg in nine renal-denervated rats. Intact renal nerves are not necessary for the development or maintenance of 1K1C hypertension. Renal denervation delays development of 1K1C hypertension, possibly by delaying the ability of these rats to retain sodium.     

Effects of hydrochlorothiazide and diltiazem on reflex vasoconstriction in hypertension

The purpose of our study was to determine the effects of treatment with hydrochlorothiazide (n = 10) or diltiazem (n = 8) on reflex humoral, hemodynamic, and vascular responses to graded lower body negative pressure in subjects with mild to moderate hypertension (supine diastolic pressure, 95-114 mm Hg). All subjects received placebo for 2 to 4 weeks followed by either hydrochlorothiazide (25-50 mg b.i.d.) or diltiazem (120-180 mg b.i.d.) to achieve a reduction in supine diastolic pressure of 10 mm Hg or more and a final pressure below 90 mm Hg. Mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and renin responses to graded lower body negative pressure (-10, -20, -40 mm Hg) and head-up tilt were examined before and after 12 weeks of treatment with either drug. Pretreatment basal values of mean arterial pressure (114 +/- 2 vs 117 +/- 2 mm Hg), forearm vascular resistance (29 +/- 3 vs 35 +/- 7 units), and plasma renin activity (0.7 +/- 0.2 vs 0.6 +/- 0.2 ng angiotensin I/ml/hr) were not significantly different between groups. There were no significant differences in basal plasma norepinephrine or in the increases of norepinephrine in response to lower body negative pressure before and after treatment in either group. Forearm vascular resistance responses to lower body negative pressure were virtually abolished in the diltiazem-treated group but not in the hydrochlorothiazide-treated group despite similar levels of mean arterial pressure and basal forearm vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of arterial baroreceptor denervation on sodium balance

During chronic increased dietary sodium intake, arterial baroreceptors buffer against sustained increases in arterial pressure, and renal sympathoinhibition contributes importantly to the maintenance of sodium balance by decreasing renal tubular sodium reabsorption and increasing urinary sodium excretion. The present study examined the effect of arterial baroreceptor denervation on sodium balance in conscious rats during low, normal, and high dietary sodium intake. Compared with measurements made before arterial baroreceptor denervation, arterial baroreceptor-denervated rats had similar sodium balance during normal dietary sodium intake but significantly more negative sodium balance during low dietary sodium intake and significantly more positive sodium balance during high dietary sodium intake. At the end of the high dietary sodium intake period, arterial pressure (under anesthesia) was 159+/-5 mm Hg after arterial baroreceptor denervation and 115+/-1 mm Hg before arterial baroreceptor denervation. Sham arterial baroreceptor denervation in time control rats had no effect on sodium balance or arterial pressure during the different dietary sodium intakes. These studies indicate that (1) arterial baroreceptor denervation impairs the ability to establish sodium balance during both low and high dietary sodium intake, and (2) arterial baroreceptor denervation leads to the development of increased arterial pressure during high dietary sodium intake in association with increased renal sodium retention.     

Effects of renal medullary and intravenous norepinephrine on renal antihypertensive function

Increasing renal arterial pressure activates at least 3 antihypertensive mechanisms: reduced renin release, pressure natriuresis, and release of a putative renal medullary depressor hormone. To examine the role of renal medullary perfusion in these mechanisms, we tested the effects of the infusion of norepinephrine, either infusion into the renal medullary interstitium or intravenous infusion, on responses to increased renal arterial pressure in pentobarbital-anesthetized rabbits. We used an extracorporeal circuit, which allows renal arterial pressure to be set to any level above or below systemic arterial pressure. With renal arterial pressure initially set at 65 mm Hg, intravenous and medullary interstitial norepinephrine (300 ng. kg(-1). min(-1)) similarly increased mean arterial pressure (by 12% to 17% of baseline) and reduced total renal blood flow (by 16% to 17%) and cortical perfusion (by 13% to 19%), but only medullary norepinephrine reduced medullary perfusion (by 28%). When renal arterial pressure was increased to approximately 160 mm Hg, in steps of approximately 65 mm Hg, urine output and sodium excretion increased exponentially, and plasma renin activity and mean arterial pressure fell. Medullary interstitial but not intravenous norepinephrine attenuated the increased diuresis and natriuresis and the depressor response to increased renal arterial pressure. This suggests that norepinephrine can act within the renal medulla to inhibit these renal antihypertensive mechanisms, perhaps by reducing medullary perfusion. These observations support the concept that medullary perfusion plays a critical role in the long-term control of arterial pressure by its influence on pressure diuresis/natriuresis mechanisms and also by affecting the release of the putative renal medullary depressor hormone.     

