Abstract
We examined how systemic blockade of type 1 angiotensin (AT1-) receptors affects reflex control of the circulation and the kidney. In conscious rabbits, the effects of candesartan on responses of systemic and renal hemodynamics and renal excretory function to acute hypoxia, mild hemorrhage, and plasma volume expansion were tested. Candesartan reduced resting mean arterial pressure (MAP, −8 ± 2%) without significantly altering cardiac output (CO), increased renal blood flow (RBF, +38 ± 9%) and reduced renal vascular resistance (RVR, −32 ± 6%). Glomerular filtration rate (GFR) was not significantly altered but sodium excretion (UNa+V) increased fourfold. After vehicle treatment, hypoxia (10% inspired O2 for 30 min) did not significantly alter MAP or CO, but reduced heart rate (HR, −17 ± 6%), increased RVR (+33 ± 16%) and reduced GFR (−46 ± 16%) and UNa+V (−41 ± 17%). Candesartan did not significantly alter these responses. After vehicle treatment, plasma volume expansion increased CO (+35 ± 7%), reduced total peripheral resistance (TPR, −26 ± 5%), increased RBF (+62 ± 23%) and reduced RVR (−32 ± 9%), but did not significantly alter MAP or HR. It also increased UNa+V (803 ± 184%) yet reduced GFR (−47 ± 9%). Candesartan did not significantly alter these responses. After vehicle treatment, mild hemorrhage did not significantly alter MAP but increased HR (+16 ± 3%), reduced CO (−16 ± 4%) and RBF (−18 ± 6%), increased TPR (+18 ± 4%) and tended to increase RVR (+18 ± 9%, P = 0.1), but had little effect on GFR or UNa+V. But after candesartan treatment MAP fell during hemorrhage (−19 ± 1%), while neither TPR nor RVR increased, and GFR (−64 ± 18%) and UNa+V (−83 ± 10%) fell. AT1-receptor activation supports MAP and GFR during hypovolemia. But AT1-receptors appear to play little role in the renal vasoconstriction, hypofiltration, and antinatriuresis accompanying hypoxia, or the systemic and renal vasodilatation and natriuresis accompanying plasma volume expansion.
Highlights
Drugs that interfere with the function of the renin-angiotensin system (RAS) are the most commonly prescribed class of agents for the treatment of hypertension (Muntner et al, 2009; Vitry and Lai, 2009)
ACUTE EFFECTS OF CANDESARTAN Administration of candesartan induced a fall in mean arterial pressure (MAP) (−8 ± 2 mmHg) and increased HR (+14 ± 5 beats/min) and renal blood flow (RBF) (+38 ± 9%), but no significant change in cardiac output (CO) was observed
Our findings support a role for the RAS, through activation of angiotensin II type 1 (AT1)-receptors, in supporting arterial pressure and glomerular filtration in the face of acute blood loss
Summary
Drugs that interfere with the function of the renin-angiotensin system (RAS) are the most commonly prescribed class of agents for the treatment of hypertension (Muntner et al, 2009; Vitry and Lai, 2009) These include inhibitors of angiotensin converting enzyme, angiotensin II type 1 (AT1) receptor antagonists, and the more recently introduced direct renin inhibitors (Riccioni et al, 2010). It is generally accepted that antihypertensive agents that target the RAS system do not impede reflex control of the circulation to the same extent as many other therapeutic modalities (Fridman et al, 1999) This property, in turn, is believed to contribute to their tolerability (Hajjar, 2005). There is a general lack of consensus regarding the effects of AT1-receptor antagonists on reflex control of the circulation and the kidney
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