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Biomedical subjects

D Ganten

Publications and source records attributed to D Ganten.

At least 91 records · Page 5Linked to original sources
PubMed1997

Cardiac angiotensin II receptors: studies on functional coupling in Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats.

The renin-angiotensin system plays an important role in the pathogenesis of cardiac hypertrophy and chronic heart failure as angiotensin II has been shown to induce cardiac hypertrophy and fibrosis. Besides these structural alterations, functional effects on cardiomyocytes have been reported in different mammalian species. Angiotensin II is known to produce a positive inotropic effect in some species, and differences in atrial and ventricular myocardium have been described. So far, the molecular events which govern angiotensin II-mediated changes in cardiac contractility are not completely understood. In order to study the dependency of the angiotensin II-induced positive inotropic effect on receptor density, we examined the effect of angiotensin II on cardiac function in atria, papillary muscles and isolated ventricular cardiomyocytes from adult Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats, which expressed the human angiotensin AT1 receptor (hAT1) specifically in the heart. In atrial myocardium from adult Sprague-Dawley rats, angiotensin II (30 micromol/l) produced an AT1-mediated positive inotropic effect (38.5% of control), whereas in papillary muscles and isolated ventricular myocytes, no inotropic response was observed. As shown by polymerase chain reaction (PCR) and radioligand binding, the human angiotensin AT1 receptor was exclusively expressed in transgenic animals, which markedly overexpressed the angiotensin AT1 receptor. However, in transgenic rats the positive inotropic effect in atrial preparations was similar to the controls, and neither in papillary muscles nor in isolated cardiomyocytes the increase in receptor density led to an inotropic effect induced by angiotensin II. These data suggest that the existence of functionally uncoupled receptors rather than the low density of receptors at the ventricular site is responsible for the inability of ventricular myocardium to respond to angiotensin II.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1997

High levels of human chymase expression in the pineal and pituitary glands.

The brain renin-angiotensin system plays a role in both cardiovascular homeostasis and neurosecretory functions. Since the mechanisms of angiotensin (Ang) II formation in the human brain have not been clarified, the aims of the present study were to determine the presence of human chymase and angiotensin I-converting enzyme (ACE) in human and non-human brains. In the human brain, the total Ang II-forming activity was significantly higher in the pineal and pituitary glands than those in other regions. In other species (rat, bovine and porcine), the level of chymase as well as total Ang II-forming activities in pineal glands were significantly lower than those in human glands. High levels of chymase-like immunoreactivity (ir) were found in the arteriolar endothelial cells, adventitial mesenchymal cells and in parenchymal cells of the human pineal and pituitary glands while ACE-ir was mostly observed in the endothelial cells and occasionally found in parenchymal cells. Our study provides the first evidence that human chymase exists in the pineal and pituitary glands. The remarkable regional and species differences in mechanisms of Ang II formation suggest a specific role of chymase or ACE in the human brain.

Adult↗
PubMed1997

Increased potency of neuropeptide Y to antagonize alpha2-adrenoceptor function in the nucleus tractus solitarii of the spontaneously hypertensive rat.

