bq-123 and Hypertension--Renal

Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade.. We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls -4+/-2%, CRF -13+/-2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8+/-23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (-44.5+/-11.3%, P<0.01 versus placebo) when given alone but not when combined with BQ-788. These changes were accompanied by a reduction in effective filtration fraction. BQ-123, alone or in combination with BQ-788, had minimal effects on the renal circulation in healthy controls, and BQ-788 alone produced both systemic and renal vasoconstriction in CRF and healthy controls.. ETA receptor antagonism was highly effective in lowering blood pressure in CRF patients currently treated for hypertension. In addition, there were effects consistent with a renoprotective action. However, because the ETB receptor appears to play a key role in the maintenance of tonic renal vasodilation, combined ETA/B receptor antagonism, although it lowered blood pressure, did not confer these renal benefits.

Topics: Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Double-Blind Method; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Proteinuria; Renal Circulation; Sodium

Endothelin 1 (ET-1) and its receptors, ETA and ETB, play important roles in regulating renal function and blood pressure, and these components are expressed in sensory nerves. Activation of transient receptor potential vanilloid (TRPV) 1 channels expressed in sensory nerves innervating the renal pelvis enhances afferent renal nerve activity (ARNA), diuresis, and natriuresis. We tested the hypothesis that ET-1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in wild-type (WT) but not TRPV1-null mutant mice. ET-1 alone or with BQ123, an ETA antagonist, perfused into the left renal pelvis increased ipsilateral ARNA in WT but not in TRPV1-null mutant mice, and ARNA increases were greater in the latter. [Ala1, 3,11,15]-endothelin 1, an ETB agonist, increased ARNA that was greater than that induced by ET-1 in WT mice only. [Ala1, 3,11,15]-endothelin 1-induced increases in ARNA were abolished by chelerythrine, a protein kinase C inhibitor, but not by H89, a protein kinase A inhibitor. Chelerythrine, H89, and BQ788, an ETB antagonist, did not affect ARNA triggered by capsaicin in WT mice. Substance P release from the renal pelvis was increased by [Ala1, 3,11,15]-endothelin 1 in WT mice only, and the increase was abolished by chelerythrine but not by H89. Chelerythrine, H89, and BQ788 did not affect capsaicin-induced substance P release. Our data show that ET1 increases ARNA via activation of ETB, whereas ETA counterbalances ETB in WT but not in TRPV1-null mutant mice, suggesting that TRPV1 mediates ETB-dependent increases in ARNA, diuresis, and natriuresis possibly via the protein kinase C pathway.

Topics: Animals; Antihypertensive Agents; Cyclic AMP-Dependent Protein Kinases; Diuresis; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension, Renal; Isoquinolines; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Natriuresis; Neurons, Afferent; Oligopeptides; Peptides, Cyclic; Piperidines; Protein Kinase C; Protein Kinase Inhibitors; Receptor, Endothelin A; Receptor, Endothelin B; Substance P; Sulfonamides; TRPV Cation Channels

As yet, there are only limited data available on the exact role of endothelin (ET) acting through endothelin-A (ETA) receptors in renal sodium and water regulation and the potential functional implications of an interaction of the renal ET system with renal nerves in normotensive and spontaneously hypertensive rats.. Experiments were carried out in 64 male conscious spontaneously hypertensive rats and in 56 normotensive Wistar-Kyoto (WKY) rats. Bilateral renal denervation (BRD) was performed in 32 spontaneously hypertensive rats and 28 WKY rats 7 days before the experiments. The ETA receptor antagonist, BQ-123 (16.4 nmol/kg x min intravenously) or the endothelin-B (ETB) receptor antagonist, BQ-788 (25 nmol/kg x min intravenously) were infused at a rate of 25 microL/min for 50 minutes.. Renal papillary ET-1 concentration in intact spontaneously hypertensive rats was 67.8% lower than in intact WKY rats (154 +/- 40 fmol/mg protein vs. 478 +/- 62 fmol/mg protein, P < 0.01). BRD decreased papillary ET-1 by 73.5% in WKY rats to 127 +/- 19 fmol/mg protein (P < 0.001), but had no effect in spontaneously hypertensive rats (122 +/- 37 fmol/mg protein). BRD, BQ-123, or BQ-788 did not affect glomerular filtration rate (GFR) or renal blood flow (RBF) in any of the groups. In intact WKY, BQ-123 decreased urine flow rate (V) from 4.65 +/- 0.44 microL/min.100 g body weight to 2.44 +/- 0.35 microL/min.100 g body weight (P < 0.01), urinary excretion of sodium (UNaV) from 238.2 +/- 27.4 to 100.2 +/- 17.0 (P < 0.01) and potassium (UKV) from 532.1 +/- 62.6 nmol/min.100 g body weight to 243.0 +/- 34.2 nmol/min.100 g body weight (P < 0.001), whereas BQ-788 decreased only V and UNaV. In renal denervated WKY, BQ-123 or BQ-788 did not alter V, UNaV, or UKV. In intact spontaneously hypertensive rats BQ-123 but not BQ-788 decreased V from 3.94 +/- 0.48 microL/min.100 g body weight to 2.55 +/- 0.44 microL/min.100 g body weight (P < 0.05). In renal denervated spontaneously hypertensive rats neither BQ-123 nor BQ-788 affected V, UNaV, or UKV.. An interaction between ET and renal nerves is involved in the control of renal function. Moreover, renal nerves participate in the regulation of ET-1 production within the kidney. Finally, decreased synthesis of ET-1 in the renal papilla of spontaneously hypertensive rats may contribute to development and/or maintenance of hypertension due to modulation of renal excretory function.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Denervation; Endothelin A Receptor Antagonists; Endothelin-1; Hypertension, Renal; Kidney Cortex; Kidney Medulla; Male; Natriuresis; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin A; Urine

