Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

May 1994

Abstract

Although tachykinins have potent vascular actions, their effect on renal resistance blood vessels is currently unknown. The vasoactive properties of tachykinins and related analogs were assessed in isolated perfused rat kidney. At a basal perfusion pressure (PP) of 75 $\pm$ 6 mm Hg (n = 5), bolus injections of substance P (SP) had no significant vasoactive effect. Following a sustained increase in baseline PP (134 $\pm$ 10 mm Hg) produced by phenylephrine (1 $\mu$M), SP evoked a dose-dependent increase in PP. The largest dose of SP increased PP by 60 $\pm$ 5 mm Hg. The vasoconstrictor response to SP was not blocked by phentolamine when angiotensin II was used to increase basal tone. Thus, the response to SP is not mediated by norepinephrine. Pressor responses to SP were not potentiated by peptidase inhibitors, captopril and thiorphan. SP(1-7) had no effect on PP, suggesting that the pressor response to SP is C-terminal dependent and tachykinin receptor mediated. The selective NK-1 receptor agonist, (Sar$\sp9$,Met(O$\sb2)\sp{11}\rbrack$SP, had no effect on PP. In contrast, both the selective NK-2 and NK-3 receptor agonists, GR-64349 and (MePhe$\sp7$) NKB, produced dose-dependent pressor responses (116 $\pm$ 8 and 134 $\pm$ 15 mm Hg increases in PP at 33 nmol, respectively) and were more potent than SP. Infusion of capsaicin (500 nM) produced an initial increase in PP following by a more prolonged decrease in PP. Clamping the renal vein produced a marked increase in PP. The localization of NK-3 receptors in rat kidney evaluated by film autoradiography using $\sp{125}$I- (MePhe$\sp7\rbrack$NKB revealed a high density of specific binding sites on the proximal ureter and renal pelvis, moderate density in the renal vein and its large branches, and a low density in the inner strip of outer medulla, but no specific binding on the renal artery system and cortex. High resolution autoradiograms demonstrated $\sp{125}$I- (MePhe$\sp7\rbrack$NKB binding sites on the tunica media of the renal vein and tunica muscularises of renal pelvis and ureter. Specific binding of $\sp{125}$I-BHSP was found in association with the renal artery and renal pelvis. No specific SP binding sites were associated with renal vein. These data indicate that the pressor effect of tachykinins in the isolated rat kidney can be mediated by NK-2 and/or NK-3 receptors. The latter may be on the vascular smooth muscle of the renal vein.

Document Type

Dissertation - unrestricted

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