The regulation by neuropeptide Y of alpha2-adrenoceptors in the nucleus tractus solitarii was evaluated in the adult normotensive Wistar Kyoto rat and the adult spontaneously hypertensive rat. The microinjection of a submaximal dose of l-noradrenaline (800 pmol in 50 nl) alone into the nucleus tractus solitarii produced a significant reduction in the mean arterial blood pressure in either strain. The threshold dose (1 pmol in 50 nl) of neuropeptide Y(1-36) for the vasodepressor response in the Wistar Kyoto rat was five times higher than that (0.2 pmol in 50 nl) in the spontaneously hypertensive rat. Furthermore, neuropeptide Y(1-36) at 0.2 pmol in 50 nl could significantly counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl) in the spontaneously hypertensive rat, but not in the Wistar Kyoto rat, in which 1 pmol in 50 nl of neuropeptide Y(1-36) must be employed to counteract the vasodepressor response to l-noradrenaline (800 pmol in 50 nl), although the vasodepressor responses are of a similar magnitude. The in situ hybridization and quantitative receptor autoradiographical experiments showed that the alpha2A-adrenoceptor messenger RNA levels and the B(max) value of the alpha2-adrenoceptor agonist [3H]p-aminoclonidine binding sites measured in the nucleus tractus solitarii of the spontaneously hypertensive rat were substantially lower than those in the Wistar Kyoto rat. The quantitative receptor autoradiographical results were consistent with the cardiovascular results and showed that in the spontaneously hypertensive rat, neuropeptide Y(1-36) at 1 nM led to a significant increase in the K(d) value of [3H]p-aminoclonidine binding sites. In the Wistar Kyoto rat, neuropeptide Y(1-36) produced this effect only at 10 nM. The present study provides evidence for an increase of the potency of neuropeptide Y(1-36) to antagonistically modulate alpha2-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat. This enhanced antagonistic action may partly be related to a reduction in the number of alpha2A-adrenoceptors in the nucleus tractus solitarii of the spontaneously hypertensive rat, since a decrease has been observed in the alpha2A-adrenoceptor messenger RNA levels and the alpha2-adrenoceptor binding sites in the spontaneously hypertensive rat. This increased potency of neuropeptide Y(1-36) to antagonize alpha2-adrenoceptor function in the nucleus tractus solitarii of the spontaneously hypertensive rat may contribute to the development of high blood pressure in this hypertensive strain.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1997

Localization of angiotensin II AT1 receptor-like immunoreactivity in catecholaminergic neurons of the rat medulla oblongata.

There exist at least two distinct subtypes of angiotensin II receptors in the brain, namely the AT1 and AT2 subtypes. The high density of angiotensin II AT1 receptors is present in the medulla oblongata. The AT1 subtype of angiotensin II receptors mainly mediates central cardiovascular events. In the present study a polyclonal antibody against the angiotensin II AT1 receptor and a monoclonal antibody against tyrosine hydroxylase were employed to evaluate the possible presence of angiotensin II AT1 receptor-like immunoreactivity in the catecholaminergic neurons of the rat medulla oblongata by means of the double colour immunofluorescence technique. A weak, diffuse cytoplasmic angiotensin II AT1 receptor-like immunoreactivity was observed in almost all the catecholaminergic cell bodies of the A2, C1, C2 and C3 cell groups, except those of the A1 cell group containing moderately intense, diffuse cytoplasmic angiotensin II AT1 receptor-like immunoreactivity, occasionally found in the noradrenergic dendrites of the A1 cell group. There was a higher density of the angiotensin II AT1 receptor-like immunoreactive profiles in the A2 cell group area than in other catecholaminergic cell group areas. In addition, the angiotensin II AT1 receptor-like immunoreactivity was seen in non-catecholaminergic neurons. The present results provide evidence for the existence of the specific angiotensin II AT1 receptor-like immunoreactivity in the noradrenergic and adrenergic neurons of the rat medulla oblongata known to have a cardiovascular role. Thus, the findings support the view that angiotensin II AT1 receptors in the medulla oblongata participate in cardiovascular control and indicate a cellular substrate for the documented interaction between the angiotensin II and adrenergic transmission lines in cardiovascular function at the level of the nucleus tractus solitarii.

Adrenergic Fibers↗
PubMed1997

Endothelial injury in transgenic (mRen-2)27 hypertensive rats.

