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Adult Ren-2 gene transgenic rats, TGR(mRen-2)27, exhibit elevated circulating and kidney angiotensin II (Ang II) levels in the presence of severe hypertension. The aim of this study was to examine whether AT1 and AT2 receptors in the kidney and renal hemodynamic and tubular responses to blockade of these receptors were altered in the Ren-2 gene transgenic rats during the maintenance phase of hypertension. Renal AT1 and AT2 receptors were mapped by in vitro autoradiography (n=8), and the effects of blockade of these receptors on mean arterial pressure (MAP), heart rate (HR), and renal cortical (CBF) and medullary blood flows (MBF) were studied in anaesthetized, adult age-matched male homozygous TGR rats (n=12) and Sprague-Dawley (SD) rats (n=7). TGR rats showed higher basal MAP (P<0.001), heart and kidney weight (P<0.001), plasma renin activity (P<0.05) and plasma Ang II level (P<0.05), and CBF (P<0.05) and MBF (P<0.05) than SD rats. AT1 receptor binding was significantly increased in the glomeruli, proximal tubules, and the inner stripe of the outer medulla of TGR rats (P<0.01), while the AT2 receptor binding was low at all renal sites of TGR and SD rats. Immunohistochemistry revealed that this increased AT1 receptor labeling occurred mainly in vascular smooth muscle layer of intrarenal blood vessels including afferent and efferent arterioles, juxtaglomerular apparatus, glomerular mesangial cells, proximal tubular cells, and renomedullary interstitial cells (RMICs) in the transgenic rats. Blockade of AT1 receptors with losartan in TGR rats markedly reduced MAP to the normotensive level (P<0.001) without altering HR. Both CBF (P<0.005) and MBF (P<0.05) were significantly increased by losartan in the transgenic rats. By contrast, losartan only caused a smaller decrease in MAP and an increase in renal CBF in SD rats (P<0.05). PD 123319 was without any renal effect in both SD and TGR rats. These findings suggest that markedly increased AT1 receptors in renal vasculature, glomerular mesangial cells, and RMICs in the presence of fulminant hypertension and elevated circulating and tissue Ang II levels may play an important role in the maintenance of hypertension in the Ren-2 gene transgenic rats.

We have previously demonstrated that angiotensin II stimulates the release of dopamine from the normotensive rat striatum via the AT1 receptor. In this study, the effect of angiotensin II-stimulated striatal dopamine release in the spontaneous hypertensive rat was compared to normotensive controls. In the spontaneous hypertensive rat, angiotensin II stimulated dopamine release to 169 +/- 13% (P < 0.05) in the experimental period, with levels remaining high in the recovery phase, 158 +/- 16% (P < 0.05). This effect was not significantly different from the response in normotensive controls, in which angiotensin II stimulated dopamine release to 149 +/- 18% (P < 0.05) in the experimental period, with the effect also persisting through the recovery period, 244 +/- 62% (P < 0.05). Thus, despite reports of increased activity of the brain angiotensin II and dopamine systems in the spontaneous hypertensive rat, there is no evidence of abnormal regulation of the striatonigral dopamine system.

1. The hypotensive response to captopril in anaesthetized spontanously hypertensive rats (SHR) is not modified by bilateral nephrectomy performed 1 or 24 h previously. 2. Intracerebroventricular injection (i.c.v.) of captopril (2 mg kg-1) significantly lowered blood pressure of conscious SHR over a 7-h period of observation but there was no significant blood pressure response to i.c.v. vehicle, or to intravenous captopril (2 mg kg-1) in SHR. 3. There was no significant blood pressure response to captopril (2 mg kg-1) i.c.v. in the normotensive Wistar Kyoto controls (NT-WK). 4. These results indicate that captopril can lower the blood pressure of SHR by mechanisms independent of the kidneys or the circulating renin-angiotensin system. 5. The hypotensive effect of central captopril in SHR but not in the NT-WK suggests biochemical differences between the brains of the two rat strains.

Preference for 0.9% saline was examined, using two-bottle preference tests over 6-7 days, in the spontaneously hypertensive rat (SHR) and normotensive Wistar Kyoto rat (WK) of the Okamoto strain, the genetically hypertensive (GHR) and normotensive rat (NT) of the Smirk strain, and the Sprague-Dawley (SD), Dark Agouti (DA), and hooded Long-Evans or Brattleboro (BB) rat. Only the SHR exhibited a sustained and marked preference for 0.9% saline on each test day. The WK, GHR, NT, and SD preferred saline in the first 24-48 h of testing but thereafter showed neither a preference for, nor aversion to, saline. The BB showed neither a preference for, nor aversion to, saline in the first 24 h of testing and thereafter showed a significant aversion to saline on each test day. Saline preference was further examined in both the SHR and WK offered a choice of water and 0.9%, 2.0, or 2.7% saline. While preference for saline decreased in both SHR and WK with increasing saline concentration, the SHR maintained a significantly greater preference for saline and greater total sodium intake than the WK at each concentration. Hydralazine (5 mg . kg-1 . day-1, po) administered to SHR, while they were offered a choice of water and 0.9% saline, significantly lowered blood pressure over a 4-day period but failed to alter their saline preference significantly. We conclude that of the seven strains of rats examined only the SHR exhibited a preference for saline in extended two-bottle preference tests. Furthermore this preference for saline appears to be maintained independently of the blood pressure of the SHR.

In conscious spontaneously hypertensive rats, intraxerebroventricular injection of captopril (2 mg/kg) resulted in a rapid hypotensive response that lasted several hours. The same dose given by intracerebroventricular injection had no significant effect on blood pressure (BP) of normotensive Wistar-Kyoto (WK) rats over 7 hours. There was no significant change in BP of conscious spontaneously hpertensive rats (SHR) in response to intracerebroventricular injection of vehicle and only a transitory fall in BP in response to intravenous injection of captopril (2 mg/kg). There was no significant differences between plasma renin activity (PRA) of conscious normotensive WKY rats and the PRA of SHR. These results suggest biochemical differences between the brains of SHR and normotensive WKY control rats. These differences could involve the brain renin-angiotensin system or other neuropeptides.

1. Angiotensin converting enzyme (ACE) was measured in homogenates of regions of rat brain using the substrate Hip-His-Leu. 2. The enzyme resembles classical ACE in its marked Cl- dependence and inhibition by both SQ 20,881 (24 micro mol/1) and EDTA (1 mmol/1). 3. Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (NT-WK) were killed at 20-22 weeks of age their brains dissected into eight regions. 4. There were marked region variations of ACE with highest levels in striatum, hippocampus, cerebellum and pituitary and lower levels in hypothalamus and cerebral cortex. 5. In three brain regions ACE was significantly lower in SHR compared to NT-WK: medulla oblongata (P < 0.05), hypothalamus (P < 0.02) and cerebral cortex (P < 0.05). In the other sites the levels were not different. 6. These region-specific differences of ACE in the SHR could lead to altered production or metabolism of central neuropeptides postulated to be involved in the control of blood pressure.

The drinking response during the 30 minutes following intracerebro-ventricular injection of angiotensin II (AII) (1 to 200 ng) was compared in male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto control rats (WK). SHR drank significantly less than WK at the 10, 50 and 100 ng doses. In contrast, responses to intracerebroventricular carbachol and intraperitoneal hypertonic saline were not different between SHR and WK. These agents are believed to induce drinking by mechanisms independent of angiotensin. Binding of I125-labelled AII to particles prepared from the hypothalamus, thalamus, septum and midbrain (HTSM) region was measured in one month old male and two month old female SHR and their respective age matched WK controls. No differences were found in binding between SHR and WK of either sex. These data demonstrate an impairment of drinking responses in the SHR which seem to be specific for angiotensin. This finding supports the hypothesis that the CNS angiotensin system might be abnormal in these animals.

Once-a-day therapy with spironolactone has been compared with a twice-a-day regimen in an open crossover trial in patients with essential hypertension. When compared with placebo, both treatments significantly lowered blood pressure. Twice-a-day therapy provided slightly better blood pressure control than the once-a-day dosing schedule. There were only minor differences in biochemical findings between the two regimens. Three of the 17 patients developed reversible gynaecomastia.

The effect of oral captopril (30 mg/kg per day) on the blood pressure, plasma aldosterone concentration, urinary electrolytes and brain angiotensin-converting enzyme activity of spontaneously hypertensive rats of the Okamoto strain was examined. Over a seven day period, captopril caused a progressive fall in blood pressure with increased sodium excretion and urine volume and a significant fall in plasma aldosterone concentration. Following captopril, angiotensin converting enzyme activity increased significantly in the midbrain and medulla oblongata; the pituitary level of angiotensin converting enzyme activity was significantly decreased. The hypotensive action of captopril in the spontaneously hypertensive rat is associated with changes in body sodium, water and plasma aldosterone concentration. The alterations in brain angiotensin-converting enzyme activity following captopril treatment suggest that, with chronic administration, captopril can alter the activity of the brain renin-angiotensin system.

1. Oral administration of the angiotensin converting enzyme inhibitor, captopril (30 mg/kg per day) to spontaneously hypertensive rats of the Okamoto strain progressively reduced arterial blood pressure by 60 mmHg over 4-5 days. 2. Oral treatment of spontaneously hypertensive rats with aspirin (200 mg/kg per day) for one week did not alter blood pressure, but it greatly reduced the vasodepressor effects of intravenous injections of arachidonic acid (3 mg/kg). 3. The fall in blood pressure of spontaneously hypertensive rats treated concurrently with both aspirin (200 mg/kg per day) and captopril (30 mg/kg per day) was not different to the fall observed in rats treated with captopril alone. 4. The hypotensive action of captopril in spontaneously hypertensive rats does not appear to be due to stimulation of vasodilator prostanoid biosynthesis.

1. The Na permeability of red cells from spontaneously hypertensive rats (SHR) has been studied. In the Japanese Wister-Kyoto strain, a significant increase of 30% in 22Na influx for male SHR was found compared with normotensive male controls. In contrast the Na influx for genetically hypertensive and normotensive New Zealand rats did not differ. Normotensive Wister-Kyoto rats rendered hypertensive by unilateral renal artery clipping, did not show any difference in Na influx from control animals. 2. These results suggest that the Japanese strain of SHR has a genetically determined increase in erythrocyte Na permeability.

Injection of angiotensin II (AII) into the cerebral ventricles at doses as low as 1 pmol h-1 results in a marked stimulation of salt and water ingestion in the rat. Evidence that AII is produced in the central nervous system independently of the circulating renin-angiotensin system (RAS) raises the possibility that endogenous brain AII is involved in the physiological regulation of thirst. The role of brain AII in salt appetite is still unclear. Here we confirm that the spontaneously hypertensive rat (SHR), believed to have elevated levels of brain AII, possesses an exaggerated salt appetite compared with its normotensive controls. We also show that this exaggerated salt appetite is reduced by chronic central treatment with the angiotensin-converting enzyme inhibitor, captopril, while that of the normotensive controls is unaffected. Our study suggests that a central neuropeptide, probably AII, is involved in the maintenance of the exaggerated salt appetite in this model of hypertension.