Pulmonary hemodynamics at birth: effect of acute cyclooxygenase inhibition in lambs

The effect of acute cyclooxygenase (CYO) inhibition on the cardiopulmonary adjustments at birth was examined in chronically instrumented, unanesthetized, term lambs before, during, and after cesarean section (spontaneous respiration). One of three infusions was started 20 min before birth: saline control (C, n = 6), indomethacin (I, n = 6), or meclofenamate (M, n = 3). The stable metabolite of prostacyclin, plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, aorta), was measured by radioimmunoassay as an index of CYO activity. Indomethacin blocked the rise of 6-keto-PGF1 alpha observed in control lambs after birth and indomethacin-treated lambs exhibited an attenuation of the postnatal decrease in mean pulmonary arterial pressure. Pulmonary arterial pressure (Ppa) was 53 +/- 2 and 47 +/- 2 Torr (mean +/- SE) at 15 min and 40 +/- 3 and 34 +/- 2 Torr at 120 min in I and C groups, respectively. There were no serial or group differences in cardiac output and cardiac right to left shunt (indicator dilution) from 15 to 120 min after birth. Arterial PO2 (PaO2) was not different between groups: 37 +/- 4 Torr at 15 min and 47 +/- 5 min at 120 min after birth (control lambs). The results for I and M were similar for all measurements.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of the renin-angiotensin system during alterations of sodium intake in conscious mice

The present studies were performed to quantify circulating components of the renin-angiotensin-aldosterone axis and to determine the functional importance of this system during alterations in sodium intake in conscious mice. Increasing sodium intake from approximately 200 to 1,000 microeq/day significantly decreased plasma renin concentration from 472 +/- 96 to 304 +/- 83 ng ANG I. ml(-1). h(-1) (n = 5) but did not alter plasma renin activity from the low-sodium level of 7.7 +/- 1.1 ng ANG I. ml(-1). h(-1). Despite the elevated plasma renin concentration, plasma ANG II in mice on low-sodium level averaged 14 +/- 3 pg/ml and was significantly suppressed to 6 +/- 1 pg/ml by high-sodium intake (n = 7). Consistent with the modulation of ANG II, plasma aldosterone significantly decreased from 41 +/- 8 to 8 +/- 3 ng/dl when sodium intake was elevated (n = 6). In a final set of experiments, the continuous infusion of ANG II (20 ng. kg(-1). min(-1)) led to a mild salt-sensitive increase in mean arterial pressure from 108 +/- 2 to 131 +/- 2 mmHg as sodium intake was varied from low to high (n = 7). In vehicle-infused mice, mean arterial pressure was unaltered from 109 +/- 2 mmHg when sodium intake was increased (n = 6). These studies indicate that the physiological suppression of circulating ANG II may be required to maintain a constancy of arterial pressure during alterations in sodium intake in normal mice.     

Circulating angiotensin II mediates sodium appetite in adrenalectomized rats

We investigated the role of circulating ANG II in sodium appetite after adrenalectomy. Adrenalectomized rats deprived of their main access to sodium (0.3 M NaCl) for 9 h drank 14.1 +/- 1.5 ml of the concentrated saline solution in 2 h of access. Intravenous infusion of captopril (2.5 mg/h) during the last 5 h of sodium restriction reduced sodium intake by 77 +/- 12% (n = 5) without affecting the degree of sodium depletion and hypovolemia incurred during deprivation. Functional evidence indicates that this dose of captopril blocked production of ANG II in the peripheral circulation, but not in the brain; that is, injection of ANG I into the lateral brain ventricle stimulated intake of both water and 0.3 M NaCl. Intravenous infusion of ANG II (starting 10-15 min before 0.3 M NaCl became available) in adrenalectomized, captopril-treated rats restored both sodium intake and blood pressure to values seen in rats not treated with captopril. Longer (20 h) infusions of captopril in 22-h sodium-restricted rats also blocked sodium appetite, but reduced or prevented sodium depletion. Intravenous infusion of ANG II after these long captopril infusions stimulated sodium intake, but intake was less than in controls not treated with captopril. These results indicate that most or all of the sodium appetite of adrenalectomized rats is mediated by circulating ANG II.     