Transgenic [(mRen-2)27] rats develop severe hypertension as the result of transfection with the mouse Ren-2 gene. This study tested the hypothesis that hypertensive [(mRen-2)27] rats have increased endothelial dysfunction by examining the extent of vascular endothelial cell injury and turnover within the thoracic aorta of age-matched female transgene positive [Tg(+)] and transgene negative [Tg(-)] littermates. Transgenic hypertensive rats had arterial pressures significantly higher than Tg(-) animals, but no differences in heart rate or body weight. The extent of endothelial cell injury was estimated in Haütchen preparations of thoracic aorta endothelium by counting cells immunostained for the presence of cytoplasmic immunoglobulin G (IgG) at sites with or without intercostal artery branches. Both Tg(+) and Tg(-) littermates had a greater percentage of injured endothelial cells at branch sites than at nonbranch aorta (P < .01). However, the number of vascular endothelial cells staining positively for IgG was significantly higher in hypertensive rats both at sites away from (P < .05) and in the immediate vicinity of (P < .1) the orifices of intercostal arteries. En face preparations of the thoracic aorta were also examined for cells incorporating 5-bromo-2 '-deoxyuridine (BrdU) to estimate the percentage of endothelial cells undergoing replication. There was no difference in endothelial cell replication at either branch or nonbranch sites between hypertensive and normotensive rats. However, the percentage of endothelial cells undergoing replication at branch sites in both Tg(+) and Tg(-) rats was significantly greater than at nonbranch sites (P < .01). These data provide the first demonstration for the effects of high blood pressure on the vascular endothelium of a monogenetic model of hypertension produced by increased activity of the renin-angiotensin system. The divergent effects of this form of hypertension on vascular endothelial injury and endothelial turnover suggest that the decrease in the reparative capacity of the vascular endothelium induced by the combination of hypertension and associated angiotensinemia may contribute to the endothelial dysfunction accompanying vascular remodeling.

Animals↗
PubMed1997

Chronic estrogen treatment in female transgenic (mRen2)27 hypertensive rats augments endothelium-derived nitric oxide release.

Postmenopausal estrogen replacement therapy is associated with a reduction in cardiovascular events in women, but the mechanisms for this protection are unclear, especially in hypertensive subjects. In this study we investigated the effects of 17beta-estradiol (E2) treatment on blood pressure and endothelial function of transgenic [(mRen2)27] hypertensive and normotensive rats. Thirty female transgenic negative [Tg(-)] and hypertensive positive [Tg(+)] rats were ovariectomized and received either E2 (1.5 mg/rat, subcutaneously, for 3 weeks) or placebo. Chronic 17beta-estradiol treatment lowered mean blood pressure in both Tg hypertensive (159 +/- 4 v 145 +/- 4 mm Hg, P < .05, placebo v E2) and normotensive rats (119 +/- 4 v 108 +/- 2 mm Hg, P < .05, placebo v E2). Pressor responses to intravenous injection of phenylephrine were augmented in the Tg(+) as compared with Tg(-) rats. With chronic E2 treatment the pressor responses to phenylephrine were attenuated in both groups. Isometric tension of aortic rings was measured in vitro in organ chambers. The acetylcholine (Ach)-induced endothelium-dependent vascular relaxation was less potent in Tg(+) versus Tg(-) rats. E2 treatment significantly enhanced the Ach-induced relaxation of both Tg(+) and Tg(-) groups (ED50: 55.5 +/- 11.7 v 10.3 +/- 2.6; 23.8 +/- 6.5 v 5.1 +/- 1.2 nmol/L, placebo v E2 in Tg(+) and Tg(-), respectively). After E2 treatment the ED50 response in Tg(+) rats was no different from Tg(-) rats. However, the maximum vasodilation elicited by Ach was attenuated in Tg(+) as compared with Tg(-) rats. The calcium ionophore (A23187)-induced endothelium-dependent relaxation was less potent in Tg(+) as compared to Tg(-) rats and was enhanced by E2 treatment only in Tg(+) animals. There were no differences in the vasodilator responses elicited by sodium nitroprusside. Removal of endothelium and blockade of NO production abolished the endothelium-dependent vasodilation. The selective NO synthase inhibitor, N(G)-monomethyl-L-arginine (LMMNA), was used to evaluate indirectly the basal contribution of NO in vascular rings. The response to LMMNA was attenuated in untreated Tg(+) as compared to Tg(-) rats. E2 treatment augmented the contraction response to NOS inhibition in both Tg(+) and Tg(-) rats, resulting in a response in Tg(+) rats that was no different from Tg(-) rats. These results indicate that untreated, surgically ovariectomized hypertensive rats show deficiencies in endothelial function, which can be improved by estrogen replacement.

