Role of intrarenal angiotensin II and alpha-adrenoceptors in renal vasoconstriction with acute hypoxemia and hypercapnic acidosis in conscious dogs.

To evaluate our previous observation of renal vasoconstriction during combined acute hypoxemia and hypercapnic acidosis preceded by acute hypoxemia, we studied 13 conscious mongrel uninephrectomized dogs with chronic renal catheters and controlled sodium intake (80 meq/day for 4 days). Five dogs were studied during combined acute hypoxemia (PaO2, 37 +/- 1 mm Hg) and hypercapnic acidosis (PaCO2, 59 +/- 1 mm Hg; pH 7.20 +/- 0.01). Each dog was studied during infusion of 1) the intrarenal vehicle (n = 5), 2) the intrarenal alpha 1-antagonist prazosin (0.2 micrograms.kg-1.min-1, n = 5), 3) intrarenal [Sar1,Ala8]angiotensin II (70 ng.kg-1.min-1, n = 5), and 4) intrarenal prazosin and [Sar1,Ala8]angiotensin II (n = 4). Immediate induction of combined hypoxemia and hypercapnic acidosis after control measurements during intrarenal vehicle infusion resulted in a decrease in effective renal plasma flow and glomerular filtration rate, increase in renal vascular resistance, and decrease in filtered sodium load in the first 20 minutes of the blood gas derangement. Intrarenal administration of [Sar1,Ala8]angiotensin II failed to reverse the effects of the combined blood gas derangement on renal function. In contrast, intrarenal prazosin administration either alone or in combination with [Sar1,Ala8]angiotensin II abrogated the increase in renal vascular resistance, decrease in glomerular filtration rate, and fall in filtered sodium load. These studies identify a major role for alpha 1-adrenoceptors in the renal vasoconstriction during combined hypoxemia and hypercapnic acidosis.     

Right ventricular performance during increased afterload impaired by hypercapnic acidosis in conscious dogs

Since heart failure may occur in the setting of lung dysfunction and CO2 retention with only modest increases in cardiac work load, we questioned whether myocardial function is impaired by hypercapnic acidosis. To determine the influence of hypercapnic acidosis on right ventricular function, we measured the effects of acute (2 hours) and chronic (2 weeks) hypercapnic acidosis on right ventricular performance during normal and increased right ventricular afterload in five conscious dogs. Systemic hemodynamic and right ventricular functions were unaltered during normal right ventricular afterload by acute hypercapnic acidosis (PaCO2 = 49 +/- 3 mm Hg, pH = 7.27 +/- 0.003). As right ventricular afterload was increased by progressive balloon occlusion of the right ventricular outflow tract during acute hypercapnic acidosis, the rise (slope) in right ventricular end-diastolic pressure was increased 4-fold (P less than 0.01) over that observed in normocapnic control. Maximum isovolumic right ventricular dP/dt rose (P less than 0.05) comparably with increasing right ventricular afterload during normocapnic control and acute hypercapnic acidosis. Chronic hypercapnic acidosis (PaCO2 = 55 +/- 2 mm Hg, pH = 7.28 +/- 0.01) resulted in systemic vasodilation and increased (P less than 0.05) heart rate and cardiac output during normal right ventricular afterload. As right ventricular afterload was increased during chronic hypercapnic acidosis, the rate of rise in right ventricular end-diastolic pressure was 2-fold (P less than 0.01) above normocapnic control but maximum isovolumic right ventricular dP/dt was unchanged in contrast to normocapnic control and acute hypercapnic acidosis. Moreover, cardiac output fell and stroke work was unchanged with increasing afterload during chronic hypercapnic acidosis. beta-Adrenergic blockade resulted in an increased (P less than 0.01) rate of rise in right ventricular end-diastolic pressure with afterload during normocapnic control and chronic hypercapnic acidosis. We conclude that hypercapnic acidosis results in diminished right ventricular performance during increased right ventricular afterload, evidenced by accentuated rise in right ventricular end-diastolic pressure, and may contribute to the congestive heart failure and edema observed in patients with pulmonary hypertension and CO2 retention.     