Diuretic response to acute hypertension is blunted during angiotensin II clamp

Acute hypertension inhibits proximal tubule (PT) fluid reabsorption. The resultant increase in end proximal flow rate provides the error signal to mediate tubuloglomerular feedback autoregulation of renal blood flow and glomerular filtration rate and suppresses renal renin secretion. To test whether the suppression of the renin-angiotensin system during acute hypertension affects the magnitude of the inhibition of PT fluid and sodium reabsorption, plasma ANG II levels were clamped by infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril (12 microg/min) and ANG II after pretreatment with the bradykinin B(2) receptor blocker HOE-140 (100 microg/kg bolus). Because ACE also degrades bradykinin, HOE-140 was included to block effect of accumulating vasodilatory bradykinins during captopril infusion. HOE-140 increased the sensitivity of arterial blood pressure to ANG II: after captopril infusion without HOE-140, 20 ng x kg(-1) x min(-1) ANG II had no pressor effect, whereas with HOE-140, 20 ng x kg(-1) x min(-1) ANG II increased blood pressure from 104 +/- 4 to 140 +/- 6 mmHg. ANG II infused at 2 ng x kg(-1) x min(-1) had no pressor effect after captopril and HOE-140 infusion ("ANG II clamp"). When blood pressure was acutely increased 50-60 mmHg by arterial constriction without ANG II clamp, urine output and endogenous lithium clearance increased 4.0- and 6.7-fold, respectively. With ANG II clamp, the effects of acute hypertension were reduced 50%: urine output and endogenous lithium clearance increased two- and threefold, respectively. We conclude that HOE-140, an inhibitor of the B(2) receptor, potentiates the sensitivity of arterial pressure to ANG II and that clamping systemic ANG II levels during acute hypertension blunts the magnitude of the pressure diuretic response.     

Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity

Excessive exposure of the fetus to maternally derived corticosteroids has been linked to the development of adult-onset diseases. To determine if early gestation corticosteroid exposure alters subsequent coronary artery reactivity, we administered dexamethasone (0.28 mg.kg(-1).day(-1)) to pregnant ewes at 27-28 days gestation (term being 145 days). Vascular responsiveness was assessed in endothelium-intact coronary and mesenteric arteries isolated from steroid-exposed and age-matched control fetal sheep at 123-126 days gestation and lambs at 4 mo of age. Lambs exposed to maternal dexamethasone had higher mean arterial blood pressures than the age-matched controls (93 +/- 3 vs. 83 +/- 5 mmHg, P < 0.05). Mesenteric arteries from the steroid-exposed fetuses displayed diminished responses to ANG II, relative to controls. In 4-mo-old lambs, prenatal dexamethasone exposure significantly increased coronary artery vasoconstriction to ANG II, ACh, and U-46619, but not KCl. In contrast, postnatal mesenteric artery reactivity was unaltered by steroid exposure. Compared with fetal mesenteric reactivity, postnatal mesenteric reactivity to ANG II, phenylephrine, and U-46619 was diminished, whereas the response to 120 mmol/l KCl was heightened. Coronary artery ANG II receptor protein expression was not significantly altered by steroid exposure in either age group. These findings demonstrate that early-gestation glucocorticoid exposure programs postnatal elevations in blood pressure and selectively enhances coronary artery responsiveness to second messenger-dependent vasoconstrictors. Glucocorticoid-induced alterations in coronary vascular smooth muscle structure or function may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease.     