Animals↗
PubMed1997

Renovascular hypertension with low-to-normal plasma renin: clinical and angiographic features.

1. Low-to-normal renin renovascular hypertension (RVH) and the accuracy of renal vein renin ratios were investigated in 129 consecutive patients referred for suspected RVH. Forty-nine had essential hypertension, 24 unilateral renoparenchymal hypertension and 56 renal artery obstruction. Of the latter, 86% were diagnosed retrospectively as RVH, based on fall in blood pressure with correction of renal ischaemia. We measured baseline, captopril-stimulated and renal vein plasma renin activity (PRA) levels, as well as several other parameters. 2. PRA was low-to-normal in 37% of the RVH patients [low-to-normal renin (LNR-) RVH group] and elevated in the remaining 63% [high-renin (HR-) RVH group]. In the LNR-RVH group, low-to-normal renin levels, by immunoreactive active renin and plasma renin concentration measurements, and a blunted response of PRA to captopril, were seen. As compared with HR-RVH, LNR-RVH patients had a longer duration of hypertension (P < 0.05), higher serum K+ (P = 0.04) and lower diastolic blood pressure (P = 0.02). However, they did not differ for the other variables, including the fall in blood pressure after correction of renal ischaemia. Although the number of bilateral stenoses was similar in the two groups, no patient in the LNR-RVH group had total renal artery occlusion compared with 53% in the HR-RVH group (P = 0.00015). The accuracy of renal vein renin indices were high enough to justify their use only in the patients with total occlusion of a renal artery. 3. Thus LNR-RVH is common in patients with longstanding hypertension without a totally occluded renal artery. Since the sensitivity of renin measurements is low, cure of hypertension would be precluded for more than one third of RVH patients, if these tests were a prerequisite for identifying RVH.

Adolescent↗
PubMed1997

Progression of renal failure after subtotal nephrectomy in transgenic rats carrying an additional renin gene [TGR(mREN2)27].

OBJECTIVE: To study the evolution of glomerulosclerosis after renal ablation in a model with abnormal regulation of the renin gene. METHODS: Four-month-old female ovariectomized hypertensive heterozygous transgenic rats (TGR) harbouring the murine REN-2 gene were compared with pressure-matched, pair-fed, stroke-prone, spontaneously hypertensive rats (SHRsp). Both groups were followed for 6 weeks after 70% subtotal nephrectomy (SNX) or sham operation. RESULTS: Blood pressures in the SNX group at the end of the experiment were 193 +/- 3 mmHg in TGR and 199 +/- 5 mmHg in SHRsp. The final C(in) was 306 +/- 68 microliters/min per 100 g body weight in TGR that had undergone SNX and 550 +/- 93 microliters/min per 100 g body weight in SHR that had undergone SNX (P < 0.02), whereas inulin clearance (C(in)) in sham-operated pair-fed TGR and SHRsp controls did not differ from each other. The glomerulosclerosis index was 1.75 +/- 0.08 in perfusion-fixed TGR that had undergone SNX versus 1.21 +/- 0.03 in SHR that had undergone SNX (P < 0.005). In addition, the media thickness of preglomerular vessels was significantly greater in TGR that had undergone SNX (7.48 +/- 0.79 microns) than it was in SHRsp that had undergone SNX (5.27 +/- 1.38 microns, P < 0.02). Rat renal renin messenger RNA (mRNA) expression and, in parallel, mouse REN-2 gene expression were lower in TGR after SNX. Plasma renin and angiotensin II (ANG II) concentrations were reduced to a similar extent in both SNX groups, but plasma prorenin was higher in TGR that had undergone SNX than it was in SHRsp that had undergone SNX. The angiotensin II:I ratio in the kidney was significantly higher in TGR (P < 0.01). There was no significant difference between sham-operated or subtotally nephrectomized TGR and SHRsp with respect to angiotensin type 1 mRNA and angiotensinogen mRNA. The renal angiotensin converting enzyme activity, however, was significantly higher in sham operated and subtotally nephrectomized TGR than it was in sham operated SHRsp and in SHRsp that had undergone SNX. CONCLUSION: Deterioration of renal function is accelerated in subtotally nephrectomized transgenic rats [TGR(mREN2)27] compared with that in comparably hypertensive SHRsp despite suppressed circulating active mRNA and decreased renal renin mRNA. Although alternative explanations are possible, this observation is consistent with a role for local ANG II in the genesis of glomerulosclerosis.

