Mouse and rat plasma renin concentration and gene expression in (mRen2)27 transgenic rats.

The (mRen2)27 transgenic rat [TGR(mRen2)27] is said to have low plasma levels of active renin. We used a direct radioimmunoassay (RIA) for mouse submaxillary renin, as well as an indirect enzyme-kinetic assay based on the generation of angiotensin I with modification of the pH optimum, to measure rat and mouse plasma renin activity (PRA), plasma renin concentration (PRC), and plasma prorenin in TGR before and after lisinopril. The relationship between rat PRC and % rat kidney extract was steepest at pH 6.0 and flat at pH 8.5, whereas the relationship between mouse PRC and purified mouse renin was steepest at pH 8.5 and flat at pH 6.0. Mouse PRC was highly correlated with direct RIA measurements (r = 0.93). PRA before lisinopril was little influenced by pH, whereas the increase with lisinopril was greatest at pH 6.5. PRC before lisinopril was fourfold higher at pH 8.5 compared with that at pH 6.0. Lisinopril increased both PRC values but reversed the pH dependency. Prorenin was fourfold higher at pH 8.5 compared with that at pH 6.0 and decreased slightly with lisinopril. Renal renin concentration was higher at pH 6.0 than at pH 8.5. With lisinopril, renal renin concentration increased at both pH values. Mouse PRC was not changed by lisinopril. Ribonuclease protection assay showed both rat and mouse renin gene expression in the kidney, which increased with lisinopril. Thus TGR have circulating active rat and mouse renin and prorenin. The notion that TGR are a "low renin" model should be revised.

Moexipril, a new angiotensin-converting enzyme (ACE) inhibitor: pharmacological characterization and comparison with enalapril.

The pharmacodynamic profile of the new angiotensin-converting enzyme (ACE) inhibitor moexipril and its active diacid, moexiprilat, was studied in vitro and in vivo. In vitro, moexiprilat exhibited a higher inhibitory potency than enalaprilat against both plasma ACE and purified ACE from rabbit lung. Upon oral administration of moexipril (10 mg/kg/day) to spontaneously hypertensive rats, plasma angiotensin II concentration decreased to undetectable levels, plasma ACE activity was inhibited by 98% and plasma angiotensin I concentration increased 8.6-fold 1 h after dosing. At 24 h, plasma angiotensin I and angiotensin II concentrations had returned to pretreatment levels, whereas plasma ACE activity was still inhibited by 56%. Four-week oral administration of moexipril (0.1-30 mg/kg/day) to spontaneously hypertensive rats lowered blood pressure and differentially inhibited ACE activity in plasma, lung, aorta, heart and kidney in a dose-dependent fashion. Equidose treatment (10 mg/kg/day) with moexipril and enalapril over 4 weeks led to comparable decreases in blood pressure, inhibition of plasma ACE and reduction of plasma angiotensinogen and to a similar attenuation of the pressor responses to angiotensin I and potentiation of the depressor responses to bradykinin. In contrast, ACE inhibition in aorta, heart and lung was significantly greater with moexipril than with enalapril, whereas in the kidney both drugs inhibited ACE activity to a similar extent. In summary, moexipril is an orally active ACE inhibitor that is comparable to enalapril in potency and duration of antihypertensive activity. The results of the present study demonstrate that 1) the antihypertensive potency of a given ACE inhibitor cannot be predicted from its in vitro characteristics and 2) the degree of blood pressure reduction does not correlate with tissue ACE inhibition.

Angiotensin as neuromodulator/neurotransmitter in central control of body fluid and electrolyte homeostasis.

Stimulation of central angiotensin receptors promotes, among others, drinking behaviour, stimulation of natriuresis and increased release of vasopressin. Angiotensin (ANG II)-containing pathways in the lamina terminalis and the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, brain areas involved in the regulation of body fluid homeostasis, have been described. All these areas express predominantly AT1 receptors. The drinking response and the vasopressin release to centrally administered ANG II are mediated by AT1 receptors, while AT2 receptors exert inhibitory effects. Evidence for the involvement of the catecholaminergic and angiotensinergic pathways in the PVN and SON in mediating the ANG II-induced release of vasopressin is presented. ANG II is released in the PVN upon local osmotic stimulation and water deprivation. Finally, we present evidence that activation of central angiotensinergic receptors, water deprivation, or hypertonicity induce transcription of immediate-early genes and expression of the respective proteins in the lamina terminalis and in the PVN and SON. The summarized data implicate ANG II as a neuromodulator/neurotransmitter in central control of body fluid and electrolyte homeostasis.

Release of angiotensin in the paraventricular nucleus in response to hyperosmotic stimulation in conscious rats: a microdialysis study.

Angiotensin peptides are thought to act as neurotransmitters or neuromodulators in central osmoregulation. We tested the hypothesis that angiotensin peptides are released in the paraventricular nucleus (PVN) of the hypothalamus upon local osmotic stimulation. Brain microdialysis and radioimmunoassay (RIA) techniques were used to measure the release of immunoreactive angiotensin II (irANG II) in the PVN following direct stimulation of this area with hyperosmotic solutions. In conscious rats, perfusion of the PVN with 0.3 M and 0.6 M NaCl in artificial cerebrospinal fluid (aCSF) elicited concentration-dependent increases in irANG II release to 5.52 +/- 0.53, (P < 0.01, n = 8) and 9.01 +/- 1.03 pg/100 microliters, (P < 0.001, n = 7), respectively, from basal values of 3.04 +/- 0.46 pg/100 microliters. Local perfusion of the PVN with 1.2 M glucose in aCSF also resulted in an increased release of irANG II from 3.07 +/- 0.87 to 6.24 +/- 0.45 pg/100 microliters (P < 0.05, n = 5). Fractionization of angiotensin peptides by HPLC followed by RIA revealed that ANG II (1-8) and ANG III (2-8) were released in similar amounts in the perfusate collected during 0.6 M NaCl stimulation (4.79 +/- 0.69 and 3.45 +/- 0.76 pg/100 microliters, respectively). Our results show that both, ANG II and ANG III are released in the PVN in response to local hyperosmotic stimulation. They support the concept that angiotensin peptides in the PVN are involved as neurotransmitters in central osmotic control.