Respiratory effects of a patent ductus arteriosus in premature newborn lambs

We examined the respiratory effects of a patent ductus arteriosus in 29 premature lambs (131-135 days gestational age) after infiltrating the ductal wall with formaldehyde solution (Formalin) and placing a snare around the ductus to regulate its patency. The lambs were given sheep surfactant, paralyzed, and mechanically ventilated at birth. We first compared 8 lambs with open ductus and 13 lambs with closed ductus during the 12 h after birth. Although lambs with open ductus had greater pulmonary blood flow (301 +/- 36 vs. 188 +/- 11 ml.min-1.kg-1, mean +/- SE, at 12 h of age) and mean pulmonary arterial (44 +/- 3 vs. 33 +/- 2 mmHg) and left ventricular end-diastolic (6 +/- 0.6 vs 4 +/- 0.7 mmHg) pressures, we found no differences in dynamic respiratory compliance (Cdyn = 0.55 +/- 0.07 vs. 0.55 +/- 0.03 ml.cmH2O-1.kg-1), midtidal volume resistance (62 +/- 5 X 10(-3) vs. 62 +/- 7 X 10(-3) cmH2O.ml-1.s), or functional residual capacity (FRC = 27 +/- 3 vs. 26 +/- 2 ml.kg-1). Alveolar-arterial PO2 difference was lower in the lambs with open ductus (238 +/- 65 vs. 362 +/- 37 Torr). Next, we challenged eight lambs with two separate saline infusions (50 ml.kg-1 over 3 min), each given with the ductus alternately closed or open. When the ductus was closed, FRC was unchanged, but Cdyn increased by 18% immediately after the infusion. When the ductus was open, FRC decreased by 16% and Cdyn decreased by 12%. We conclude that the premature lamb is surprisingly resistant to changes in respiratory function from ductal patency during the immediate neonatal period.     

Effects of truncated angiotensins in humans after double blockade of the renin system

Angiotensins different from ANG II exhibit biological activities, possibly mediated via receptors other than ANG II receptors. We studied the effects of 3-h infusions of ANG III, ANG-(1-7), and ANG IV in doses equimolar to physiological amounts of ANG II (3 pmol. kg-1. min-1), in six men on low-sodium diet (30 mmol/day). The subjects were acutely pretreated with canrenoate and captopril to inhibit aldosterone actions and ANG II synthesis, respectively. ANG II infusion increased plasma angiotensin immunoreactivity to 53 +/- 6 pg/ml (+490%), plasma aldosterone to 342 +/- 38 pg/ml (+109%), and blood pressure by 27%. Glomerular filtration rate decreased by 16%. Concomitantly, clearance of endogenous lithium fell by 66%, and fractional proximal reabsorption of sodium increased from 77 to 92%; absolute proximal reabsorption rate of sodium remained constant. ANG II decreased sodium excretion by 70%, potassium excretion by 50%, and urine flow by 80%, whereas urine osmolality increased. ANG III also increased plasma aldosterone markedly (+45%), however, without measurable changes in angiotensin immunoreactivity, glomerular filtration rate, or renal excretion rates. During vehicle infusion, plasma renin activity decreased markedly ( approximately 700 to approximately 200 mIU/l); only ANG II enhanced this decrease. ANG-(1-7) and ANG IV did not change any of the measured variables persistently. It is concluded that 1) ANG III and ANG IV are cleared much faster from plasma than ANG II, 2) ANG II causes hypofiltration, urinary concentration, and sodium and potassium retention at constant plasma concentrations of vasopressin and atrial natriuretic peptide, and 3) a very small increase in the concentration of ANG III, undetectable by usual techniques, may increase aldosterone secretion substantially.     

Inhibition of sympathetic responses at birth in sheep by lesion of the paraventricular nucleus

Birth is characterized by a surge in sympathetic outflow, heart rate (HR), mean arterial blood pressure (MABP) and circulating catecholamines. The paraventricular nucleus (PVN) of the hypothalamus is an important central regulatory site of sympathetic activity, but its role in the regulation of sympathoexcitation at birth is unknown. To test the hypothesis that the PVN regulates sympathetic activity at birth, experiments were performed in chronically instrumented near-term (137- to 142-day gestation, term 145 days) sheep before and after delivery by cesarean section. Stereotaxic guided electrolytic lesioning of the PVN (n = 6) or sham lesioning (n = 6) was performed 48 h before study. At 30 min after birth, renal sympathetic nerve activity (RSNA) increased 128 +/- 26% above fetal values in the sham-lesioned animals (P < 0.05). In contrast, at a similar time point, RSNA decreased to 52 +/- 12% of the fetal value in the PVN-lesioned animals. Lesioning of the PVN did not affect the usual postnatal increases in MABP and epinephrine levels although HR failed to rise above fetal values. ANG II but not arginine vasopressin or norepinephrine levels increased in PVN-lesioned animals after birth, whereas all three hormones increased (P < 0.05) in sham-lesioned animals. Fetal and newborn HR baroreflex responses were similar in both groups. However, the usual postnatal attenuation of baroreflex-mediated inhibition of RSNA was blunted in the PVN-lesioned group. The results of this study demonstrate that ablation of the PVN abolishes sympathoexcitation with birth at near-term gestation. The PVN may play a critical role in physiological adaptation at birth.     

