Role of TRPV1 channels in renal haemodynamics and function in Dahl salt-sensitive hypertensive rats

Abstract

This study tests the hypothesis that dysfunction of transient receptor potential vanilloid type 1 (TRPV1) channels occurs and contributes to the decrease in the glomerular filtration rate (GFR) and sodium/water excretion in Dahl salt-sensitive hypertensive rats. Recirculating Krebs-Henseleit buffer added with inulin was perfused at a constant flow in the isolated kidneys of Dahl salt-sensitive (DS) or Dahl salt-resistant (DR) rats fed a high-salt (HS) or low-salt (LS) diet for 3 weeks. Perfusion pressures (PP) were pre-adjusted to three levels ( approximately 100, approximately 150 or approximately 190 mmHg) with or without phenylephrine. Capsaicin, a selective TRPV1 agonist, in the presence or absence of capsazepine, a selective TRPV1 antagonist, was perfused. Basal GFR, urine flow rate (UFR) and Na(+) excretion (U(Na)V) were significantly lower in DS-HS than in DR-HS, DS-LS and DR-LS rats. Capsaicin caused pressure-dependent decreases in PP and increases in GFR, UFR and U(Na)V in all groups, with less magnitude of decreases in PP and increases in GFR, UFR and U(Na)V in DS-HS than in DR-HS, DS-LS and DR-LS rats. Capsazepine completely blocked the effect of capsaicin on PP, GFR, UFR and U(Na)V in all groups. Thus, these results show that TRPV1 function is impaired in the kidney of DS rats fed a high-salt diet, which may contribute to the decrease in GFR and renal excretory function in DS rats in the face of salt challenge.

Figure 1

Mean arterial pressure (MAP, panel A) in Dahl salt-sensitive rats fed a high salt (DS-HS) or a low salt diet (DS-LS) and Dahl salt-resistant rats fed a high salt (DR-HS) or a low salt (DR-LS) diet; basal glomerular filtration rate (GFR, panel B), urine flow rate (UFR, panel C), and sodium excretion (U_NaV, panel D) in the isolated kidney perfused at a basal perfusion pressure of 95–100 mmHg. In panel A: n=16, *p<0.001 vs DS-HS. In panel B: n=5, *p<0.05 vs DS-HS. In panel C: n=5–10, *p<0.001 vs DS-HS. In panel D: n=5, *p<0.05 vs DS-HS.

Figure 2

The effects of capsaicin (Cap, 10µmol/L), a selective agonist of transient receptor potential vanilloid type 1 (TRPV1) channel, on renal perfusion pressure (PP) in the isolated kidneys of Dahl salt-sensitive rats fed a high salt (DS-HS) or a low salt (DS-LS) diet and Dahl salt-resistant rats fed a high salt (DR-HS) or a low salt (DR-LS) diet. The isolated kidneys were perfused at different perfusion pressures: PP1 = 95–100 mmHg (panel A), PP2 = 145–150 mmHg (panel B), PP3 = 185–190 mmHg (panel C). ΔPP representing the differences in PP between Cap and vehicle (panel D). N=5–6. In panel B: *p<0.01 vs corresponding vehicle, +p<0.05 vs DS-HS-Cap. In panel C: *p<0.001 vs corresponding vehicle, +p<0.01 vs DS-HS-Cap. In panel D: *p<0.05 vs corresponding DS-HS, + p<0.001 vs DS-HS(PP1), ++ p<0.001 vs DS-HS(PP2), # p<0.001 vs DR-HS(PP1), ## p<0.01 vs DR-HS(PP2), $ p<0.001 vs DS-LS(PP1), $$ p<0.01 vs DS-LS(PP2), @ p<0.001 vs DR-LS(PP1), @@ p<0.01 vs DR-LS(PP2).

Figure 3

The effects of capsaicin (Cap, 10µmol/L), a selective agonist of transient receptor potential vanilloid type 1 (TRPV1) channel, on glomerular flow rate (GFR) in the isolated kidneys of Dahl salt-sensitive rats fed a high salt (DS-HS) or a low salt (DS-LS) diet and Dahl salt-resistant rats fed a high salt (DR-HS) or a low salt (DR-LS) diet. The isolated kidneys were perfused at different perfusion pressures: PP1 = 95–100 mmHg (panel A), PP2 = 145–150 mmHg (panel B), PP3 = 185–190 mmHg (panel C). ΔGFR representing the differences in GFR between Cap and vehicle (panel D). N=5. In panel A: *p<0.05 vs DS-HS-vehicle, + p<0.01 vs DS-HS-Cap. In panel B: *p<0.01 vs corresponding vehicle, +p<0.01 vs DS-HS-vehicle, # p<0.01 vs DS-HS-Cap. In panel C: *p<0.001 vs corresponding vehicle, +p<0.05 vs DS-HS-vehicle, # p<0.01 vs DS-HS-Cap. In panel D: *p<0.05 vs corresponding DS-HS, + p<0.05 vs DS-HS (PP1), # p<0.01 vs DR-HS (PP1), ## p<0.01 vs DR-HS (PP2), $ p<0.05 vs DS-LS (PP1), $$ p<0.001 vs DS-LS (PP2), @ p<0.001 vs DR-LS (PP1), @@ p<0.001 vs DR-LS (PP2).

