Abnormal pressure-natriuresis in hypertension: role of cytochrome P450 metabolites of arachidonic acid.

The pressure-natriuresis relationship is shifted to higher pressures in genetic and experimental models of hypertension; however, the factors responsible for altering kidney function remain to be determined. In spontaneously hypertensive (SHR) and Lyon hypertensive rats, the resetting of pressure-natriuresis results from increased preglomerular renal vascular tone, whereas sodium reabsorption is elevated in the thick ascending loop of Henle (TALH) of Dahl S rats. Recently, a new route for the renal metabolism of arachidonic acid (AA) has been described, and there is evidence that this pathway contributes to the resetting of renal function in hypertension. In the kidney, cytochrome P450 (CYP) enzymes metabolize AA primarily to 20-HETE and EETs. 20-HETE is a potent constrictor of renal arterioles that has an important role in autoregulation of renal blood flow and tubuloglomerular feedback. 20-HETE and EETS also inhibit sodium reabsorption in the proximal tubule and TALH. In the SHR, the renal production of 20-HETE is elevated and inhibitors of the formation of 20-HETE decrease arterial pressure. Blockade of 20-HETE formation also reduces blood pressure or improves renal function in deoxycorticosterone acetate (DOCA)-salt, angiotensin II--infused, and Lyon hypertensive rats. In contrast, 20-HETE formation is reduced in the TALH of Dahl S rats and this contributes to elevated sodium reabsorption. Induction of 20-HETE synthesis improves pressure-natriuresis and lowers blood pressure in Dahl S rats, whereas inhibitors of the synthesis of 20-HETE promote the development of hypertension in Lewis rats. These findings indicate that the renal production of CYP metabolites of AA is altered in genetic and experimental models of hypertension and that this system contributes to the resetting of pressure-natriuresis and the development of hypertension in some models.

Effects of converting enzyme inhibitors on renal P-450 metabolism of arachidonic acid.

The effects of blockade of the renin-angiotensin system on the renal metabolism of arachidonic acid (AA) were examined. Male Sprague-Dawley rats were treated with vehicle, captopril (25 mg x kg(-1) x day(-1)), enalapril (10 mg x kg(-1) x day(-1)), or candesartan (1 mg x kg(-1) x day(-1)) for 1 wk. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) by renal cortical microsomes increased in rats treated with captopril by 59 and 24% and by 90 and 58% in rats treated with enalapril. Captopril and enalapril increased 20-HETE production in the outer medulla by 100 and 143%, respectively. In contrast, blockade of ANG II type 1 receptors with candesartan had no effect on the renal metabolism of AA. Captopril and enalapril increased cytochrome P-450 (CYP450) reductase protein levels in the renal cortex and outer medulla and the expression of CYP450 4A protein in the outer medulla. The effects of captopril on the renal metabolism of AA were prevented by the bradykinin-receptor antagonist, HOE-140, or the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester. These results suggest that angiotensin-converting enzyme inhibitors may increase the formation of 20-HETE and EETs secondary to increases in the intrarenal levels of kinins and NO.

Intrarenal infusion of bradykinin elicits a pressor response in conscious rats via a B2-receptor mechanism.

Bradykinin (BK) is a peptide known to activate afferent nerve fibers from the kidney and elicit reflex changes in the cardiovascular system. The present study was specifically designed to test the hypothesis that bradykinin B2 receptors mediated the pressor responses elicited during intrarenal bradykinin administration. Pulsed Doppler flow probes were positioned around the left renal artery to measure renal blood flow (RBF). A catheter, to permit selective intrarenal administration of BK, was advanced into the proximal left renal artery. The femoral artery was cannulated to measure mean arterial pressure (MAP). MAP, heart rate (HR), and RBF were recorded from conscious unrestrained rats while five-point cumulative dose-response curves during an intrarenal infusion of BK (5-80 microg x kg(-1) x min(-1)) were constructed. Intrarenal infusion of BK elicited dose-dependent increases in MAP (maximum pressor response, 26+/-3 mmHg), accompanied by a significant tachycardia (130+/-18 beats/min) and a 28% increase in RBF. Ganglionic blockade abolished the BK-induced increases in MAP (maximum response, -6+/-5 mmHg), HR (maximum response 31+/-14 beats/min), and RBF (maximum response, 7+/-2%). Selective intrarenal B2-receptor blockade with HOE-140 (50 microg/kg intrarenal bolus) abolished the increases in MAP and HR observed during intrarenal infusion of BK (maximum MAP response, -2+/-3 mmHg; maximum HR response, 15+/-11 beats/min). Similarly, the increases in RBF were prevented after HOE-140 treatment. In fact, after HOE-140, intrarenal BK produced a significant decrease in RBF (22%) at the highest dose of BK. Results from this study show that the cardiovascular responses elicited by intrarenal BK are mediated predominantly via a B2-receptor mechanism.

Bradykinin B2-receptors mediate the pressor and renal hemodynamic effects of intravenous bradykinin in conscious rats.

Bradykinin (BK) is a peptide which evokes remarkably different changes in cardiovascular function. Systemic bolus injection of BK results in a rapid drop in blood pressure via an endothelium-dependent mechanism. On the other hand, local administration of BK can activate a powerful pressor reflex by stimulating afferent nerves located in the abdominal viscera, the heart, and the kidney. In the present study, the cardiovascular and renal hemodynamic effects during sustained (intravenous infusion) and transient (intravenous bolus injection) elevations in circulating BK were characterized and the receptor mechanism eliciting these effects was investigated. Mean arterial pressure (MAP), heart rate (HR), and renal blood flow (RBF) were recorded from conscious unrestrained rats while five-point cumulative dose-response curves were constructed during infusion or bolus injection of BK (5-80 microg kg(-1)). Infusion of BK produced dose-dependent increases in MAP (maximum response = 27 +/- 3 mmHg) accompanied by a significant tachycardia (maximum response = 159 +/- 20 bpm), a 28 +/- 6% increase in RBF, and no changes in renal vascular resistance (RVR). The BK-induced increases in MAP, HR, and RBF were abolished after treatment with a ganglion blocker (maximum responses: MAP = 2 +/- 3 mmHg, HR = 13 +/- 4 bpm, RBF = 4 +/- 2%) or with an agent which blocks B2-receptors (maximum responses: MAP = 1 +/- 1 mmHg, HR = 6 +/- 5 bpm, RBF = 6 +/- 2%). In marked contrast, bolus administration of BK resulted in hypotensive responses (maximum decline in MAP = -37 +/- 4 mmHg), reflex tachycardia (maximum increase in HR = 45 +/- 9 bpm), increases in RBF (maximum response = 13 +/- 4%), and significant reductions in RVR (maximum response = 38 +/- 5%). These responses were also prevented when B2-receptors were blocked (maximum responses: MAP = 3 +/- 2 mmHg, HR = 17 +/- 6 bpm, RBF = 3 +/- 3%, RVR = 9 +/- 4%). In summary, BK infusions activated a cardiopressor reflex while BK injections caused hypotension. These opposite effects were both mediated via B2-receptors. These findings suggest that BK can have complex effects on the cardiovascular system that may be dependent on the sites, magnitude, and duration of elevated BK concentrations.