Effects of aminophylline on hypoxemia-induced ventilatory depression in the cat

We designed experiments to evaluate changes in ventral medullary (VM) extracellular fluid (ECF) PCO2 and pH during hypoxemia-induced ventilatory depression (VD). Our aim was to investigate effects of aminophylline on VD and VM ECF acid-base variables. We used aminophylline because it inhibits adenosine, which is released within the brain during hypoxemia and could mediate VD. Experiments were performed in seven cats with acute bilateral denervation of carotid sinus nerves and vagi. Cats were anesthetized with chloralose-urethan and breathed spontaneously at a regulated and elevated arterial PCO2 (PaCO2). Measurements were made during normoxemia, hypoxemia, and recovery before (phase I) and after (phase II) aminophylline. By use of strict criteria for definition of VD, during phase II two kinds of responses were observed. Aminophylline prevented VD in five cats. In these cats in phase I, with mean arterial PO2 (PaO2) = 105 and PaCO2 = 42.2 Torr, VM ECF PCO2, [H+], and [HCO3-] were 59.5 +/- 8.6 Torr (mean +/- SD), 60.2 +/- 9.4 neq/l, and 23.1 +/- 3.7 meq/l, respectively. When mean PaO2 dropped to 49 Torr, ventilation decreased 21%, with only small changes in VM ECF acid-base variables. Studies were repeated 30 min after aminophylline (17 mg/kg iv). In phase II, during normoxemia (PaO2 = 110 Torr) VM ECF Pco2, [H+], and [HCO3-] were 55.4 +/- 8.1 Torr, 62.0 +/- 8.0 neq/l and 20.7 +/- 2.5 meq/l, respectively. During hypoxemia (PaO2 = 48 +/- 4 Torr) mean ventilation, VM ECF PCO2, [H+], and [HCO3-] did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Infusion of angiotensin II (ANG II) causes salt-sensitive hypertension. It is unclear whether this is due to the body's inability to suppress ANG II during increased salt intake or, rather, an elevated basal level of plasma ANG II itself. To distinguish between these mechanisms, Sprague-Dawley rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of drugs, respectively. The sensitivity of arterial pressure to salt was measured in four groups with the following treatments: 1) saline control (Con, n = 12); 2) administration of the angiotensin-converting enzyme inhibitor enalapril to block endogenous ANG II (ANG-Lo, n = 10); 3) administration of enalapril and 5 ng.kg(-1).min(-1) ANG II to clamp plasma ANG II at normal levels (ANG-Norm, n = 10); and 4) administration of enalapril and 20 ng.kg(-1).min(-1) ANG II to clamp ANG II at high levels (ANG-Hi, n = 10). Rats ingested a 0.4% NaCl diet for 3 days and then a 4.0% NaCl diet for 11 days. Arterial pressure of rats fed the 0.4% NaCl diet was lower in ANG-Lo (84 +/- 2 mmHg) compared with Con (101 +/- 3 mmHg) and ANG-Norm (98 +/- 4 mmHg) groups, whereas ANG-Hi rats were hypertensive (145 +/- 4 mmHg). Salt sensitivity was expressed as the change in arterial pressure divided by the change in sodium intake on the last day of the 4.0% NaCl diet. Salt sensitivity (in mmHg/meq Na) was lowest in Con rats (0.0 +/- 0.1) and progressed from ANG-Lo (0.8 +/- 0.2) to ANG-Norm (1.5 +/- 0.5) to ANG-Hi (3.5 +/- 0.5) rats. We conclude that the major determinant of salt sensitivity of arterial pressure is the basal level of plasma ANG II rather than the responsiveness of the renin-angiotensin system.     

Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces alterations in postnatal cardiovascular physiology, including hypertension. To determine whether autonomic function and systemic vascular reactivity are altered by in utero programming before the development of systemic hypertension, we examined arterial baroreflex function and in vivo hemodynamic and in vitro vascular responses to vasoactive agents in 10- to 14-day-old newborn lambs exposed to early gestation glucocorticoids. Dexamethasone (Dex, 0.28 mg.kg-1.day-1) or saline was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term 145 days), and lambs were allowed to deliver (n=6 in each group). Resting mean arterial blood pressure (MABP; 77+/-1 vs. 74+/-3 mmHg) and heart rate (HR; 249+/-9 vs. 226+/-21 beats/min) were similar in Dex-exposed and control animals, respectively. The arterial baroreflex curve, relating changes in HR to MABP, was significantly shifted toward higher pressure in the Dex-exposed lambs although no change in the sensitivity (gain) of the response was seen. In vivo changes in blood pressure in response to bolus doses of ANG II (20, 50, and 100 ng/kg) and phenylephrine (2, 5, and 10 microg/kg) were similar in the two groups. However, Dex lambs displayed greater decreases in MABP in response to ganglionic blockade with tetraethylammonium bromide (10 mg/kg; -30+/-3 vs. -20+/-3 mmHg, P<0.05) and greater increases in MABP after nitric oxide synthase blockade with NG-nitro-L-arginine (25 mg/kg; 23+/-3 vs. 13+/-2 mmHg, P<0.05) compared with control lambs. By in vitro wire myography, mesenteric and femoral artery microvessel contractile responses to KCl were similar, whereas responses to endothelin (in mesenteric) and norepinephrine (in femoral) were significantly attenuated in Dex lambs compared with controls. Femoral vasodilatory responses to forskolin and sodium nitroprusside were similar in the two groups (n=4). These findings suggest that resetting of the baroreflex, accompanied by increased sympathetic activity and altered nitric oxide-mediated compensatory vasodilatory function, may be important contributors to programming of hypertension.     

Umbilical cord compression produces pulmonary hypertension in newborn lambs: a model to study the pathophysiology of persistent pulmonary hypertension in the newborn

We investigated the effects of chronic intrauterine hypoxaemia produced by prolonged partial umbilical cord compression on the circulation shortly after birth in lambs. Vascular catheters were inserted in 10 fetal sheep at 120 to 130 days gestation to measure descending aortic blood gases, arterial pH, and arterial O2 saturation. An inflatable silicone rubber balloon cuff was also placed around the umbilical cord. After recovery and the return of descending aortic blood gases to the normal range, the balloon was gradually inflated, decreasing the PaO2 from 21.2 +/- 3.6 to 17.5 +/- 1.3 mm Hg and the arterial O2 saturation from 57.1 +/- 9.2% to 37.2% +/- 5.2. After 14.3 +/- 3.7 days of partial umbilical cord compression, the lambs were delivered by Caesarean section, instrumented to measure systemic and pulmonary arterial, right atrial and pulmonary arterial wedge pressures, pulmonary and systemic blood flows, and mechanically ventilated. Five normal lambs were also studied. From 60 to 120 min after delivery, when compared to normal lambs, the umbilical compression lambs had an increased pulmonary arterial pressure (P less than 0.05) pulmonary vascular resistance (P less than 0.05), and right atrial pressure (P less than 0.05) with similar arterial blood gases. In both groups, hypoxic ventilation produced an increase in pulmonary arterial pressure (P less than 0.05) which on return to room air ventilation decreased to baseline in the normal lambs but not in the umbilical cord compression lambs (P less than 0.05). Prolonged partial umbilical cord compression produces chronic fetal hypoxaemia and pulmonary arterial hypertension after birth. This may represent a model to study the pathophysiology of persistent pulmonary hypertension syndrome.     

Hormonal regulation of renal sodium and water excretion during normotensive sodium loading in conscious dogs

Saline was infused intravenously for 90 min to normal, sodium-replete conscious dogs at three different rates (6, 20, and 30 micromol x kg(-1) x min(-1)) as hypertonic solutions (HyperLoad-6, HyperLoad-20, and HyperLoad-30, respectively) or as isotonic solutions (IsoLoad-6, IsoLoad-20, and IsoLoad-30, respectively). Mean arterial blood pressure did not change with any infusion of 6 or 20 micromol x kg(-1) x min(-1). During HyperLoad-6, plasma vasopressin increased by 30%, although the increase in plasma osmolality (1.0 mosmol/kg) was insignificant. During HyperLoad-20, plasma ANG II decreased from 14+/-2 to 7+/-2 pg/ml and sodium excretion increased markedly (2.3+/-0.8 to 19+/-8 micromol/min), whereas glomerular filtration rate (GFR) remained constant. IsoLoad-20 decreased plasma ANG II similarly (13+/-3 to 7+/-1 pg/ml) concomitant with an increase in GFR and a smaller increase in sodium excretion (1.9+/-1.0 to 11+/-6 micromol/min). HyperLoad-30 and IsoLoad-30 increased mean arterial blood pressure by 6-7 mm Hg and decreased plasma ANG II to approximately 6 pg/ml, whereas sodium excretion increased to approximately 60 micromol/min. The data demonstrate that, during slow sodium loading, the rate of excretion of sodium may increase 10-fold without changes in mean arterial blood pressure and GFR and suggest that the increase may be mediated by a decrease in plasma ANG II. Furthermore, the vasopressin system may respond to changes in plasma osmolality undetectable by conventional osmometry.     

Acute hypoxic pulmonary vasoconstriction in conscious dogs decreases renin and is unaffected by losartan.

Acute hypoxic pulmonary vasoconstriction (HPV) may be mediated by vasoactive peptides. We studied eight conscious, chronically tracheostomized dogs kept on a standardized dietary sodium intake. Normoxia (40 min) was followed by hypoxia (40 min, breathing 10% oxygen, arterial oxygen pressures 36 +/- 1 Torr) during both control (Con) and losartan experiments (Los; iv infusion of 100 microg. min-1. kg-1 losartan). During hypoxia, minute ventilation (by 0.9 l/min in Con, by 1.3 l/min in Los), cardiac output (by 0.36 l/min in Con, by 0.30 l/min in Los), heart rate (by 11 beats/min in Con, by 30 beats/min in Los), pulmonary artery pressure (by 9 mmHg in both protocols), and pulmonary vascular resistance (by 280 and 254 dyn. s. cm-5 in Con and Los, respectively) increased. Mean arterial pressure and systemic vascular resistance did not change. In Con, PRA decreased from 4.2 +/- 0.7 to 2.5 +/- 0.5 ng ANG I. ml-1. h-1, and plasma ANG II decreased from 11.9 +/- 3.0 to 8.2 +/- 2.1 pg/ml. The renin-angiotensin system is inhibited during acute hypoxia despite sympathetic activation. Under these conditions, ANG II AT1-receptor antagonism does not attenuate HPV.     

Bradykinin is degraded in hypoxic lungs and does not affect epithelial permeability

To investigate the effect of intravenous infusions of bradykinin (BK) on the permeability of the hypoxic pulmonary epithelium to small solutes, experiments (n = 7) were performed in yearling sheep with chronic vascular catheters. Sheep were anesthetized, intubated, paralyzed, and ventilated. After establishing stable and normal base-line pulmonary hemodynamics and blood gas tensions, the lungs were insufflated with a submicronic aerosol of technetium-99m-labeled diethylenetriaminepentaacetate (99mTc-DTPA, mol wt = 492). Radioactivity arising from the right hemithorax was measured by an NaI probe with a parallel-holed collimator. The base-line pulmonary clearance rate (k) for 99mTc-DTPA was 0.51 +/- 0.09% (SE)/min, while the sheep were ventilated with a fractional concentration of inspired O2 (FIO2) of 0.5 [arterial partial pressure of O2 (PaO2) = 196 +/- 11.4 (SE) Torr]. Clearance of 99mTc-DTPA was unaffected by hypoxia alone or BK infusions in nonhypoxic lungs. The combination of an intravenous infusion of BK at either 1.2 (n = 3) or 2.4 micrograms . kg-1 . min-1 (n = 4) and alveolar hypoxia [FIO2 = 0.11, PaO2 = 28 +/- 1.6 (SE) Torr] did not affect pulmonary clearance of 99mTc-DTPA [k = 0.43 +/- 0.08% (SE)/min]. In contrast, a 0.05-ml/kg intravenous infusion of oleic acid increased clearance 10-fold in one sheep. During combined hypoxia and BK infusion the pulmonary arterial BK concentration (radioimmunoassay) increased from 0.82 +/- 0.16 (SE) to 7.05 +/- 1.86 ng/ml (P less than 0.001), but the systemic arterial concentrations were unchanged [0.67 +/- 0.19 (SE) to 0.66 +/- 0.09 ng/ml].(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acetazolamide on cerebral acid-base balance

Acetazolamide (AZ) inhibition of brain and blood carbonic anhydrase increases cerebral blood flow by acidifying cerebral extracellular fluid (ECF). This ECF acidosis was studied to determine whether it results from high PCO2, carbonic acidosis (accumulation of H2CO3), or lactic acidosis. Twenty rabbits were anesthetized with pentobarbital sodium, paralyzed, and mechanically ventilated with 100% O2. The cerebral cortex was exposed and fitted with thermostatted flat-surfaced pH and PCO2 electrodes. Control values (n = 14) for cortex ECF were pH 7.10 +/- 0.11 (SD), PCO2 42.2 +/- 4.1 Torr, PO2 107 +/- 17 Torr, HCO3- 13.8 +/- 3.0 mM. Control values (n = 14) for arterial blood were arterial pH (pHa) 7.46 +/- 0.03 (SD), arterial PCO2 (PaCO2) 32.0 +/- 4.1 Torr, arterial PO2 (PaO2) 425 +/- 6 Torr, HCO3- 21.0 +/- 2.0 mM. After intravenous infusion of AZ (25 mg/kg), end-tidal PCO2 and brain ECF pH immediately fell and cortex PCO2 rose. Ventilation was increased in nine rabbits to bring ECF PCO2 back to control. The changes in ECF PCO2 then were as follows: pHa + 0.04 +/- 0.09, PaCO2 -8.0 +/- 5.9 Torr, HCO3(-)-2.7 +/- 2.3 mM, PaO2 +49 +/- 62 Torr, and changes in cortex ECF were as follows: pH -0.08 +/- 0.04, PCO2 -0.2 +/- 1.6 Torr, HCO3(-)-1.7 +/- 1.3 mM, PO2 +9 +/- 4 Torr. Thus excess acidity remained in ECF after ECF PCO2 was returned to control values. The response of intracellular pH, high-energy phosphate compounds, and lactic acid to AZ administration was followed in vivo in five other rabbits with 31P and 1H nuclear magnetic resonance spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin II mediates hyperadrenergic activity evoked by sodium restriction in essential hypertension

We examined the possible involvement of angiotensin II in the modulation of circulating norepinephrine produced by acute sodium restriction in essential hypertensive patients (n = 18). Sodium restriction potentiated plasma level of norepinephrine in parallel with an increased plasma renin activity (r = 0.81, F = 31.2, p less than 0.05 given by the percent changes). An intravenous infusion of sarcosine-1, isoleucine-8 angiotensin II produced a significant fall in mean arterial pressure (-6 +/- 2 mmHg, p less than 0.05) in patients on sodium restriction but not before sodium restriction, while the infusion of the antagonist produced a greater decrease (p less than 0.05) in plasma norepinephrine with sodium restriction (-158 +/- 23 pg/ml, p less than 0.05) when compared to that obtained before sodium restriction (-91 +/- 11 pg/ml, p less than 0.05). A single oral administration of an angiotensin I converting enzyme inhibitor, captopril caused a greater fall (p less than 0.01) in mean arterial pressure after sodium restriction (-32 +/- 3 mmHg, p less than 0.05) compared to that given before (-21 +/- 3 mmHg, p less than 0.05). However, sodium restriction did not affect the magnitude of reflex increase in plasma norepinephrine to hypotension evoked by captopril (from +88 +/- 16 pg/ml to +87 +/- 17 pg/ml; p greater than 0.05). It can be interpreted that acute sodium depletion results in a substantial contribution of angiotensin II to the expression of hyperadrenergic activity.     