Figure 4

The effects of capsaicin (Cap, 10µmol/L), a selective agonist of transient receptor potential vanilloid type 1 (TRPV1) channel, on urine flow rate (UFR) in the isolated kidneys of Dahl salt-sensitive rats fed a high salt (DS-HS) or a low salt (DS-LS) diet and Dahl salt-resistant rats fed a high salt (DR-HS) or a low salt (DR-LS) diet. The isolated kidneys were perfused at different perfusion pressures: PP1 = 95–100 mmHg (panel A), PP2 = 145–150 mmHg (panel B), PP3 = 185–190 mmHg (panel C). ΔUFR representing the differences in UFR between Cap and vehicle (panel D). N=5. In panel A: *p<0.05 vs DS-HS-vehicle, + p<0.01 vs DS-HS-Cap. In panel B: *p<0.01 vs corresponding vehicle, +p<0.01 vs DS-HS-vehicle, # p<0.01 vs DS-HS-Cap. In panel C: *p<0.001 vs corresponding vehicle, +p<0.05 vs DS-HS-vehicle, # p<0.01 vs DS-HS-Cap. In panel D: *p<0.05 vs corresponding DS-HS, + p<0.05 vs DS-HS (PP1) and DS-HS (PP2), # p<0.01 vs DR-HS (PP1), ## p<0.05 vs DR-HS (PP2), $ p<0.05 vs DS-LS (PP1), $$ p<0.01 vs DS-LS (PP2), @ p<0.01 vs DR-LS (PP1), @@ p<0.01 vs DR-LS (PP2).

Figure 5

The effects of capsaicin (Cap, 10µmol/L), a selective agonist of transient receptor potential vanilloid type 1 (TRPV1) channel, on urine Na⁺ excretion (U_NaV) in the isolated kidneys of Dahl salt-sensitive rats fed a high salt (DS-HS) or a low salt (DS-LS) diet and Dahl salt-resistant rats fed a high salt (DR-HS) or a low salt (DR-LS) diet. The isolated kidneys were perfused at different perfusion pressures: PP1 = 95–100 mmHg (panel A), PP2 = 145–150 mmHg (panel B), PP3 = 185–190 mmHg (panel C). ΔU_NaV representing the differences in U_NaV between Cap and vehicle (panel D). N=5. In panel A: *p<0.05 vs DS-HS-vehicle, + p<0.01 vs DS-HS-Cap. In panel B: *p<0.01 vs corresponding vehicle, +p<0.01 vs DS-HS-vehicle, # p<0.01 vs DS-HS-Cap. In panel C: *p<0.001 vs corresponding vehicle, +p<0.05 vs DS-HS-vehicle, # p<0.01 vs DS-HS-Cap. In panel D: *p<0.05 vs corresponding DS-HS, + p<0.05 vs DS-HS (PP1) and DS-HS (PP2), # p<0.01 vs DR-HS (PP1), ## p<0.05 vs DR-HS (PP2), $ p<0.05 vs DS-LS (PP1), $$ p<0.01 vs DS-LS (PP2), @ p<0.01 vs DR-LS (PP1), @@ p<0.01 vs DR-LS (PP2).

Figure 6

The blockade effects of capsazepine (Capz, 30 µmol/L), a selective antagonist of transient receptor potential vanilloid type 1 (TRPV1) channel on capsaicin (Cap, 10 µmol/L)-induced changes in perfusion pressure (PP, panel A), glomerular filtration rate (GFR, panel B), urine flow rate (UFR, panel C), and sodium excretion (U_NaV, panel D) in the isolated kidneys of Dahl salt-sensitive rats fed a high salt (DS-HS) or a low salt (DS-LS) diet and Dahl salt-resistant rats fed a high salt (DR-HS) or a low salt (DR-LS) diet. The isolated kidneys were perfused at perfusion pressure of 185–190 mmHg. N=5. * p<0.01 vs corresponding vehicle and Capz-Cap.