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Biomedical subjects

C M Ferrario

Publications and source records attributed to C M Ferrario.

At least 73 records · Page 4Linked to original sources
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

Bovine aortic endothelial cells contain an angiotensin-(1-7) receptor.

Angiotensin-(1-7) is a novel peptide of the renin-angiotensin system that counteracts the pressor and proliferative responses to angiotensin II. We now report that cultured bovine aortic endothelial cells contain a saturable, high-affinity [125I]angiotensin-(1-7) binding site with an affinity of 19.3 +/- 10.7 nmol/L and a density of 1351 +/- 710 fmol/mg protein. Angiotensin-(1-7) competed at a second lower-affinity site, with an IC50 of 2.9 mumol/L. The high-affinity angiotensin II receptor antagonist sarcosine1-isoleucine8-angiotensin II blocked [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells at both a high- (IC50 = 1.3 nmol/L) and a low-affinity (IC50 = 6.2 mumol/L) binding site. In contrast, D-alanine7-angiotensin-(1-7) completely blocked [125I]angiotensin-(1-7) binding, with an IC50 of 19.8 nmol/L, suggesting that D-alanine7-angiotensin-(1-7) may selectively block responses to angiotensin-(1-7) in endothelial cells. Neither the AT1 antagonist losartan nor the AT2 antagonist PD 123319 exhibited significant competition for [125I]angiotensin-(1-7) binding to endothelial cells isolated from bovine aorta, in agreement with the absence of detectable mRNAs encoding typical angiotensin receptor subtypes 1 or 2 (AT1 or AT2). Angiotensin II also competed for [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells; however, the relative affinity was 13-fold lower than angiotensin-(1-7), suggesting a preference for angiotensin-(1-7) over angiotensin II. These results demonstrate that bovine aortic endothelial cells contain a unique non-AT1, non-AT2 angiotensin receptor that preferentially binds angiotensin-(1-7).

Angiotensin I↗
PubMed1997

Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide.

Recent studies have shown that angiotensin-(1-7) [Ang-(1-7)] interacts with kinins and augments bradykinin (BK)-induced vasodilator responses by an unknown mechanism. In this study, we evaluated whether the potentiation of the BK-induced vasodilation by Ang-(1-7) may be attributable to inhibition of BK metabolism, release of nitric oxide, or both. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers. 125I-[Tyr0]-BK metabolism was determined in vascular rings by assessing the degradation of the peptide by high-performance liquid chromatography. Ang-(1-7) augmented the vasodilation induced by BK in a concentration-dependent manner in rings preconstricted with the thromboxane analog U46619. The EC50 of BK (2.45 +/- 0.51 nmol/L versus 0.37 +/- 0.08 nmol/L) was shifted leftward by 6.6-fold in the presence of 2 mumol/L concentration of Ang-(1-7). The response was specific for BK. since Ang-(1-7) did not augment the vasodilation induced by either acetylcholine (0.05 mumol/L) or sodium nitroprusside (0.1 mumol/L). Moreover, neither angiotensin I nor angiotensin II (Ang II) duplicated the augmented BK response of Ang-(1-7). Pretreatment of vascular rings with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NA; 100 mumol/L) completely abolished the effects of Ang-(1-7) on BK-induced vasodilation whereas pretreatment with indomethacin (10 mumol/L) was without effect. The potent specific BK B2 receptor antagonist, Hoe 140. nearly abolished the BK and the Ang-(1-7) potentiated responses at 2 mumol/L, whereas at a lower concentration (20 nmol/L) Hoe 140 shifted the response curve to the right for both Ang-(1-7) and vehicle; however, the augmented response to Ang-(1-7) persisted. Preincubation of vascular rings with 20 mumol/L of the AT1 (CV11974), AT2 (PD123319), or nonselective (Sar1 Thr8-Ang II) receptor antagonists had no significant effect on the Ang-(1-7)-enhanced vasodilator response to BK. Lisinopril (2 mumol/L) significantly enhanced the BK-induced vasodilator response while at the same time it abolished the synergistic action of Ang-(1-7) on BK. In addition, pretreatment with 2 mumol/L Ang-(1-7) significantly inhibited the degradation of 125I-[Tyr0]-BK and the appearance of the BK-(1-7) and BK-(1-5) metabolites in coronary vascular rings. Ang-(1-7) inhibited purified canine angiotensin converting enzyme activity with an IC50 of 0.65 mumol/L. In conclusion. Ang-(1-7) acts as a local synergistic modulator of kinin-induced vasodilation by inhibiting angiotensin converting enzyme and releasing nitric oxide.