Angiotensins↗
PubMed1997

Actions of angiotensin and lisinopril on thalamic somatosensory neurons in normotensive, non-transgenic and hypertensive, transgenic rats.

OBJECTIVE: To investigate the effects of angiotensin II on discharge rates of somatosensory thalamic neurons and whether these effects are altered in hypertensive transgenic rats [TGR(mREN-2)27] and by long-term treatment with the angiotensin converting enzyme inhibitor lisinopril. DESIGN AND METHODS: Three strains of rats anesthetized with urethane were used (normotensive Wistar and Sprague-Dawley rats (SDR), and [TGR(mREN-2)27]). In addition, the effects of lisinopril treatment on SDR and transgenic animals were tested. The neuronal discharge frequency and the pattern were recorded extracellularly, and their behaviors in response to angiotensin and angiotensin antagonists administered iontophoretically were analyzed. RESULTS: Angiotensin-sensitive neurons located in the ventral posteromedial and ventral posterolateral thalamic nuclei, and in the zona incerta were excited mainly by angiotensin II. The increase in the firing rates induced by administration of angiotensin II often coincided with an increase in the number of bursts of discharges. Effects induced by angiotensin II could be blocked by administration of specific antagonists (losartan, PD 123319). Long-term treatment with lisinopril reduced the neuronal responsiveness to angiotensin II in SDR significantly in comparison with that of untreated SDR controls. Lisinopril-treated SDR had a significantly lower responsiveness to angiotensin II than did hypertensive transgenic rats that had been treated with lisinopril. CONCLUSION: The results show for the first time that administration of angiotensin II induced changes in discharge rates of somatosensory neurons, and that long-term administration of lisinopril caused a significant difference between the neuronal responsiveness to angiotensin of normotensive SDR and that of hypertensive transgenic rats.

Angiotensin II↗
PubMed1997

Endothelial vasoconstrictor prostanoids modulate contractions to acetylcholine and ANG II in Ren-2 rats.

We investigated vascular function in mouse Ren-2 transgenic rats with hypertension. Mesenteric resistance arteries of transgenic and Sprague-Dawley rats (controls) were isolated at ages 6 and 12 wk and suspended in myographs for isometric tension recording. Systolic blood pressure was higher in transgenic than control rats (P < 0.05). Contractions to norepinephrine and endothelin-1 were comparable in transgenic and control rats, but the sensitivity decreased with age in both strains (P < 0.05). Contractions to angiotensin I were comparable in 6-wk-old transgenic rats and controls, but the response to angiotensin I was more pronounced in transgenic rats at 12 wk of age. Contractions to angiotensin II were higher in transgenic rats and decreased with age in both strains. Preincubation with the cyclooxygenase inhibitor meclofenamate or the thromboxane receptor antagonist SQ-30741 blunted the response only in 6-wk-old transgenic rats. In quiescent vascular rings, acetylcholine evoked endothelium-dependent contractions after inhibition of nitric oxide formation by N omega-nitro-L-arginine methyl ester only in transgenic rats. These contractions were inhibited by SQ-30741 (P < 0.05) but not by the thromboxane synthase inhibitor CGS-13080. Contractions to the thromboxane analogue U-46619 were comparable in both strains at the age of 6 wk; sensitivity was increased in transgenic rats at 12 wk (P < 0.05). In conclusion, in mesenteric resistance arteries of Ren-2 transgenic rats I) contractions to angiotensin I and II but not to norepinephrine and endothelin-1 are increased, and 2) acetylcholine as well as angiotensin II modulate endothelium-dependent contractions mediated by prostaglandin H2. These alterations together with increased sensitivity to thromboxane could contribute to maintenance as well as to impaired tissue perfusion of this form of hypertension.