Renal denervation abolishes hypertension in low-birth-weight offspring from pregnant rats with reduced uterine perfusion

Low birth weight is a risk factor for the subsequent development of hypertension in humans. We previously reported that reduced uterine perfusion in the pregnant rat results in growth-restricted offspring predisposed to the development of hypertension. The purpose of this study was to determine whether the sympathetic nervous system plays a role in mediating hypertension in this model of low birth weight. Weight at birth was significantly decreased in male growth-restricted offspring (5.9+/-0.1 grams) as compared with male control offspring (6.5+/-0.2 grams; P<0.05). At 10 weeks of age, growth-restricted offspring and control offspring were randomly assigned to either an intact group (sham-denervated) or a group subjected to bilateral renal denervation. For sham-denervated offspring, mean arterial pressure was significantly elevated in growth-restricted offspring (145+/-4 mm Hg; n=7) as compared with control offspring (134+/-3 mm Hg; P<0.05; n=9) at 12 weeks of age. Bilateral renal denervation resulted in a marked reduction in arterial pressure in growth-restricted offspring (125+/-3 mm Hg; P<0.01; difference of 20 mm Hg versus sham growth-restricted; n=8) but no significant decrease in control offspring (127+/-3 mm Hg; difference of 7 mm Hg versus sham control; n=9). Adequacy of renal denervation was verified by >90% reduction in renal norepinephrine content. Therefore, these findings indicate the renal nerves play an important role in mediating hypertension in adult growth-restricted offspring.     

Effect of hypoxemia on sodium and water excretion in chronic obstructive lung disease

To determine the role of hypoxemia in the pathogenesis of impaired sodium and water excretion in advanced chronic obstructive lung disease, 11 clinically stable, hypercapneic patients requiring long-term supplemental oxygen were studied. The renal, hormonal, and cardiovascular responses to sodium and water loading were determined during five-and-a-half-hour studies on a control day (arterial oxygen tension = 80 +/- 6 mm Hg) and on an experimental day under hypoxic conditions (arterial oxygen tension = 39 +/- 2 mm Hg). Hypoxemia produced a significant decrease in urinary sodium excretion but did not affect urinary water excretion. Hypoxemia also resulted in concomitant declines in mean blood pressure, glomerular filtration rate, and filtered sodium load. Renal plasma flow and filtration fraction were unchanged whereas cardiac index rose. On the control day, plasma renin activity and norepinephrine levels were elevated whereas aldosterone and arginine vasopressin levels were normal; none of these four hormones was affected by hypoxemia. Renal tubular function did not appear to be altered by hypoxemia as there was no significant change in fractional reabsorption of sodium. The concurrent decreases in glomerular filtration rate, filtered sodium load, and mean blood pressure at constant renal plasma flow suggest that the reduction in urinary sodium excretion was due to an effect of hypoxemia on glomerular function, possibly related to impaired renovascular autoregulation.     

Synergistic effects of acute hypoxemia and hypercapnic acidosis in conscious dogs. Renal dysfunction and activation of the renin-angiotensin system

The effects of acute hypoxemia and hypercapnic acidosis were examined in five unanesthetized dogs in which sodium intake was controlled at 80 mEq/24 hours for 4 days prior to study. Each animal was studied during combined acute hypoxemia and hypercapnic acidosis (Pao2 = 36 +/- 1 mm Hg, Paco2 = 52 +/- 1 mm Hg, pH = 7.18 +/- 0.02), acute hypoxemia alone (Pao2 = 32 +/- 1 mm Hg, Paco2 = 32 +/- 1mm Hg, pH = 7.34 +/- 0.01), and acute hypercapnic acidosis alone (Pao2 = 82 +/- 2 mm Hg, Paco2 = 51 +/- 1 mm Hg, pH = 7.18 +/- 0.02). Although mean arterial pressure, cardiac output, and heart rate increased during combined hypoxemia and hypercapnic acidosis, effective renal plasma flow and glomerular filtration rate decreased. In addition, filtered sodium load and urinary sodium excretion decreased during combined hypoxemia and hypercapnic acidosis. Either acute hypoxemia or hypercapnic acidosis alone resulted in increased mean arterial pressure, cardiac output, and heart rate. However, in contrast to their combined effects, renal hemodynamic function was unchanged and natriuresis was observed. Measurement of plasma renin activity and angiotensin II concentrations indicated that hypoxemia or hypercapnic acidosis alone resulted in moderate activation of the renin-angiotensin system. Moreover, combined hypoxemia and hypercapnic acidosis acted synergistically resulting in major renin-angiotensin activation. Systemic angiotensin II blockade using 1-sarcosine, 8-alanine, angiotensin II (2 micrograms/kg per min) during combined acute hypoxemia and hypercapnic acidosis resulted in decreased renal hemodynamic function. We conclude that acute hypoxemia and hypercapnic acidosis act synergistically to increase mean arterial pressure, diminish renal hemodynamic function and activate the renin-angiotensin system. Systemic angiotensin inhibition studies suggest activation of the renin-angiotensin system maintains renal hemodynamic function during combined hypoxemia and hypercapnic acidosis, instead of mediating the renal vasoconstriction.     