Angiotensin I↗
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

Counterregulatory actions of angiotensin-(1-7).

Angiotensin (Ang)-(1-7) is a bioactive component of the renin-angiotensin system that is formed endogenously from either Ang I or Ang II. The first actions described for Ang-(1-7) indicated that the peptide mimicked some of the effects of Ang II, including the release of prostanoids and vasopressin. However, Ang-(1-7) is devoid of vasoconstrictor, central pressor, or thirst-stimulating actions. In fact, new findings reveal depressor, vasodilator, and antihypertensive actions that may be more apparent in hypertensive animals or humans. Thus, the accumulating evidence suggests that Ang-(1-7) may oppose the actions of Ang II either directly or by stimulation of prostaglandins and nitric oxide. These observations are significant because they may explain the effective antihypertensive action of converting enzyme inhibitors in a variety of non-renin-dependent models of experimental and genetic hypertension as well as most forms of human hypertension. In this context, studies in humans and animals showed that the antihypertensive action of converting enzyme inhibitors correlated with increases in plasma levels of Ang-(1-7). In this review, we summarize our knowledge of the mechanisms accounting for the counterregulatory actions of Ang-(1-7) and elaborate on the emerging concept that Ang-(1-7) functions as an antihypertensive peptide within the cascade of the renin-angiotensin system.

Angiotensin I↗
PubMed1997

Nonpeptide angiotensin II antagonist losartan inhibits thromboxane A2-induced contractions in canine coronary arteries.

We investigated the selectivity of a nonpeptide angiotensin II AT1 receptor antagonist losartan for the vascular thromboxane A2 (TxA2)/prostaglandin endoperoxide (PGH2) receptor in canine coronary arteries. Isometric tension was measured in canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2. The TxA2 analog, U46619, produced dose-dependent vasoconstdction in coronary rings (EC50, 10.6 +/- 0.9 nmol/l). Pretreatment with losartan (10(-8)-10(-5) mol/l) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in dose-dependent manner. The EC50 of U46619 was increased 3- and 13-fold in the presence of both 1 and 10 micromol/l of losartan without a change in maximal contraction. The selective TxA2/PGH2 receptor antagonist SQ29548 blocked U46619-induced contraction with greater potency than losartan in isolated coronary arteries. The active metabolite of losartan EXP3174 at 1 micromol/l did competitively block U46619-induced contractions in canine coronary rings. In contrast, the contractile responses produced by U46619 were unaffected by exposure to the nonpeptide AT1 receptor antagonist CV11974, the AT2 receptor antagonist PD123319 or the nonselective peptide angiotensin II antagonist Sar1Thr8-Ang II, each at 1 micromol/l concentration. These data indicate that losartan and its active metabolite EXP3174 are antagonists to the TxA2/PGH2 receptor in canine coronary arteries. The antagonistic effect of losartan and EXP3174 on the vascular TxA2/ PGH2 receptor may contribute to the long-term blood pressure-lowering effects of angiotensin antagonists in hypertension.

Animals↗
PubMed1996

Pathologic consequences of increased angiotensin II activity.

Advances in molecular medicine and pharmacology have allowed clinicians to critically reassess the renin-angiotensin system. Angiotensin II (AII) participates in the control of cardiovascular function and electrolyte balance, and plays a part in the regulation of cellular oncogenes and the expression of growth factors. The expression of the proteins of the renin-angiotensin system in organs other than the kidneys suggests that these diverse actions are associated with the peptide in the local environment. Tissue renin-angiotensin activity has prompted the investigation of alternate pathways for the production of AII and characterization of novel forms of angiotensin peptides that counteract the vasoconstrictor and proliferative actions of AII. The heptapeptide angiotensin-(1-7) appears to be critically involved in regulating the angiotensinogen activity of AII through stimulation of vasodilator prostaglandins and release of nitric oxide. Study in this area has been accelerated by the identification of receptors that convey the actions of angiotensin peptides at the cellular level and the pharmacologic characterization of agents that inhibit the ability of AII to bind to target receptors. The introduction of a new class of orally active AII-receptor blockers has provided a specific test of the role of AII in the development of essential hypertension and the potential for improved therapy for hypertension and cardiac and vascular sequelae.

Angiotensin II↗
PubMed1996

Benefits of adherence to anti-hypertensive drug therapy.