Pattern of variables describing desaturator COPD patients, as revealed by cluster analysis

STUDY OBJECTIVES: The aims of this study were to define, by cluster analysis, a pattern of clinical variables that differentiate desaturator (D) from nondesaturator (ND) patients affected by COPD, and to identify daytime variables that are predictive of nocturnal desaturation. PATIENTS: Fifty-one random, consecutive COPD outpatients (20 women; mean [+/- SD] age, 69.6 +/- 4.0 years) with mild daytime hypoxemia (Pao(2), 60 to 70 mm Hg) were enrolled into the study. Obstructive sleep apnea syndrome patients were excluded. MEASUREMENTS AND RESULTS: Lung volumes, arterial blood gas levels, and mean pulmonary artery pressure (MPAP) were measured, and nocturnal desaturation was evaluated with nighttime polygraphy. With least squares simple linear regression, the percentage of total recording time was highly correlated with a total nocturnal recording time of arterial oxygen saturation of < 90 mm Hg (T90) and MPAP (R = 0.84; R2= 71.20%); T90 was also highly correlated with daytime Paco2 (R = 0.70; R2= 48.96%). Multiple regression showed that T90 was highly correlated with both MPAP and Paco2 (R2= 97.75%). Hierarchical cluster analysis conducted with these three variables showed that D and ND patients differed in both nocturnal and daytime variables. The mean T90 was 30 +/- 3.5% in 19.2% and 8%, respectively, of the D and ND groups. Moreover, two D subgroups differing in MPAP and two ND subgroups differing in Paco2 were identified. CONCLUSIONS: D patients may be identified by a pattern of T90, MPAP, and Paco2 values, rather than by T90 alone, with the latter two variables being predictors of nocturnal desaturation severity.     

Combined oximetry-cutaneous capnography in patients assessed for long-term oxygen therapy

STUDY AIM: To evaluate the feasibility of combined oximetry (pulse oximetric saturation [Spo(2)]) and cutaneous capnography (transcutaneous carbon dioxide tension [Ptcco(2)]) for oxygen titration in patients requiring long-term oxygen therapy. METHODS: Twenty patients with obstructive or restrictive lung disease underwent oxygen titration using a combined cutaneous oximetry-capnography sensor. The goal of titration was to achieve an oxygen saturation of > 90% without a significant rise in carbon dioxide. Spo(2) and Ptcco(2) measurements at the end of titration were compared with blood gas levels using Bland-Altman analysis and linear regression analysis. RESULTS: The mean (+/- SE of the estimate) Pao(2) while breathing room air was 53.2 +/- 8.1 mm Hg and increased to 75.9 +/- 13.3 mm Hg with oxygen supplementation (p < 0.0001). The mean Paco(2) was 45.9 +/- 8.7 mm Hg at baseline and 47.8 +/- 9.0 mm Hg after oxygen titration (p = 0.003). Bland-Altman analysis for comparison of Ptcco(2) and Paco(2) showed a bias of 0.86 mm Hg with a precision of 3.48 mm Hg. Bland-Altman analysis for the comparison of Spo(2) and arterial oxygen saturation showed a bias of 0.14% with a precision of 1.13%. CONCLUSION: Combined oximetry and cutaneous capnography is feasible during oxygen titration in patients needing long-term oxygen therapy. This noninvasive approach has the potential to reduce the number of arterial blood gas samplings performed.     

Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats

The renin-angiotensin system is a far more complex enzymatic cascade than realized previously. Mounting evidence suggests sex-specific differences in the regulation of the renin-angiotensin system and arterial pressure. We examined the hemodynamic responses, angiotensin II receptor subtypes, and angiotensin-converting enzyme 2 gene expression levels after graded doses of angiotensin II in males and females. Mean arterial pressure was measured via telemetry in male and female rats in response to a 2-week infusion of vehicle, low-dose (50 ng/kg per minute SC) or high-dose (400 ng/kg per minute SC) angiotensin II. The effect of concurrent infusion of the angiotensin II type 2 receptor (AT(2)R) blocker (PD123319) was also examined. The arterial pressure response to high-dose angiotensin II was attenuated in females compared with males (24+/-8 mm Hg versus 42+/-5 mm Hg; P for the interaction between sex and treatment <0.002). Remarkably, low-dose angiotensin II decreased arterial pressure (11+/-4 mm Hg; P for the interaction between sex and treatment <0.02) at a dose that did not have an effect in males. This decrease in arterial pressure in females was abolished by AT(2)R blockade. Renal AT(2)R, angiotensin-converting enzyme 2, and left ventricular AT(2)R mRNA gene expressions were markedly greater in females than in males with a renal angiotensin II type 1a receptor:AT(2)R ratio of approximately 1 in females. Angiotensin II infusion did not affect renal AT(2)R mRNA expression but resulted in significantly less left ventricular mRNA expression. Renal angiotensin-converting enzyme 2 mRNA expression levels were greater in females than in males treated with high-dose angiotensin II (approximately 2.5 fold; P for the interaction between sex and treatment <0.05). In females, enhancement of the vasodilatory arm of the renin-angiotensin system, in particular, AT(2)R and angiotensin-converting enzyme 2 mRNA expression, may contribute to the sex-specific differences in response to renin-angiotensin system activation.     

Limitations of transcutaneous carbon dioxide measurements for assessing long-term mechanical ventilation

STUDY OBJECTIVES: Transcutaneous CO(2) pressure (Ptcco(2)) and transcutaneous O(2) pressure (Ptco(2)) measurements are routinely used in pediatric ICUs in order to avoid serial arterial punctures. The aim of this study was to determine the value of Ptcco(2) assessment during the evaluation of home ventilation in 12 adult patients with COPD or restrictive respiratory failure in the stable state (mean [+/- SD] basal Paco(2), 48.8 +/- 8.3 mm Hg) who were treated by mask or tracheotomy-mediated ventilation. METHODS: After radial catheter insertion, patients were instructed to breathe spontaneously for 40 min and then to receive ventilation for 40 min according to their individual home ventilation modalities. An in vivo calibration was performed in the initial stage of the study in order to optimize the arterial Pco(2) and Ptcco(2) values. Every 5 min, transcutaneous measurements were performed and simultaneously compared with arterial values. MEASUREMENTS AND RESULTS: Ptcco(2) and Ptco(2) were correlated with arterial values (p < 0.0001) except for Paco(2) values of > 56 mm Hg and Pao(2) values of > 115 mm Hg. During ventilation, Paco(2) decreased >or= 4 mm Hg in seven patients. Ptcco(2) variations recorded during consecutive 5-min periods while the patient received mechanical ventilation were well correlated with the arterial variations (p = 0.0033), with a delay of < 5 min. CONCLUSION: Ptcco(2) values and variations accurately reflected Paco(2) values and variations during mechanical ventilation. However, the accuracy of these data seems to be restricted to patients with Paco(2) values of < 56 mm Hg.     

