Systemic hemodynamics and renal function during long-term pathophysiological increases in circulating endothelin

Abstract

Although recent studies have reported endogenous plasma endothelin levels to be elevated two- to fivefold in chronic pathophysiological states, whether such an increase in circulating endothelin levels alone can lead to significant long-term alterations in cardiovascular and renal function is not known. The purpose of this study was to examine the long-term systemic hemodynamic and renal effects of a pathophysiological increase in plasma endothelin concentration in chronically instrumented, conscious dogs (n = 7). Infusion of endothelin-1 (2.5 ng.kg-1.min-1) for 8 days increased plasma concentration of immunoreactive endothelin approximately two- to threefold from 6.7 +/- 0.4 to 16.0 +/- 2.2 pg/ml. Mean arterial pressure increased 21% from a control value of 86.7 +/- 2.1 to 105.0 +/- 2.5 mmHg during the endothelin infusion period. Cardiac output averaged 2,200 +/- 205 ml/min during control and fell by 33% on day 4 of endothelin infusion (1,484 +/- 146 ml/min) and was still 14% below control after day 8 of endothelin infusion (1,885 +/- 154 ml/min). Endothelin increased total peripheral resistance from 42.0 +/- 3.1 to 80.3 +/- 9.1 mmHg.l-1.min. Increasing plasma endothelin two- to threefold was associated with an increase in renal vascular resistance and decreases in glomerular filtration rate and renal plasma flow. Endothelin-1 had no long-term effect on plasma renin activity or aldosterone concentration. These data indicate the importance of pathophysiological levels of endothelin in controlling renal and cardiovascular function in chronic conditions. Furthermore, the results indicate that endothelin may play a role as a mediator of chronic hypertension in pathophysiological states associated with endothelial dysfunction.

Novel Mechanisms Responsible for Postmenopausal Hypertension

“…39,40 Endothelin also stimulates oxidative stress by causing upregulation of the subunits of NAD(P)H oxidase and increasing superoxide. 41 In postmenopausal women, plasma endothelin levels have been shown to be increased.…”

“…Endothelin is a potent vasoconstrictor that, when administered on a long-term basis, causes increases in sodium reabsorption in the kidney 39 and increases blood pressure. 39,40 Endothelin also stimulates oxidative stress by causing upregulation of the subunits of NAD(P)H oxidase and increasing superoxide.…”

Adverse effects of pneumoperitoneum on renal function: involvement of the endothelin and nitric oxide systems

“…Interestingly, in vivo studies revealed that administration of ET-1 resulted in reduced renal hemodynamics and kidney dysfunction, similar to those found during pneumoperitoneum (9). For instance, whole organ studies in intact rats have demonstrated that a shortlasting infusion of ET-1 into the renal artery decreases renal plasma flow (RPF), GFR, and urine volume (5,22,38,46). Similarly, a long-term infusion of ET-1 into conscious dogs results in increased renal vascular resistance and decreased GFR and RPF (5,46).…”

“…For instance, whole organ studies in intact rats have demonstrated that a shortlasting infusion of ET-1 into the renal artery decreases renal plasma flow (RPF), GFR, and urine volume (5,22,38,46). Similarly, a long-term infusion of ET-1 into conscious dogs results in increased renal vascular resistance and decreased GFR and RPF (5,46). Hence, it is proposed that activation of the ET system may be involved in pneumoperitoneum-induced renal dysfunction.…”

Participation of renal and circulating endothelin in salt-sensitive essential hypertension

“…47 In contrast, endothelial ET B stimulation acts as an opposing vasodilator, by enhancing the synthesis of relaxing compounds, such as nitric oxide and prostaglandins. 48 In the kidney, locally generated endothelin produces ET A -mediated vasoconstriction and antinatriuresis 49 but also very important ET B -mediated diuresis and natriuresis via inhibition of vasopressin-induced synthesis of cyclic AMP, 50 and of the activity of tubular Na + /K + ATPase. 51 Endothelins were discovered and described predominantly as pressor agents.…”