Long-term adherence or compliance with anti-hypertensive drug therapy is poor. It has been estimated that within the first year of treatment 16-50% of hypertensives discontinue their anti-hypertensive medications. Even among those who remain on therapy long term, missed medication doses are common. Epidemiological studies have shown that drug-treated hypertensives have higher blood pressures than age-, gender- and body mass index-matched normotensives. In addition, drug-treated hypertensive men and women who achieve blood pressure normalization are less likely to die over a 9.5-year period than those whose blood pressure remains elevated while taking anti-hypertensive drugs. Thus, one reason for less than optimal reduction of blood pressure-related cardiovascular-renal risk in drug-treated hypertensives is inadequate blood pressure lowering. Quantifiable excess risk has been documented even in the short term ( < 1 year) after interruption or discontinuation of anti-hypertensive medications as total healthcare costs are higher, mostly because of higher hospitalization rates. Data from the Treatment of Mild Hypertension Study (TOMHS) are relevant to long-term adherence to various anti-hypertensive drug monotherapies. At 48 months, 82.5% and 77.8% of participants remained on amlodipine and acebutolol, respectively (both P < 0.01 compared with placebo). However, only 67.5%, 66.1% and 68.1%, respectively, of chlorthalidone, doxazosin and enalapril participants remained on these drugs as monotherapy at 48 months. Differential adherence to long-term anti-hypertensive drug therapy could translate into a greater risk of blood pressure-related complications and higher overall healthcare expenditures. Strategies to minimize the deleterious impact of therapeutic non-adherence with anti-hypertensive medications as well as the clinical and cost implications of the TOMHS data will be discussed.

Antihypertensive Agents↗
PubMed1996

Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension.

OBJECTIVE: To evaluate the contribution of angiotensin-(1-7) [Ang-(1-7)] and prostaglandins to the acute and long-term antihypertensive actions of captopril in mild-to-moderate essential hypertensive patients. DESIGN AND METHODS: Blood pressure, cardiac rate and the plasma concentrations of angiotensin I (Ang I), angiotensin II (Ang II), Ang-(1-7), prostaglandin E2 and 6-keto prostaglandin F1 alpha (the breakdown product of prostacyclin) were determined in the peripheral venous blood of 24 essential hypertensive subjects before and 3 h after administration of 50 mg captopril. Eleven of 24 patients completed a 6-month treatment period with captopril monotherapy (50 mg twice a day). The hemodynamic and hormonal response produced by a last 50 mg dose of captopril was determined once again in the 11 subjects who maintained blood pressure control with captopril monotherapy for 6 months. RESULTS: The fall in blood pressure produced 3 h after drug intake was comparable for the first and the last 50 mg captopril dose. Although the first response to captopril increased plasma levels of Ang I only, the response to the last dose of the drug (6 months after) caused significantly higher levels of Ang I and Ang-(1-7). Neither acute nor chronic therapy with captopril had a significant effect on plasma concentrations of Ang II. Although plasma levels of prostaglandin E2 and 6-keto prostaglandin F1 alpha were not modified by a first exposure to captopril, the concentrations of 6-keto prostaglandin F1 alpha but not prostaglandin E2 rose significantly in subjects treated with the inhibitor for 6 months. A negative correlation was also demonstrated between diastolic blood pressure and plasma Ang-(1-7) levels in the 11 essential hypertensive subjects in whom blood pressure was controlled with captopril monotherapy. CONCLUSIONS: Inhibition of angiotensin converting enzyme with captopril had a significant effect on blood pressure that was not directly accounted for by a suppression of plasma Ang II levels. Continuous therapy with captopril unmasked a contribution of Ang-(1-7) and prostacyclin to the antihypertensive actions of this drug.

Adolescent↗
PubMed1996

Role of paraventricular angiotensin AT1 receptors in salt-sensitive hypertension in mRen-2 transgenic rats.

We have previously demonstrated that mRen-2 transgenic [Tg(+)] rats show a salt-induced exacerbation of hypertension (Callaha, M., P. Li, C. M. Ferrario, D. Ganten, and M. Morris. Hypertension Dallas 27: 573-577, 1996). In this study, we examined the role of paraventricular (PVN) angiotensin type-1 (AT1) receptors in the salt sensitivity of this model. Male Tg(+) and Tg(-) rats were instrumented with PVN cannulas for intracerebral drug administration and carotid catheters for chronic cardiovascular monitoring. Substitution of 2% NaCl for drinking water for 4 days caused a significant elevation (23 mmHg) of mean arterial pressure (MAP) in Tg(+) rats but not in Tg(-) rats. PVN injection of AT1 receptor antisense oligodeoxynucleotides (ASODN), but not scrambled oligodeoxynucleotides (SCODN), produced a rapid decrease in MAP of 24 +/_ 8 mmHg in salt-treated Tg(+) rats. There was no effect of either AT1 ASODN or SCODN on MAP in salt-loaded Tg(-) rats or in Tg(+) rats consuming tap water. Salt loading significantly increased subfornical organ AT1 receptors in Tg(+) rats with no changes produced by ASODN or SCODN. In contrast, there was a 40% decrease in PVN AT1 receptors 20 h after direct PVN injection of AT1 ASODN injection, compared with SCODN in Tg(+) rats. We conclude that PVN AT1 receptors are critical in the expression of salt sensitivity in mRen-2 transgenic rats.

