Renal effects of intrathecally injected tachykinins in the conscious saline-loaded rat: receptor and mechanism of action.

Abstract

1. The effects of intrathecally (i.t.) injected substance P (SP), neurokinin A (NKA), [beta-Ala8]NKA (4-10) and [MePhe7]neurokinin B (NKB) at T13 thoracic spinal cord level were investigated on renal excretion of water, sodium and potassium in the conscious saline-loaded rat. Antagonists selective for NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 820; 3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) receptors were used to characterize the spinal effect of SP on renal function. 2. Saline gavage (4.5% of the body weight) enhanced renal excretion of water, sodium and potassium over the subsequent hour of measurement. Whereas these renal responses were not affected by 0.65 nmol SP, the dose of 6.5 nmol SP blocked the natriuretic response (aCSF value 3.9 +/- 0.8; SP value 0.7 +/- 0.3 micromol min(-1), P<0.01) as well as the renal excretion of water (aCSF value 48.9 +/- 5.8; SP value 14.5 +/- 4.0 microl min(-1), P<0.01) and potassium (aCSF value 4.8 +/- 0.6; SP value 1.5 +/- 0.6 micromol min(-1), P<0.01) at 30 min post-injection. SP had no significant effect on urinary osmolality. The SP-induced renal inhibitory effects during the first 30 min were abolished in rats subjected to bilateral renal denervation 1 week earlier or in rats injected i.t. 5 min earlier with 6.5 nmol RP 67580. In contrast, the co-injection of SR 48968 and R 820 (6.5 nmol each) did not affect the inhibitory responses to SP. On their own, these antagonists had no direct effect on renal excretion function. Since SP induced only transient changes in mean arterial blood pressure (-18.8 +/- 3.8 mmHg at 1 min and +6.3 +/- 2.4 mmHg at 5 min post-injection), it is unlikely that the renal effects of SP are due to systemic haemodynamic changes. 3. NKA (6.5 nmol but not 0.65 nmol) produced a transient drop in renal excretion of water (aCSF value 31.2 +/- 5.1; NKA value 11.3 +/- 4.2 microl min(-1), P<0.05), sodium (aCSF value 1.7 +/- 0.8; NKA value 0.4 +/- 0.2 micromol min(-1), P<0.05) and potassium (aCSF value 4.1 +/- 0.7; NKA value 1.5 +/- 0.4 micromol min(-1), P<0.05) at 15 min post-injection. However, the same doses (6.5 nmol) of selective agonists for tachykinin NK2 ([beta-Ala8]NKA(4-10)) and NK3 ([MePhe7]NKB) receptors were devoid of renal effects. 4. This study provided functional evidence that tachykinins may be involved in the renal control of water and electrolyte excretion at the level of the rat spinal cord through the activation of NK1 receptors and the sympathetic renal nerve.