In two kidney-one clip renovascular hypertension (2K1C), blood flow is reduced in the clipped kidney leading to ischaemia. The non-clipped kidney is characterized by increased shear stress. Circulating Ang II is elevated. All these factors are stimuli of the paracrine renal endothelin system. Indeed, we demonstrated an activation of the renal endothelin system in the 2K1C rat model.. We analysed the effects of chronic treatment with the ETA receptor antagonist BQ-123 on blood pressure, heart rate, plasma renin activity, and on the progression of glomerulosclerosis, interstitial fibrosis and vascular remodeling in the clipped and non-clipped kidney.. Long-term treatment with BQ-123 led to a fibrotic atrophy of the clipped kidney characterized by a significantly reduced weight of the clipped kidney compared to the clipped kidney of the placebo-treated group. Computer-aided image analysis revealed a markedly enhanced interstitial fibrosis of these clipped kidneys after long-term ETA blockade. The effects of ETA receptor antagonists on the non-clipped kidney were less pronounced. Neither blood pressure nor plasma renin activity were significantly altered by BQ-123 treatment.. The present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.

Topics: Animals; Atrophy; Creatinine; Endothelin Receptor Antagonists; Fibrosis; Hypertension, Renal; Kidney; Male; Organ Size; Peptides, Cyclic; Rats; Rats, Inbred WKY; Receptor, Endothelin A; Renin

We reported previously that the endothelin converting enzyme (ECE) inhibitor phosphoramidon lowers mean arterial pressure (MAP) when infused in conscious, spontaneously hypertensive rats (SHRs). In this study we determined the dose-response relationship for this action in SHRs and in a high-renin hypertensive model, the renal artery-ligated rat. We also determined whether the ETA receptor antagonist BQ-123 (cyclo [D-Trp-D-Asp-Pro-D-Val-Leu]) might lower MAP in hypertensive rats. Phosphoramidon lowered MAP by 9 +/- 4, 31 +/- 4, and 40 +/- 4 mm Hg after 5 h when infused in SHRs at 10, 20, and 40 mg/kg/h. This lowering of MAP was associated with dose-related inhibition of the pressor response to a bolus intravenous injection of big ET (1-39) at 1 nmol/kg. BQ-123 also lowered MAP in SHRs (by 25 +/- 3 mm Hg), but only at a very high dose (50 mg/kg/h for 5 h). At this dose, BQ-123 blocked the pressor response to a bolus intravenous injection of ET-1 (1 nmol/kg), but the blockade was incomplete. Phosphoramidon infused in conscious, renal hypertensive rats lowered MAP by 31 +/- 9, 46 +/- 8, and 54 +/- 1 mm Hg after 5 h at 10, 20, and 40 mg/kg/h, respectively. This lowering of MAP was associated with blockade of the pressor response to big ET (1-39). BQ-123 did not lower MAP in renal hypertensive rats when infused at 30 mg/kg/h for 5 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Angiotensin I; Animals; Aspartic Acid Endopeptidases; Blood Pressure; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Glycopeptides; Hypertension; Hypertension, Renal; Male; Metalloendopeptidases; Molecular Sequence Data; Neprilysin; Peptides, Cyclic; Protein Precursors; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley