Andreas Dr Knorr

Effects of Angiotensin II Type 1 Receptor Blockade and Angiotensin-Converting Enzyme Inhibition on Cardiac β-Adrenergic Signal Transduction

Inhibition of the renin-angiotensin system has been shown to improve symptoms and prognosis in heart failure. We compared the effects of inhibition of angiotensin-converting enzyme or blockade of angiotensin II type 1 (AT1) receptors in a model with renin-induced hypertension that is known to exhibit similar changes in sympathetic activation and beta-adrenergic desensitization, as observed in heart failure. Treatment with captopril (100 mg/kg of feed) or the AT1-antagonist Bay 10-6734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2d gene [TG(mREN2)27]. Neuropeptide Y and angiotensin II levels, adenylyl cyclase activity, beta-adrenergic receptors, G(salpha), and G(ialpha) were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial angiotensin II concentrations. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities and beta-adrenergic receptor density were reduced, whereas the catalyst and G(salpha)-function were unchanged. G(ialpha) protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ventricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroeffector defects are similarly reversed by angiotensin-converting enzyme inhibition or AT1 antagonism. The data support the concept that pharmacological interventions in the myocardial renin-angiotensin system significantly reverse local sympathetic neuroeffector defects. This could be important for the beneficial effects of these agents.

Treatment in Hypertensive Cardiac Hypertrophy, I: Neuropeptide Y and β-Adrenoceptors

In the present study, we investigated serum and myocardial neuropeptide Y concentrations as measures of sympathetic activity as well as myocardial beta-adrenoceptors and beta-adrenoceptor-stimulated adenylyl cyclase activity in spontaneously hypertensive rats (SHR). SHR and control rats at 10 weeks of age were kept on oral treatment with captopril, nitrendipine, or both for 20 weeks. Treatment only slightly reduced but did not normalize blood pressure and cardiac hypertrophy in SHR. The elevated serum concentration of neuropeptide Y, the reduced number of beta-adrenoceptors, and the depressed beta-adrenoceptor-stimulated adenylyl cyclase activity were partly normalized compared with the values observed in control rats. We conclude that antihypertensive treatment, at doses that failed to normalize systolic pressure and to reverse cardiac hypertrophy completely, is able to reduce sympathetic activity in SHR, thereby resensitizing the depressed beta-adrenoceptor-adenylyl cyclase system.

Treatment in hypertensive cardiac hypertrophy. II: Postreceptor events

We investigated the effect of pharmacological treatment with captopril, nitrendipine, and captopril plus nitrendipine on myocardial heterologous adenylyl cyclase desensitization and the underlying postreceptor defects in spontaneously hypertensive rats (SHR). In myocardial membranes from SHR, stimulation of adenylyl cyclase with guanylylimido-diphosphate (P < .001) and forskolin (P < .05) was significantly reduced, whereas no difference with forskolin was obtained in the presence of manganese chloride. Reconstitution of Gs alpha into Gs alpha-deficient S49 cyc- mouse lymphoma cells revealed no difference between SHR and control rats. In contrast, pertussis toxin labeling of Gi alpha was significantly increased in SHR. The reduction of adenylyl cyclase in SHR was abolished after pertussis toxin treatment of membranes. Treatment with captopril, nitrendipine, or both reduced Gi alpha and increased guanylylimidodiphosphate-stimulated adenylyl cyclase activity in SHR. In summary, heterologous adenylyl cyclase desensitization due to an increase of Gi alpha but in the presence of an unchanged activity of Gs alpha or the catalyst occurs in SHR. This alteration, which could contribute to the progression of contractile dysfunction by producing adrenergic subsensitivity, is sensitive to pharmacological treatment most likely because of a reduction of sympathetic activity.