In vivo comparison of renal and femoral vascular sensitivity and local angiotensin generation

Experiments were conducted to compare the relative importance of the local renin-angiotensin systems in the rabbit renal and femoral vascular beds and their functional role in hemodynamic regulation. Angiotensin I (Ang I) (0.15 microgram/kg i.v.) elevated mean arterial blood pressure by 18 +/- 1 mm Hg in the renal experimental group and 19 +/- 1 mm Hg in the femoral experimental group; it decreased renal blood flow by 35 +/- 3% but increased femoral blood flow by 31 +/- 8%. All these effects were blocked by intravenous administration of captopril (2 mg/kg bolus injection plus 1 mg/kg/hr). Captopril also lowered mean arterial pressure by 17 +/- 3 and 16 +/- 2 mm Hg in the renal and femoral experimental groups, respectively, and it increased renal blood flow by 32 +/- 10% but reduced femoral blood flow by 21 +/- 4%. As a result, renal vascular resistance was decreased by 36 +/- 5%, but femoral vascular resistance remained unchanged. After captopril, plasma angiotensin II (Ang II) levels were decreased and Ang I levels increased in the two groups. The renal venous-arterial difference of Ang I was increased by captopril, but the femoral venous-arterial difference of Ang I was not, suggesting greater generation of Ang I in the kidney. In a separate group of bilateral nephrectomized rabbits, plasma Ang II levels as well as mean arterial pressure, femoral blood flow, and femoral vascular resistance were not changed by intravenous administration of captopril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bradykinin contribution to renal blood flow effect of angiotensin converting enzyme inhibitor in the conscious sodium-restricted dog

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Transcutaneous PCO2 monitoring during initiation of noninvasive ventilation

BACKGROUND: To assess the efficacy of transcutaneous Pco2 (Ptcco2) measurements for monitoring alveolar ventilation in patients requiring noninvasive positive-pressure ventilation (NPPV). METHODS: In a prospective study on method agreement pairs of Paco2 and Ptcco2 (SenTec Digital Monitor; SenTec AG; Therwil, Switzerland), measurements were performed every 10 min during the establishment of NPPV over a 4-h period in 10 patients (8 patients with COPD) presenting with acute-on-chronic hypercapnic respiratory failure, thus providing 250 pairs of measurement. RESULTS: Mean (+/- SD) Paco2 decreased from 67.2 +/- 11.9 mm Hg (Ptcco2, 65.5 +/- 13.9 mm Hg) to 54.6 +/- 8.8 mm Hg (Ptcco2, 47.8 +/- 8.8 mm Hg), and mean pH increased from 7.36 +/- 0.03 to 7.44 +/- 0.04. Following Ptcco2 assessment, Ptcco2 in the ensuing 2-min period was the strongest predictor for Paco2 compared to Ptcco2 in the ensuing 5-min period and to real-time measurements. Ptcco2 was highly correlated with Paco2 (r = 0.916; p < 0.001), as determined by linear regression analysis. The mean difference between Paco2 and Ptcco2 was 4.6 mm Hg, and the limits of agreement (bias +/- 1.96 SDs) ranged from -3.9 to 13.2 mm Hg, following the Bland and Altman analysis. Retrospective drift correction produced an even higher correlation (r = 0.956; p < 0.001) with lower limits of agreement (-1.7 to 7.5 mm Hg). CONCLUSIONS: Ptcco2 measurements provide a sensitive, continuous, and noninvasive method for monitoring alveolar ventilation in patients who are receiving short-term NPPV therapy. Drift correction of Ptcco2 measurements improves the accuracy of Ptcco2 monitoring compared to the "gold standard" Paco2 assessment. A lag time of approximately 2 min is present for reliable Ptcco2 values compared to Paco2 values. However, individual variance between Paco2 and Ptcco2 cannot be excluded. Trial registration: www.uniklinik-freiburg.de/zks/live/uklregister/Oeffentlich.html Identifier:UKF001271.     