Ventrolateral medullary surface blood flow determined by hydrogen clearance

The H2 clearance technique was used to determine the blood flow of the postulated respiratory chemosensitive areas near the ventrolateral surface of the medulla. In 12 pentobarbital sodium-anesthetized cats, flow (mean +/- SD) was measured from 25-micron Teflon-coated platinum wire electrodes implanted to a depth of 0.3-0.7 mm. Flow (in ml X min-1 X 100 g-1, n = 35) was 52.8 +/- 28.5 in hypocapnia [arterial CO2 partial pressure (PaCO2) = 21.8 +/- 1.6 Torr], 57.8 +/- 27.5 in normocapnia (PaCO2 = 31.9 +/- 2.2 Torr), and 75.0 +/- 31.7 in hypercapnia (PaCO2 = 44.5 +/- 3.0 Torr). Flow determined from 15 electrodes in adjacent pyramidal tracts (white matter) was less at all levels of CO2; 22.9 +/- 12.3 in hypocapnia, 29.1 +/- 15.9 in normocapnia, and 33.9 +/- 13.9 in hypercapnia. In hypoxia [arterial O2 partial pressure (PaO2) = 39.9 +/- 6.3 Torr] ventrolateral surface flow rose to 87.9 +/- 47.6, and adjacent white matter flow was 35.8 +/- 15.6. These results indicate that flow in the postulated central chemoreceptor areas exceeds that of white matter and is sensitive to variations in PaCO2 and PaO2.     

Circumventricular organs and ANG II-induced salt appetite: blood pressure and connectivity

A lesion of the subfornical organ (SFO) may reduce sodium depletion-induced salt appetite, which is largely dependent on ANG II, and yet ANG II infusions directly into SFO do not provoke salt appetite. Two experiments were designed to address this apparent contradiction. In experiment 1 sustained infusions of ANG II into SFO did not produce a sustained elevation of blood pressure, and neither a reduction of blood pressure alone with minoxidil and captopril nor a reduction of both blood pressure and volume with furosemide and captopril enhanced salt appetite. Infusions of ANG II in the organum vasculosum laminae terminalis (OVLT) did evoke salt appetite without raising blood pressure. In experiment 2 knife cuts of the afferent and efferent fibers of the rostroventral pole of the SFO abolished water intake during an infusion of ANG II into the femoral vein but failed to reduce salt appetite during an infusion of ANG II into the OVLT. We conclude that 1) hypertension does not account for the failure of infusions of ANG II in the SFO to generate salt appetite and 2) the OVLT does not depend on its connectivity with the SFO to generate salt appetite during ANG II infusions.     

Attenuated renal vascular responses to acute angiotensin II infusion in smooth muscle-specific Na+/Ca2+ exchanger knockout mice

Recent studies in smooth muscle-specific Na(+)/Ca(2+) exchanger-1 knockout (NCX1(sm-/-)) mice reveal reduced arterial pressure and impaired myogenic responses compared with heterozygous littermates. In this study, we determined renal function in male anesthetized NCX1(sm-/-) mice and NCX1 heterozygous (NCX1(+/-)) littermates before and during acute ANG II infusions. Systolic blood pressure in awake mice was lower in NCX1(sm-/-) mice compared with NCX1(+/-) mice (119 ± 4 vs. 131 ± 3 mmHg, P < 0.05). Acute ANG II infusions (5 ng·min(-1)·g(-1) body wt) increased mean arterial pressure in anesthetized NCX1(+/-) (109 ± 2 to 134 ± 3 mmHg, P < 0.001, n = 8) and NCX1(sm-/-) (101 ± 8 to 129 ± 8 mmHg, P < 0.01, n = 6) mice to a similar extent (Δ25 ± 1 vs. Δ28 ± 4 mmHg, P > 0.05). In response to ANG II infusions, PAH clearance (C(PAH)) decreased from 1.39 ± 0.27 to 0.98 ± 0.22 ml·min(-1)·g(-1) (P < 0.05) and glomerular filtration rate (GFR) was reduced from 0.50 ± 0.09 to 0.32 ± 0.06 ml·min(-1)·g(-1) (P < 0.05) in NCX1(+/-) mice. In contrast, the NCX1(sm-/-) did not exhibit significant reductions in either C(PAH) (1.16 ± 0.30 to 1.22 ± 0.34 ml·min(-1)·g(-1), P > 0.05) or GFR (0.48 ± 0.08 to 0.41 ± 0.05 ml·min(-1)·g(-1), P > 0.05) during acute ANG II infusions. Using flometry to measure renal blood flow continuously, NCX1(sm-/-) mice had significantly attenuated responses to ANG II infusions (-34.2 ± 3.9%, P < 0.05) compared with those in NCX1(+/-) mice (-48 ± 2%) or in wild-type mice (-69 ± 7%). These data indicate that renal vascular responses to ANG II are attenuated in NCX1(sm-/-) mice compared with NCX1(+/-) mice and that NCX1 contributes to the renal vasoconstriction response to acute ANG II infusions.