Myocardial adrenergic dysfunction in rats with transgenic, human renin-dependent hypertension

We investigated cardiac function in rats transgenic for the human renin and angiotensinogen genes (TGR) to test the hypothesis that elevated local angiotensin II precipitates adrenergic dysfunction and abnormal contractile function.

Hearts from TGR and Sprague-Dawley control rats, aged 6 weeks, were studied using the Langendorff model and papillary muscle preparations (n = 6-10 per group). Incremental isoproterenol (1 - 1000 nmol/l) and external Ca2+-concentrations (0.75-6.0 mmol/l) were tested. Cardiac protein and mRNA expression levels were determined by Western blot and RNAase protection assay.

TGR rats showed left ventricular hypertrophy (54%), higher blood pressures (76 mmHg), and elevated plasma renin activity (seven-fold) compared to controls (P < 0.01). The effect of isoproterenol on TGR rat systolic and diastolic left ventricular performance was decreased in both in-vitro models compared to controls (two- to threefold, P < 0.01). TGR rat papillary muscles showed impaired force generation with abnormal basal and Ca2+-dependent relaxation. Gialpha2 and Gialpha3 protein levels were increased (20-30%) and SERCA2a and adenylyl cyclase protein levels were decreased (23 and 37%, respectively) in TGR hearts compared to controls, while Gsalpha or beta1 and beta2-receptor levels were unchanged. Cardiac angiotensin converting enzyme and atrial natriuretic peptide mRNA levels were increased more than four-fold in TGR with no differences for the angiotensin type1 receptor, beta1-receptor, SERCA2a, phospholamban, adenylyl cyclase V and angiotensinogen genes.

TGR rat hearts develop severe adrenergic dysfunction with decreased adenylyl cyclase and abnormal intracellular Ca2+-homeostasis. Our findings emphasize angiotensin II as a major risk factor promoting early functional decline in cardiac hypertrophy. The data may have implications for patients with activating polymorphisms of the renin-angiotensin system and support the need for an early therapeutic intervention.