Role of Substance P in Blood Pressure Regulation in Salt-Dependent Experimental Hypertension

Abstract

The partlclpatlon of substance Pm the pathogenesls of five models of expenmental hypertension, le, DOCA-salt, subtotal nephrectomy, one-kidney-one chp renovascular, two-kldney-one clip renovascular, and spontaneous hypertension, was evaluated via an acute infusion of a newly synthesized potent, specific nonpeptlde antagonist of substance P at the NK-1 receptor, the agent CP 96,345 In conscious unrestrained rats, CP 96,345 induced significant and sustained increases m mean arterial pressure of DOCA-salt, subtotal nephrectomy, and onekidney-one clip renovascular hypertensive rats but only small and nonslgmficant changes m blood pressure of two-hdney-one chp renovascular and spontaneously hypertensive rats CP 96,345 had no effect on the blood pressure of sham-treated controls and Wlstar-Kyoto rats This NK-1 receptor antagomst did not sIgnifscantly affect the heart rate of any expenmental model studied The data suggest that endogenous substance P may act as a partial counterregulatory mechanism against vasoconstrlctlon m models of salt-dependent hypertension (Hypertension. 1997;29[part 21: 506-509.) Key Words l experlmental hypertension l sodlumdependent hypertension l substance P l receptors NK-I l tachyknuns S ubstance P, a member of the family of tachykmms,' 1s involved m numerous physlologlcal actlvmes, such as neurotransmlssion-neuromodulatlon,*,3 stlmulatlon of salivary secretIon, smooth muscle contraction,5 and vasodilatlon.6.7The vasochlatory action of substance P 1s endothelmm dependentg9 and is mediated by the neurokmm NK-1 receptors located on the endothehal cells. Besides its vasodllatory properties, m some vascular beds substance P also exerts a contracting action on the vascular smooth muscle lo-12 These vasoactlve properties of substance P enable this peptide to participate m the regulation of blood flow of various organs 5.6The participation of endogenous substance P in hypertension has been evaluated by a few mvestlgators, mainly by measurement of the plasma levels of this peptide,'? 14 whereas the pharmacological effects have been explored by administration of synthetic substance P or related analogues 15.16 Reduced plasma levels of this peptlde have been described m both stroke-prone spontaneously hypertensive rats 13 and m human essential hypertennon, 14 suggestmg that elevated blood pressure m these SubJects could be related, at least m part, to the lack of adequate counterregulatory action exerted by this endogenous vasodllator.Recently, a potent, specific, nonpeptlde antagonist of the NK-1 receptor, devoid of agomstlc actions was syn- In previous studies from our laboratories, we were able to demonstrate that an acute mfuslon of this compound increases blood pressure of DOCA-salt hypertensive rats m the early stages (6 weeks) of the hypertensive state However, when we Infused the same agent m rats at later phases of DOCA-salt hypertension (12 weeks), no wgmficant increases m blood pressure were observed 1~0 These observations suggest that partlclpatlon of substance P m the pathoge...

Substance P in Subtotal Nephrectomy-Salt Hypertension

“…This is unlikely as in our previous studies on DOC-salt hypertension, control animals that underwent uninephrectomy did not exhibit a pressor response on intravenous administration of span-II. 15 The results presented herein are consistent with the findings of Kohlmann et al, 10 who showed that acute inhibition of the NK-1 receptor with a non-peptide SP antagonist increased the MAP in 3 salt-dependent models, DOC-salt, SN-salt, and 1-kidney-1 clip, but failed to do so in genetic and saltindependent models such as the spontaneously hypertensive rats (SHR) and the 2-kidney-1 clip model. We have since extended these results to the DOC-salt model of hypertension, in which the neuronal expression and release of SP is increased as a compensatory mechanism to the elevated BP, 15 and in the DAHL-salt model (a genetic and salt-independent model of hypertension), in which SP does not seem to play a compensatory vasodilator role.…”

“…7,8 Whereas in DOC-salt hypertension the antihypertensive activity of CGRP is mediated through an increase in neuronal expression and peptide release, in SN-salt hypertension this antihypertensive activity is mediated via enhanced sensitivity of the vasculature to the vasodilator activity of this peptide. 9 Likewise, Kohlmann et al 10 reported that endogenous SP acts to attenuate the blood pressure (BP) increase in 3 rat models of salt-dependent hypertension, including the SN-salt model. However, the status of SP expression, peptide release, as well as the mechanism of its counterregulatory role has not been determined in this setting.…”

Calcitonin gene-related peptide and substance P contribute to reduced blood pressure in sympathectomized rats

“…2B). The MAP began to rise 30 s after administration and was elevated for ϳ180 s similar to CGRP 8 -37. Spantide II is a peptide that is also rapidly degraded in the circulation (33). No significant changes in heart rate were observed with either antagonist.…”

“…In previous studies (3,11,14,20,32,33,45,50,51,53) the participation of these sensory neuropeptides in the regulation of systemic BP has been observed primarily in rodent models of experimental hypertension. In these studies our laboratory and others have reported that CGRP and/or SP play a compensatory vasodilator role in pulmonary hypertension (3,11,32,53); DOC salt (30,50); SN salt (51); two-kidney, one-clip (14); and L-NAME-induced hypertension during pregnancy (20).…”

“…Our laboratory and other investigators (31,47,49) have previously reported that in the SHR there is an age-related decrease in the expression of CGRP that may contribute to the elevated BP observed in this setting. SP expression is also markedly reduced in this strain of genetically hypertensive rat (33). In addition, neonatal sympathectomy of the SHR significantly attenuates the development of hypertension.…”