Acetylcholine↗
PubMed1997

Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS.

In pursuit of the hypothesis that estrogen shifts the vasoconstrictor-vasodilator balance of the renin-angiotensin system, we investigated the cardiovascular responses to administration of angiotensin-(1-7) [ANG-(1-7)] and angiotensin II (ANG II) in female transgenic (mRen2)27-positive [Tg(+)] and -negative [Tg(-)] rats in the presence and absence of 3 wk of estrogen replacement therapy. Fifty-three female Tg(-) and Tg(+) rats were oophorectomized and received either 17 beta-estradiol (1.5 mg/rat s.c. for 3 wk) or vehicle. At the end of 3 wk of estrogen treatment, mean blood pressure was lowered in freely moving chronically cannulated Tg(+) (159 +/- 4 vs. 145 +/- 5 mmHg, P < 0.05) and Tg(-) (119 +/- 4 vs. 108 +/- 2 mmHg, P < 0.05) rats. Moreover, the magnitude of the depressor component of the biphasic response to ANG-(1-7) was significantly enhanced in estrogen-treated Tg(+) rats, whereas the pressor component to ANG-(1-7) was attenuated in both Tg(+) and Tg(-) rats. Estrogen replacement significantly attenuated the pressor response to ANG II in both Tg(+) and Tg(-) rats. In addition, estrogen replacement therapy significantly reduced plasma ANG-converting enzyme activity in association with a reduction in circulating levels of ANG II. Tissue levels (kidney and aorta) of ANG-converting enzyme were also reduced with chronic estrogen replacement therapy. On the other hand, estrogen augmented the levels of plasma ANG-(1-7) in Tg(+) animals. Plasma renin activity was unchanged with estrogen treatment. These findings provide the first evidence demonstrating that estrogen is protective against hypertension, possibly by amplifying the vasodilator contributions of ANG-(1-7), while reducing the formation and vasoconstrictor actions of ANG II.

Angiotensin I↗
PubMed1997

Enalapril and pressure-diuresis in hypertensive rats transgenic for mouse renin gene.

The recent development of a transgenic rat strain bearing the mouse ren-2 renin gene [TGR(mRen2)27] has provided a new monogenetic model of hypertension. Other hypertensive rat strains are characterized by a blunted pressure-diuresis-natriuresis response such that higher renal perfusion pressures are required to excrete normal amounts of water and sodium. Dysfunction of the renin-angiotensin and nitric oxide systems may cause in this abnormality. This study examined the effect of enalapril on the pressure-natriuresis response and urinary nitric oxide metabolite excretion in 6-month-old TGR(mRen2)27 rats. The slope of the line relating renal perfusion pressure and urine flow rate in TGR (0.08+/-0.01 microl x min(-1) x g kidney weight(-1) mm Hg[-1]) was significantly lower than that in control rats (0.15+/-0.01 microl x min(-1) x g kidney weight(-1) mm Hg[-1]). Pressure-natriuresis responses were also shifted to higher pressure levels in TGR. Treatment with enalapril for 3 months lowered the mean arterial pressure from 94+/-2 to 84+/-4 mm Hg in control rats and from 146+/-3 to 89+/-3 mm Hg in TGR. The slopes of lines relating renal perfusion pressure and urine flow rate as well as sodium excretion were significantly increased by enalapril in control and transgenic animals. Urinary nitric oxide metabolite excretion rose similarly with increasing renal perfusion pressure in both control and TGR rats and was not affected by enalapril. These results confirm that older TGR rats have a blunted pressure-diuresis-natriuresis response that can be corrected by inhibition of the renin-angiotensin system and suggest that their production of nitric oxide is normal.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Role of the alpha-, beta-, and gamma-subunits of epithelial sodium channel in a model of polygenic hypertension.