Animals↗
PubMed1996

Renal actions of angiotensin-(1-7): in vivo and in vitro studies.

In vivo studies were conducted in Na-replete anesthetized male Wistar rats with denervated kidneys. Intrarenal injections of angiotensin-(1-7) [ANG-(1-7) at > 1 nmol/kg produced a shallow dose-dependent decrease in renal blood flow that was mediated by the AT1-type ANG II receptor. A constant intrarenal infusion of ANG-(1-7) at 0.1 and 1 nmol.min-1.kg-1 had minimal effects on renal blood flow and blood pressure and resulted in an elevated urinary excretion of Na and water compared with the time-control saline-infused group. To determine whether ANG-(1-7) may have a direct action on tubular epithelium to inhibit Na reabsorption, we examined the effect of ANG-(1-7) on transport-dependent O2 consumption (Qo2) in fresh suspensions of rat proximal tubules in vitro. ANG-(1-7) inhibited Qo2 in a concentration-dependent fashion with a threshold concentration of approximately 100 pM. Stimulating Na-K-adenosinetriphosphatase (Na-K-ATPase) activity with nystatin caused a leftward shift of the inhibitory concentration-response curve to ANG-(1-7). The 22% inhibition of Qo2 by 1 pM ANG-(1-7) was abolished by pretreatment with 5 mM ouabain (Na-K-ATPase inhibitor), unaltered by pretreatment with 1 microM PD-123319 (AT2 receptor antagonist), partially attenuated by 1 microM losartan (AT1 receptor antagonist), and abolished by 1 microM [Sar1, Thr8]ANG II (nonselective ANG receptor antagonist). Together these findings indicate that ANG-(1-7) has biological activity in the kidney and, at nonvasoconstrictor doses, results in increased Na and water excretion in vivo. One site of action is the proximal tubule, where ANG-(1-7) can inhibit an ouabain-sensitive Na-K-ATPase exit step in cellular Na transport. This novel inhibitory action of ANG-(1-7) appears to be mediated by an AT1 receptor (minor component) and a non-AT1, non-AT2 ANG receptor (major component).

Angiotensin I↗
PubMed1996

Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide.

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.

Angiotensin I↗
PubMed1996

Salt-sensitive hypertension in (mREN-2)27 transgenic rats.

The (mREN-2)27 transgenic model of hypertension was developed to investigate the effect of genetic over activity of angiotensin II systems as a contributing factor in the development of arterial hypertension. In this model, transgene-positive rats demonstrate elevated renin-angiotensin system activity not only in the circulatory system but also in adrenal gland, reproductive organs, and brain. Since evidence indicates that angiotensin peptides and osmotic stimuli interact synergistically to produce exaggerated behavioral, endocrine, and cardiovascular effects, we examined the effect of salt consumption on arterial pressure, plasma vasopressin, and body fluid balance in male (mREN-2)27 transgene-positive and -negative rats. Four days of drinking 2% NaCl increased mean arterial pressure from 165 +/- 10 to 199 +/- 7 mm Hg in transgene-positive rats. In contrast, transgene-negative rats showed no change in arterial pressure (126 +/- 5 to 128 +/- 3 mm Hg). Plasma vasopressin levels were significantly elevated only in transgene-positive rats, whereas pituitary levels of vasopressin were significantly lower in transgene-positive rats compared with transgene-negative controls (18 +/- 3 and 118 +/- 14 ng, respectively). Although transgene-positive rats consumed significantly more 2% NaCl than did transgene-negative rats, during this period 24-hour sodium balance did not differ between the groups. Since fluid and electrolyte balance is similar between the two groups of rats, the data suggest that transgene-positive rats may be more sensitive to the effects of increased NaCl intake in terms of both endocrine and cardiovascular responses.

Animals↗
PubMed1996

Role of area postrema in transgene hypertension.