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)     

Intermittent short-term negative pressure ventilation and increased oxygenation in COPD patients with severe hypercapnic respiratory failure

With the aim of testing a method that allows increasing concentrations of oxygen to be administered to patients with severe hypoxemia and hypercapnia while avoiding the risk of increasing respiratory acidosis, we studied 17 male patients with advanced chronic obstructive pulmonary disease (COPD) and severe hypercapnic respiratory failure. During 6 h and on one day only, all patients were given intermittent negative pressure ventilation (INPV) together with oxygenation starting at a concentration of 24 percent and increasing to 30 percent. Using this procedure, it was possible to raise arterial PaO2 to safe levels (from 47.2 +/- 3 mm Hg to 61.5 +/- 6 mm Hg, p less than 0.001) without increasing hypercapnia, and a significant drop in PaCO2 levels (from 74.4 +/- 9 mm Hg to 65.6 +/- 12 mm Hg, p less than 0.005) was even observed. One hour after INPV ended, the mean values of PaO2, PaCO2, oxygen saturation, and pH were also significantly better than prestudy values. We conclude that INPV and oxygen therapy with increasing oxygen flow could constitute an alternative option to intubation and mechanical ventilation in cases of severe hypercapnic respiratory failure due to advanced COPD.     

Effect of home mechanical ventilation on inspiratory muscle strength in COPD

BACKGROUND: The mechanism responsible for chronic hypercapnic respiratory failure (HRF) in patients with COPD remains unclear. In this study, we tested the hypothesis that chronic HRF in patients with COPD is associated with low-frequency fatigue (LFF) of the diaphragm. METHODS: To test this hypothesis, we measured the twitch transdiaphragmatic pressure (Tw Pdi) elicited by stimulation of the phrenic nerves in 25 patients with chronic HRF (mean [+/- SD] Paco(2), 55.2 +/- 5.2 mm Hg) due to COPD before and 2 months after the initiation of noninvasive mechanical ventilation (NIV) [pressure-cycled ventilation with inspiratory positive airway pressure of 19.0 +/- 2.5 cm H(2)O]. We reasoned that had LFF been present, Tw Pdi should rise after effective NIV. RESULTS: The treatment compliance with NIV was good (median of machine usage was 7.1 h per night). Paco(2) decreased from 55.2 +/- 5.2 to 48.8 +/- 5.9 mm Hg (p < 0.001), and Pao(2) increased from 53.1 +/- 5.9 to 57.7 +/- 7.0 mm Hg (p = 0.007). Mean Tw Pdi at baseline was 11.1 +/- 6.6 cm H(2)O and after treatment was 11.7 +/- 7.2 cm H(2)O (not significant). Also, maximal static inspiratory mouth pressure did not change significantly (44.3 +/- 15.9 cm H(2)O vs 46.5 +/- 19.7 cm H(2)O). CONCLUSION: LFF of the diaphragm does not accompany chronic HRF in patients with COPD.     

Effects of acute angiotensin converting enzyme inhibition on renal blood flow in patients with stable congestive heart failure

Renal blood flow was serially measured as the left renal vein blood flow using the continuous thermodilution technique during acute angiotensin converting enzyme inhibition in 20 patients with stable congestive heart failure. Eleven patients received captopril orally, and the remaining nine patients received enalaprilat intravenously. During the control period, left renal vein blood flow and cardiac output did not correlate closely (r = 0.57). Following administration of captopril or enalaprilat, stroke volume index increased from 20 +/- 7 to 25 +/- 8 ml/M2 (p less than 0.001), while pulmonary capillary wedge pressure decreased from 26 +/- 8 to 19 +/- 8 mm Hg (p less than 0.001). Left renal vein blood flow increased in all patients despite a consistent reduction in systemic arterial pressure. At peak effect, left renal vein blood flow increased from 295 +/- 86 to 443 +/- 122 ml/min (p less than 0.001), while mean systemic arterial pressure fell from 81 +/- 13 to 71 +/- 14 mm Hg (p less than 0.001). Thus, in patients with stable congestive heart failure, acute angiotensin converting enzyme inhibition, although decreasing substantially systemic arterial pressure, consistently enhances renal blood flow.     

