Renin-Angiotensin System Inhibition in Conscious Dogs during Acute Hypoxemia

Abstract

A B S T R A C T The role of the renin-angiotensin system in mediating the circulatory and metabolic responses to hypoxia was studied in three groups of conscious dogs that were infused continuously with normal saline, teprotide (10 ug/kg per min), and saralasin (1 ,tg/kg per min), respectively. Hypoxia was produced by switching from breathing room air to 5 or 8% oxygen-nitrogen mixture. Plasma renin activity increased from 2.3+0.4 to 4.9±0.8 ng/ml per h during 8% oxygen breathing, and from 2.8±0.4 to 8.4+1.8 ng/ ml per h during 5% oxygen breathing. As expected, cardiac output, heart rate, mean aortic blood pressure, and left ventricular dPldt and dP/dtIP increased during both 5 and 8% oxygen breathing in the saline-treated dogs; greater increases occurred during the more severe hypoxia. Teprotide and saralasin infusion diminished the hemodynamic responses to 5% oxygen breathing, but did not affect the responses to 8% oxygen breathing significantly. In addition, the increased blood flows to the myocardium, kidneys, adrenals, brain, intercostal muscle, and diaphragm that usually occur during 5% oxygen breathing were reduced by both agents. These agents also reduced the increases in plasma norepinephrine concentration during 5% oxygen breathing, but had no effects on tissue aerobic or anaerobic metabolism.In dogs pretreated with propranolol and phentolamine, administration of teprotide (0.5 5% oxygen breathing reduced mean aortic blood pressure and total peripheral vascular resistance, and increased cardiac output and heart rate, but did not affect left ventricular dPldt, dPldtlP, and end-diastolic pressure. Simultaneously, renal and myocardial blood flows increased and myocardial oxygen extraction decreased, while myocardial oxygen consumption did not change significantly.These results suggest that the renin-angiotensin system plays an important role in the hemodynamic responses to severe hypoxia. It appears that angiotensin not only exerts a direct vasoconstrictor action, especially upon the coronary and renal circulations, but also potentiates the cardiovascular effects of sympathetic stimulation that occur during severe hypoxia. INTRODUCTIONIncreasing evidence has accumulated that hypoxia stimulates the renin-angiotensin system. Low oxygen tension increases the granularity of human juxtaglomerular cells cultured in vitro (1). Alveolar hypoxia in vivo also increases the number of granules ofjuxtaglomerular cells (2, 3), plasma renin activity (4, 5), plasma angiotensin II levels (6), and the angiotensin converting enzyme activity both in the lungs and in the serum (7). The mechanisms of renin release during hypoxia are not clearly elucidated. The increase in the granularity of juxtaglomerular cells (1)(2)(3) would suggest a direct action of hypoxia on renin release, but acute local renal perfusion with hypoxic blood did not increase the renin activity in renal venous blood (8). On the other hand, renin may be released by sympathetic discharge (9) produced by hypoxia. Furthermore, renal

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

“…The increase in plasma renin activity (Liang and Gavras, 1978) and circulating angiotensin II (Zakheim et al, 1976) during acute hypoxemia has been observed in previous laboratory investigations in unanesthetized animals. In addition, the rise in plasma renin activity during acute hypercapnic acidosis in conscious dogs has been reported previously (Rose et al, 1982).…”

“…Previous studies which have documented diminished renal function during acute hypoxemia or hypercapnic acidosis were performed in anesthetized, mechanically ventilated animals. To date, induction of moderate acute hypoxemia (Axelrod and Pitts, 1952;Ullman, 1961;Tuffley et al, 1970;Liang and Gavras, 1978) or acute hypercapnic acidosis (Barbour et al, 1953;Anderson et al, 1980;The effects of combined hypoxemia and hypercapnic acidosis on renal and cardiovascular function are poorly understood. Recently, combined acute hypoxemia and hypercapnic acidosis resulted in diminished renal blood flow in conscious dogs (Koehler et al, 1980).…”

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension

“…). A possible potentiating role of angiotensin II in the modulation of HPV is supported by reports of increased RAS activity during acute hypoxia (Liang & Gavras , Hubloue et al . ), but results have been inconsistent (Szidon et al .…”

The role of the renin‐angiotensin system in the renal response to moderate hypoxia in the rat.

“…Not only is the evidence of whether the renin-angiotensin system is activated in hypoxia equivocal, but very few attempts have been made to directly test whether the renin-angiotensin system is important in determining renal haemodynamics or function in systemic hypoxia, the results reported so far being far from comprehensive. Thus, Liang & Gavras (1978) found that in conscious dogs, teprotide, an angiotensin-converting enzyme (ACE) inhibitor, or saralasin, an AII receptor antagonist, reduced the increase in cardiac output, mean arterial pressure (MABP) and renal blood flow (RBF) that were induced by severe hypoxia (5% 02 for 20 min), but not the smaller increases induced by 8% 02. Further, in the Saffananaesthetized cat, another ACE inhibitor, captopril, allowed RBF to increase during systemic hypoxia induced by breathing 6% 02 for 20 min, whereas before captopril it remained constant (Marshall & Metcalfe, 1990).…”