The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the beta- and gamma-subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and a Wistar-Kyoto rat (WKY-1HD) reference strain. We carried out genetic mapping and chromosomal assignment of the alpha-, beta-, and gamma-subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the beta- and gamma-subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the beta-/gamma-subunit locus. The alpha-subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSPHD and WKY-1HD strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSPHD and WKY-1HD. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.

Animals↗
PubMed1997

High human renin hypertension in transgenic rats.

We developed a model of spontaneously high human renin hypertension in the rat by producing two transgenic strains, one for human angiotensinogen with the endogenous promoter and one for human renin with the endogenous promoter. Neither transgenic strain was hypertensive. These strains were then crossed, producing a double transgenic strain. The double transgenic rats, both males and females, developed severe hypertension (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days if untreated. The rats had a human plasma renin concentration of 269 +/- 381 (+/-SD) ng angiotensin I (Ang I)/mL per hour, plasma renin activity of 177 +/- 176 ng Ang I/mL per hour, rat angiotensinogen concentration of 1.49 +/- 1 microgram Ang I/mL, and human angiotensinogen concentration of 78 +/- 39 micrograms Ang I/mL (n = 49). Control rats had plasma renin activity of 3.7 +/- 3.9 ng Ang I/mL per hour and rat angiotensinogen of 1.32 +/- 0.16 micrograms Ang I/mL. Angiotensinogen transgene expression by RNase protection assay was ubiquitously present but most prominent in liver. Renin transgene expression was high in kidney but absent in liver. The rats featured severe cardiac hypertrophy, with increased cross section of cardiomyocytes but little myocardial fibrosis. The kidneys showed atrophic tubules, thickened vessel walls, and increased interstitium. Both the angiotensin-converting enzyme inhibitor lisinopril and the specific human renin inhibitor remikiren lowered blood pressure to normal values. Double transgenic mice have been developed that exhibit features quite similar to those described here; their gene expressions are similar. The specificity of rodent and human renin is similarly documented. Although many elegant physiological studies can now be done in mice, rats nevertheless offer flexibility, particularly in terms of detailed cardiac and renal physiology and pharmacology. We conclude that this double transgenic strain will facilitate simultaneous investigation of genetic and pathophysiological aspects of renin-induced hypertension. The fact that human renin can be studied in the rat is a unique feature of this model.

Angiotensinogen↗
PubMed1997

Hypothalamic substance P release. Attenuated angiotensin responses in mRen2(27) transgenic rats.

Increases in arterial pressure and paraventricular nucleus vasopressin release in response to intracerebroventricular injections of angiotensin peptides are blunted in mRen2(27) renin transgenic [TG(+)] rats. Intraventricular injections of tachykinin peptides mimic several of the actions of angiotensin peptides, and angiotensin peptides evoke substance P release from hypothalamic brain slices. The present study assessed whether diminished substance P release occurs in response to angiotensin peptides in TG(+) rats. Systolic blood pressure at 8 to 12 weeks of age averaged 197 +/- 4 mm Hg (n = 20; P < .05) in TG(+) rats compared with 123 +/- 4 mm Hg in normotensive control [TG(-)] rats (n = 18). Body weight was lower in hypertensive than in normotensive rats (305 +/- 14 versus 344 +/- 13 g, respectively; P < .05). Brain slices from hypothalamus were perfused at 37 degrees C with oxygenated Krebs' bicarbonate buffer. Substance P was measured before (basal) and during perfusion with either Krebs' buffer (control) or 2 mumol/L angiotensin-(1-7) or angiotensin II. Basal substance P release was 92 +/- 10 pg/g wet tissue in TG(+) and 98 +/- 12 pg/g in TG(-) rats (P > .05). Angiotensin-(1-7) and angiotensin II significantly increased substance P release from hypothalamus of TG(-) rats (82% and 70% above control: P < .05) but not TG(+) rats. These studies further support the hypothesis that the cardiovascular effects of angiotensin peptides are mediated in part by substance P and that this relationship is blunted in a hypertensive model that results from excess tissue production of angiotensins.