Reversal of low dose angiotension hypertension by angiotensin receptor antagonists

During acute angiotension II (Ang II) infusion (200 ng/kg/min i.v.) into anesthetized rats, mean arterial pressure rose from 124 +/- 1 to 154 +/- 2 mm Hg. The peptidic Ang II antagonist saralasin lowered arterial pressure in a dose-dependent manner. The maximal decrease in pressure was similar to that observed after the Ang II infusion was discontinued. The nonpeptide Ang II antagonist, 4'-[( 2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole-1-yl] methyl) [1,1'-biphenyl] -2-carboxylic acid (SC-48742), lowered acutely elevated arterial pressure to a level similar to that on discontinuation of the angiotensin infusion. Chronic (8 days) infusion of Ang II (20 ng/kg/min i.v.) increased mean arterial pressure from 116 +/- 3 to 164 +/- 7 mm Hg, which then decreased to 121 +/- 6 mm Hg on termination of the infusion. Saralasin (10 micrograms/kg/min, a maximally effective dose during acute angiotensin infusion) decreased mean arterial pressure from 168 +/- 7 to 141 +/- 3 mm Hg, a pressure significantly higher (p less than 0.05) than the pressure observed after the angiotensin infusion was discontinued. SC-48742 decreased mean arterial pressure from 167 +/- 7 to 127 +/- 3 mm Hg, a pressure not statistically different from the minimum pressure observed after the angiotensin infusion was terminated. The mechanism of blood pressure elevation during acute high dose or chronic low dose Ang II infusion is different, the latter having a significant neural component as measured by the response to trimethaphan. The peptidic antagonist saralasin was fully effective in lowering acute angiotensin hypertension but only partially effective during chronic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bovine regional brain blood flow during sojourn at a simulated altitude of 3500 m

Regional distribution of brain blood flow (15 micron diameter radionuclide labelled microspheres injected into the left atrium) was studied in 6 unanesthetized calves during the 7th-8th weeks of exposure to a simulated altitude of 3500 m (PB = 500 mm Hg). Measurements were made during chronic hypoxemia (PaO2 = 48 +/- 1 mm Hg) and acute normoxemia (PaO2 = 91 +/- 1 mm Hg). Five calves, born and raised at sea level, were also studied in a similar manner during normoxemia (PaO2 = 86 +/- 2 mm Hg) and at 12 and 22 min of acute hypoxemia (PaO2 = 49 +/- 1 mm Hg) to serve as controls. Acute hypoxemia in sea level calves resulted in a marked uniform increase in blood flow to all regions of the brain and the brain O2 delivery remained similar to its normoxemic value. By comparison, however, blood flow in all regions of the brain in calves sojourning at 3500 m remained unchanged between hypoxemia and normoxemia. In these calves brain O2 delivery decreased during hypoxemia. These experiments demonstrated that blood flow in the bovine brain-stem and cerebellum behaved in the same manner as in the cerebrum during exposure to acute as well as chronic hypoxia. It is suggested that there are likely to be differences in adaptation of bovine cerebral circulation to acute vs chronic hypoxia.     

Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis

To determine and to quantify the pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis, we measured in 10 cirrhotics blood gases, P50, hemodynamics, ventilation, and the distribution of ventilation-perfusion ratios (VA/Q) using the multiple inert gas elimination technique. Seven patients had an arterial hypoxemia (PaO2 = 69 +/- 6 mm Hg, mean +/- SD), and three patients were normoxemic (PaO2 = 89 +/- 6 mm Hg). In each hypoxemic patient, the VA/Q distributions were characterized by the presence of low VA/Q units. A negative logarithmic correlation was found between the dispersion of the blood flow distribution and the arterial PO2. An acute inspiratory hypoxia (FIO2, 0.125) elicited an increase in pulmonary vascular resistance by 58.5% in the hypoxemic group and by 81.6% in the normoxemic one (p = NS between the two groups). The percent change in pulmonary vascular resistance induced by hypoxia was not correlated with the percent change in the dispersion of the blood flow distribution. A theoretical analysis showed that the mean arterial PO2 of 69 mm Hg of the hypoxemic group differed from a normal reference value of 96 mm Hg as a result of the combined effects of reduced hemoglobin (-4 mm Hg), increased P50 (+4 mm Hg), increased ventilation (+10 mm Hg), low VA/Q (-35 mm Hg), and true shunt (-2 mm Hg). These results show that the "hypoxemia of liver cirrhosis" is essentially caused by VA/Q mismatching, which is not explained by an abnormal hypoxic pulmonary vasoconstriction.     