Transgenic [Tg(+)] rats carrying the mouse Ren-2d gene [(mRen-2d)27] are a newly established monogenetic form of experimental hypertension. To determine whether the area postrema contributes to the development of hypertension in mRen-2 Tg(+) rats, this circumventricular organ in the fourth ventricle was removed from 5-week-old Tg(+) rats. From weeks 4 through 9, systolic blood pressure was measured weekly by tail-cuff plethysmography in area postrema-lesioned and sham-lesioned Tg(+) rats. Although systolic blood pressure rose markedly in sham-lesioned Tg(+) rats, the increase in systolic blood pressure was significantly attenuated in area postrema-lesioned Tg(+) rats. At 9 weeks of age, a femoral artery was cannulated for the measurement of arterial pressure in awake rats. Mean arterial pressure (MAP) in area postrema-lesioned Tg(+) rats was significantly (P < .01) lower than that in sham-lesioned rats: 171 +/- 7 and 132.+/- 5 mm Hg, respectively. Baroreceptor reflex was evaluated by intravenous infusion of sodium nitroprusside. There was no significant difference in baroreceptor reflex sensitivity between the two groups. Intravenous pentolinium (5 mg/kg), used to produce sympathetic ganglionic block, caused significant decreases in MAP in both groups. However, the reduction of MAP in the sham-lesioned group was significantly (P < .05) greater than that in the area postrema-lesioned group: -73 +/- 4 and -48 +/- 6 mm Hg, respectively. The ratio of left ventricular weight to body weight in sham-lesioned Tg(+) rats was significantly larger than that of area postrema-lesioned rats. These results suggest that ablation of the area postrema markedly attenuates the development of hypertension in mRen-2d Tg(+) rats, and this attenuation may be attributed to decrease in sympathetic outflow.

Animals↗
PubMed1996

Angiotensin-(1-7) inhibits vascular smooth muscle cell growth.

Although angiotensin II (Ang II) and the heptapeptide Ang-(1-7) differ by only one amino acid, the two peptides produce different responses in vascular smooth muscle cells. We previously showed that Ang II stimulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) released prostaglandins. We now report that Ang II and Ang-(1-7) differentially modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [3H]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang II. The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) depended on the concentration of the heptapeptide over the range of 1 nmol/L to 1 mumol/L, with a maximal inhibition of 60% by 1 mumol/L Ang-(1-7). Ang-(1-7) also inhibited the serum-stimulated increase in cell number to a maximum of 77% by 1 mumol/L Ang-(1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected by antagonists selective for angiotensin type 1 (AT1) or type 2 (AT2) receptors; however, [Sar1,Ile1]Ang II and [Sar1,Thr2]Ang II were effective antagonists, indicating that growth inhibition by Ang-(1-7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [3H]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimulation of 314% at 1 mumol/L Ang II. Ang II also increased the total number of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell proliferation. The AT1 antagonist losartan or L-158,809 but not AT2 antagonists blocked [3H]thymidine incorporation by Ang II. These results suggest that Ang-(1-7) and Ang II exhibit opposite effects on the regulation of vascular smooth muscle cell growth. The inhibition of proliferation by Ang-(1-7) appears to be mediated by a novel angiotensin receptor that is not inhibited by AT1 or AT2 receptor antagonists.

Angiotensin I↗
PubMed1996

Differential regulation of angiotensinogen transcripts after renin infusion.

To investigate angiotensinogen regulation in high-renin hypertension, we infused porcine renin intravenously at either a low (4 mU/kg per hour, n = 6) or high (20 mU/kg per hour, n = 9) dose into male Sprague-Dawley rats (225 to 250 g) for 5 days using osmotic minipumps. Control rats received 0.9% NaCl. In renin-infused rats, mean arterial pressure and plasma renin activity were significantly elevated. Both low- and high-renin infusions lowered plasma angiotensinogen levels. Plasma angiotension II was elevated in rats given renin but reached statistical significance only at the higher dose. Angiotensinogen mRNA isolated from the liver, adrenal gland, kidney, and brain was measured by slot blot analysis. Both renin doses were associated with significant decreases in the levels of liver and hypothalamic angiotensinogen mRNA. In the medulla oblongata, angiotensinogen mRNA was reduced only by the higher renin dose. The lower dose increased angiotensinogen mRNA in the adrenal gland, and in kidney, angiotensinogen mRNA level was unchanged by renin infusion. Angiotensinogen mRNA visualized on Northern blots showed that the number of mRNA species in liver decreased from three in control rats to a single mRNA species after renin infusion. Tissue differences in the size of the major angiotensinogen mRNA species were also apparent. This, together with changes in the total hybridization signal of angiotensinogen mRNA in tissues, suggests that renin differentially affects the different angiotensinogen mRNA transcripts. Results of this study indicate that angiotensinogen gene expression is regulated not only by alterations in levels of circulating angiotensin II but also by other mechanisms, presently unidentified, that are activated by renin infusions.

Angiotensinogen↗