Dietary sodium loading increases arterial pressure in afferent renal-denervated rats

In rats fed high sodium diet, increasing renal pelvic pressure > or =3 mm Hg activates renal mechanosensory nerves, resulting in a renorenal reflex-induced increase in urinary sodium excretion. The low activation threshold of the renal mechanosensory nerves suggests a role for natriuretic renorenal reflexes in the regulation of arterial pressure and sodium balance. If so, interruption of the afferent renal innervation by dorsal rhizotomy (DRX) at T9-L1 would impair urinary sodium excretion and/or increase arterial pressure during high dietary sodium intake. DRX and sham-DRX rats were fed either a high or a normal sodium diet for 3 weeks. Mean arterial pressure measured in conscious rats was higher in DRX than in sham-DRX rats fed a high sodium diet, 130+/-2 vs 100+/-3 mm Hg (P<0.01). However, mean arterial pressure was similar in DRX and sham-DRX rats fed a normal sodium diet, 115+/-1 and 113+/-1 mm Hg, respectively. Steady-state urinary sodium excretion was similar in DRX and sham-DRX rats on high (17.9+/-2.2 and 16.4+/-1.8 mmol/24 h, respectively) and normal (4.8+/-0.3 and 5.0+/-0.4 mmol/24 h, respectively) sodium diets. Studies in anesthetized rats showed a lack of an increase in afferent renal nerve activity in response to increased renal pelvic pressure and impaired prostaglandin E2-mediated release of substance P from the renal pelvic nerves in DRX rats fed either a high or a normal sodium diet, suggesting that DRX resulted in decreased responsiveness of peripheral renal sensory nerves. In conclusion, when the afferent limb of the renorenal reflex is interrupted, a high sodium diet results in increased arterial pressure to facilitate the natriuresis and maintenance of sodium balance.     

Modest pressure natriuresis and autoregulation during water diuresis in dogs.

The effects of renal arterial pressure change on renal output of sodium and volume were measured during water diuresis in 25 chloralose-anesthetized dogs. Conditions included a minimal invasive stress, limited sodium administration, and mean renal arterial pressures varied suprarenally, by aortic balloon inflation to lowermost levels of 82-106 mm Hg. Group A dogs received no aldosterone; group B, C and D dogs were given aldosterone. Dogs of group C also received (1-Sar, 8-Ile)-angiotensin II. Group D dogs received phenylephrine which elevated arterial and right atrial pressures moderately without decrease in renal blood flow. In groups A, B and C, mean changes in sodium output, volume output, fractional excretions and free water clearances were not detectable with mean renal arterial pressure reductions, which averaged 29 +/- 2.9, 22 +/- 2.8 and 27 +/- 5.2 mm Hg, respectively. Right atrial pressures, effective renal blood flows and glomerular filtration rates did not change with the renal arterial pressure changes in these groups. In the group D dogs, during the larger pressure reductions of 54 +/- 6.6 mm Hg from higher values of 158 +/- 7.0 mm Hg, mean urine flow and effective renal blood flow remained constant while glomerular filtration rate and sodium output decreased only slightly. Output efficiency ratios related to perfusion pressure were calculated. With no more than modest pressure-induced excretory changes, it is concluded that excretory sodium and urinary volume autoregulation in concert with nearly perfect circulatory autoregulation were demonstrated with regionally varied mean renal arterial pressure. The same preglomerular myogenic responses to transvascular pressure, which restrict glomerular and transcapillary pressures, are viewed dominantly responsible for both circulatory and excretory autoregulation under normal conditions of minimal stress and low fractional sodium excretions. Homeostatic implications are discussed concerning likely relevance to the Guyton-Coleman theory for the long-term control of arterial blood pressure.