Angiotensin I↗
PubMed1997

Dose effects of human renin in rats transgenic for human angiotensinogen.

We examined the effect of chronic human renin infusion and human renin inhibition on blood pressure in a unique transgenic rat model. We infused incremental doses of human renin (1 to 500 ng/h) with minipumps for 10 days into rats harboring the human angiotensinogen gene [TGR (hAOGEN)1623]. We measured blood pressure and heart rate continuously by telemetry. We found that human renin at 5 ng/h was necessary to increase blood pressure, whereas 10 ng/h caused systolic blood pressure to increase to 215 +/- 13 mm Hg. Heart rate decreased initially but then increased by 100 beats per minute compared with basal values. Drinking behavior also increased. Doses as high as 500 ng/h did not increase blood pressure further. A linear relationship was found between the log of plasma renin activity and systolic blood pressure that increased in slope from days 2 to 9. Rat angiotensinogen levels were low and not influenced by human renin infusion. Human angiotensinogen levels remained stable until 500 ng/h human renin was infused, at which time they decreased by 50% at 9 days. Rat renin gene expression (RNase protection assay) was decreased by human renin infusion, whereas rat and human angiotensinogen gene expressions in liver and kidney as well as angiotensin-converting enzyme gene expression in kidney were not affected. The human renin inhibitor Ro 42-5892 was given by gavage repeatedly to rats receiving human renin at 40 ng/h. Ro 42-5892 lowered blood pressure promptly to basal values. High human renin hypertension in this model is dose dependent, features a steeper relationship between blood pressure and plasma renin activity over time, and is associated with tachycardia and increased drinking. We conclude that the human angiotensinogen transgenic rat offers new perspectives in the study of human renin-induced hypertension.

Angiotensinogen↗
PubMed1997

Enalapril and renal function in hypertensive rats transgenic for mouse renin gene.

We examined the effect of long-term enalapril treatment on renal function and histology in the monogenetically hypertensive TGR(mRen2)27 rat strain. Untreated transgenic rats had significantly (P<.01) higher blood pressures than treated transgenic and control animals throughout the study. Urinary nitric oxide metabolite excretion was significantly lower in young transgenic rats and rose with enalapril, suggesting abnormal TGR nitric oxide production and its correction by enalapril. Converting enzyme inhibition produced preferential preglomerular vasodilatation and increased renal blood flow (6.5 +/- 0.5 versus 9.0 +/- 0.7 mL/min per gram kidney weight, P<.05) without altering whole-kidney and single-nephron glomerular filtration rates in TGR(mRen2)27. Glomerular capillary pressure fell modestly in treated transgenic animals (54 +/- 1 versus 50 +/- 1 mm Hg, P<.05). These hemodynamic changes were associated with reductions in albuminuria (59 +/- 6 versus 9 +/- 2 mg/d, P<.01) and glomerulosclerosis in TGR. However, urinary albumin excretion (15 +/- 3 versus 3 +/- 1 mg/d, P<.05) and glomerulosclerosis also declined in treated control animals in the absence of significant alterations in glomerular hemodynamics. The mechanism of the beneficial effect of enalapril on the TGR(mRen2)27 kidney is unclear but could involve either control of hypertension or suppression of the intrarenal renin-angiotensin system.

Animals↗