Enalapril and Pressure-Diuresis in Hypertensive Rats Transgenic for Mouse Renin Gene

Abstract

The recent development of a transgenic rat strain bearing the mouse ren-2 renin gene [TGR(mRen2)27] has provided a new monogenetic model of hypertension. Other hypertensive rat strains are characterized by a blunted pressure-diuresis-natriuresis response such that higher renal perfusion pressures are required to excrete normal amounts of water and sodium. Dysfunction of the renin-angiotensin and nitric oxide systems may cause in this abnormality. This study examined the effect of enalapril on the pressure-natriuresis response and urinary nitric oxide metabolite excretion in 6-month-old TGR(mRen2)27 rats. The slope of the line relating renal perfusion pressure and urine flow rate in TGR (0.08 ± 0.01 µl · min^-1 · g kidney weight^-1 · mm Hg^-1) was significantly lower than that in control rats (0.15+0.01 µl·min^-1 g kidney weight^-1 mm Hg^-1). Pressure-natriuresis responses were also shifted to higher pressure levels in TGR. Treatment with enalapril for 3 months lowered the mean arterial pressure from 94 ± 2 to 84 ± 4 mm Hg in control rats and from 146 ± 3 to 89+3 mm Hg in TGR. The slopes of lines relating renal perfusion pressure and urine flow rate as well as sodium excretion were significantly increased by enalapril in control and transgenic animals. Urinary nitric oxide metabolite excretion rose similarly with increasing renal perfusion pressure in both control and TGR rats and was not affected by enalapril. These results confirm that older TGR rats have a blunted pressure -diuresis-natriuresis response that can be corrected by inhibition of the renin-angiotensin system and suggest that their production of nitric oxide is normal.

Antihypertensive action of soluble epoxide hydrolase inhibition in Ren‐2 transgenic rats is mediated by suppression of the intrarenal renin–angiotensin system

“…In addition, it has been demonstrated that EETs play an important role in the regulation of the afferent arteriole autoregulatory responses to changes in perfusion pressure by limiting pressure‐mediated vasoconstriction . It was therefore conceivable to assume that net intrarenal deficiency of EETs in TGR contributes to the well‐known impairment of the pressure–natriuresis relationship and, in accordance with the concept originally proposed by Guyton et al . and supported by findings from several other groups, this impairment is the critical mechanism responsible for the pathophysiology of hypertension.…”

“…Moreover, it has been shown that chronic pharmacological blockade of sEH in these models results in an antihypertensive action that is associated with increased intrarenal availability of EETs, as well as improvements in renal haemodynamic autoregulatory efficiency and the pressure–natriuresis relationship . Because TGR reveal a well‐documented impairment of the autoregulation of renal haemodynamic and pressure–natriuresis relationship, and in view of our recent finding that TGR exhibit reduced tissue availability of EETs, we hypothesized that inhibition of sEH may result in an antihypertensive action that is mediated by an increase in EET bioavailability, with consequent improvement of both renal haemodynamic autoregulation and the impaired pressure–natriuresis relationship.…”

Impairment of the autoregulation of renal hemodynamics and of the pressure-natriuresis relationship precedes the development of hypertension in Cyp1a1-Ren-2 transgenic rats

“…It is also well established that the renin-angiotensin system (RAS) can modulate the slope of the pressure-natriuresis mechanism and, when activated, it can lead to a marked suppression of the pressure-natriuresis relationship [17][18][19]. Despite our knowledge, so far it has not been demonstrated that impairment of the pressure-natriuresis mechanism really precedes the development of ANG IIdependent forms of hypertension; all available studies [7][8][9][11][12][13][14][15] have revealed a blunted pressure-natriuresis relationship in ANG II-dependent forms of hypertension only in rats that already exhibited a hypertensive phenotype.…”

“…In addition, it has been demonstrated that the slope of the pressure-natriuresis relationship can be substantially influenced by alterations in the basal levels of angiotensin II (ANG II) and it has been shown that ANG II-dependent models of hypertension exhibit a suppression of the pressure-natriuresis relationship that is implicated to play a role in the pathophysiology of hypertension in these models [7][8][9][10][11][12][13][14][15][16][17][18]. According to the hypothesis proposed by Guyton et al [19], the impairment of the pressure-natriuresis mechanism should precede the development of hypertension.…”

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

“…Solhaug et al (1996a) suggested that NO is vital in the developing kidney to maintain normal physiological function and to protect the immature kidney during pathophysiological stress. Springate et al (1997) noted that mouse renin genetransgenic rats had a blunted pressure-diuresis-natriuresis response that was corrected by inhibition of the renin-ANG system and suggested that their production of NO was normal. It was suggested that the infusion of L-arginine caused diuresis and natriuresis, possibly via the formation of NO in the rat kidney and that endogenous ANG II was not involved in the L-arginine-induced renal actions (Urabe et al, 1996).…”