Synergistic Effects of AT ₁ and ET _A Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model

Abstract

Abstract-Angiotensin II and endothelin may participate in increasing blood pressure and inducing end-organ damage, but the evidence is conflicting. We tested the hypothesis that endothelin A receptor blockade would ameliorate blood pressure and end-organ damage in a rat model of human renin-dependent hypertension. We studied rats that were transgenic for both the human renin and angiotensinogen genes. Experimental groups (nϭ12 each) of untreated transgenic rats, transgenic rats receiving subdepressor doses of losartan (10 mg/kg), transgenic rats receiving LU 135252 (30 mg/kg), transgenic rats receiving both drugs, and nontransgenic rats were studied between 6 to 10 weeks of age. Blood pressure was measured with tail-cuff sphygmomanometry. Gene expression for atrial natriuretic peptide, collagen III, and ACE was measured. The mortality rate in untreated transgenic rats was 42%, which is consistent with previous observations in this line. Single losartan or LU 135252 treatment reduced mortality incidence to 1 rat per group (8%), without significantly lowering blood pressure. In the combination group, blood pressure was normalized and all rats survived. The drug combination also decreased elevated water intake in transgenic rats to normal levels and significantly reduced cardiac hypertrophy. Furthermore, the combination of drugs decreased cardiac atrial natriuretic peptide, ACE gene, and renal collagen III gene expression. We suggest that endothelin participates in this model of angiotensin II-induced hypertension and end-organ damage. Key Words: endothelin Ⅲ angiotensin Ⅲ rats, transgenic Ⅲ hypertrophy, cardiac Ⅲ thirst Ⅲ hypertension, arterial N umerous cellular events are triggered by angiotensin (Ang) II via its Ang II type 1 (AT 1 ) receptor, which can directly stimulate cellular hypertrophy and hyperplasia. Ang II is capable of inducing severe end-organ damage, independent of its blood pressure (BP)-raising effects. 1 ACE inhibitors, AT 1 receptor blockers, and possibly the combination of these agents have proved to be effective treatment for much of Ang II-induced cardiovascular injury. However, complete amelioration is not generally achieved. One possible explanation includes the participation of other pathogenic factors in end-organ damage that are elicited by Ang II or facilitate Ang II-dependent effects. A strong candidate for such secondary effects is the endothelin (ET) system. Ang II was shown to be a powerful stimulator of ET synthesis and release in vascular smooth muscle and endothelial cells. 2,3 Furthermore, Ang II promotes the ability of ET to produce vascular hypertrophy. The importance of ET in these interactions and for cardiovascular damage was recently reviewed. 4,5 The availability of specific antagonists to the two ET receptors (ET A and ET B ) permits the direct testing of such an interaction. We studied the possible pathophysiological role of ET in a unique, high human renin form of hypertension in the transgenic rat (TGR). Rats were made transgenic for the human renin (hREN) gene and c...

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

“…Whereas some authors reported that ET A blockade lowers BP in various hypertensive models, ie, in Sabra salt-sensitive rats, 29 DOCAsalt rats, 30 salt-loaded SHR-SP, 31 or rats transgenic for human angiotensinogen and renin genes. 32 Rothermund et al 10 did not find a protective effect of ET A blockade in heterozygous Ren-2 animals. Although quite opposite to our findings, their results could be explained by different timing of the experiments, ie, different age of animals, and by using heterozygous instead of homozygous animals.…”

Next generation multifunctional angiotensin receptor blockers

“…65 A number of preclinical studies have established that dual blockade of AT 1 and endothelin receptors results in greater blood pressurelowering effects than does the blockade of either receptor alone. [66][67][68][69] An early series of dual AT 1 and ET receptor antagonists was described by Merck, 70 following the recognition of structural and functional similarities between the endothelin and AT 1 receptors, and similar structure-activity relationships seen for their peptide agonist ligands. A starting point for the discovery of bifunctional AT 1 /ET A antagonists was the existing Merck library of compounds blocking the AT 1 receptor.…”

Endothelin-Converting Enzyme Inhibition Ameliorates Angiotensin II–Induced Cardiac Damage

“…The findings document the observation that Ang II-induced cardiac injury is in part mediated by ET-1-related mechanisms. 3,4 We were surprised that long-term ECE inhibitor treatment did not ameliorate renal damage. We showed earlier that the ET A/B receptor blocker bosentan effectively reduced cardiac and renal damage.…”