The absence of sympathoexcitation during the development of hypertension in Cyp1a1 Ren-2 transgenic rats

Abstract

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.

Altered Renal Vascular Responsiveness to Vasoactive Agents in Rats with Angiotensin II-Dependent Hypertension and Congestive Heart Failure

“…Our present finding of normal plasma aldosterone levels in sham-operated TGR is in agreement with that of previous studies [ 55 , 56 ], which indicated that the adrenal gland is the major site of Ren-2 renin gene expression; notably, aldosterone production is altered only locally, without affecting circulating aldosterone levels. Moreover, our finding that circulating and intrarenal NE levels are not elevated in sham-operated TGR as compared with sham-operated HanSD rats again supports the previous notion that increased sympathetic nervous system (SNS) activity is not a primary cause of hypertension in the models obtained by the insertion of the mouse Ren-2 renin gene into the rat genome, that is, either TGR or inducible Cyp1a1 Ren-2 TGRs [ 56 – 58 ]. Our novel finding is that even though plasma and kidney ANG 1–7 levels are similar in sham-operated TGR and sham-operated HanSD rats, the circulating and intrarenal balance between the vasodilator axis and vasoconstrictor axis of the RAAS (expressed as ANG 1–7 to ANG II ratio) is shifted toward the latter.…”

Mechanisms Modified by (−)-Epicatechin and Taxifolin Relevant for the Treatment of Hypertension and Viral Infection: Knowledge from Preclinical Studies

“…The interactions between the SNS and RAS play an important role in hypertension development even when hypertension is induced by distinct pathophysiological stimuli in animal models [144][145][146]. The enhanced SNS activity, stimulation of the RAS, increased release of noradrenaline and adrenaline into circulation, and renal vasoconstriction are known hallmarks of hypertension.…”