Stimulation of the renin-angiotensin system by endothelin subtype A receptor blockade in conscious dogs.

Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ETA/B) or selective endothelin subtype A (ETA) receptor blockade on renal vascular resistance and mean arterial blood pressure. A possible mechanism underlying this interaction may be a stimulation of the renin-angiotensin system during endothelin (ET) receptor blockade. We therefore investigated whether plasma renin activity and renin release are regulated by the ETA receptor. Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ETA receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the administration of LU 135252 (n=5), heart rate (99+/-7 versus 81+/-6 bpm; P<0.05) and renal blood flow (327+/-40 versus 278+/-36 mL/min; P<0.05) were increased significantly, whereas mean arterial blood pressure tended to be lower (93+/-5 versus 105+/-7 mm Hg). These changes were associated with a 2-fold increase in plasma renin activity (0.74+/-0.12 versus 0.37+/-0.10 ng angiotensin I per milliliter per hour; P<0.05). Measurements of renin release at various renal perfusion pressures (n=5) with the use of a vascular occluder implanted around the left renal artery revealed that ETA receptor blockade did not alter renin release at resting renal perfusion pressure (78+/-25 versus 71+/-39 U/min) but strongly enhanced the sensitivity of pressure-dependent renin release <80 mm Hg approximately 2.2-fold. In conclusion, selective ETA receptor blockade is associated with a stimulation of the circulating renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of blood pressure values falling into the low pressure range, where renin release is stimulated. These find-ings strengthen the view that ET and the renin-angiotensin system closely interact to regulate vascular resistance and provide a physiological basis for synergistic hypotensive effects of a combined blockade of both pressor systems.     

Acute hemodynamic and hormonal effects of ramipril in chronic congestive heart failure and comparison with captopril

Acute hemodynamic and hormonal responses to ramipril in comparison with captopril were studied in 10 patients with moderate to severe congestive heart failure in an open, randomized study. Both drugs were given to 5 patients each in 2 increasing doses on 2 successive days. After 5 mg of ramipril angiotensin converting enzyme (ACE) activity was significantly decreased during 24 hours with a maximum decrease 4 hours after administration. Mean arterial blood pressure decreased from 84 +/- 5 to 62 +/- 5 mm Hg at 4 hours and 71 +/- 4 mm Hg at 12 hours, respectively, after this dose. Capillary wedge pressure decreased from 19 +/- 1 mm Hg to 13 +/- 1 mm Hg at 4 hours with a maximum increase in cardiac output from 3.8 +/- 0.3 liters/min to 4.4 +/- 0.3 liters/min at 2 hours. No significant cardiac effects were present 8 hours after administration. After 10 mg of ramipril, cardiac and hormonal effects showed a quicker onset of action and longer duration compared with the 5 mg dose. Mean arterial pressure decreased to 61 +/- 6 mm Hg. Similar effects were seen after captopril, but with a significantly shorter duration. Mean arterial pressure decreased from 82 +/- 4 mm Hg to 64 +/- 5 mm Hg after 12.5 mg and to 58 +/- 6 mm Hg after 25 mg of captopril. In patients with congestive heart failure ramipril has the hemodynamic profile of a long-acting and potent ACE inhibitor. Significant cardiac effects are present during 4 to 8 hours and ACE activity is still significantly inhibited 24 hours after a single dose of ramipril.(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.