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Influence of Angiotensin II Subtype 2 Receptor (AT(2)R) Antagonist, PD123319, on Cardiovascular Remodelling of Aged Spontaneously Hypertensive Rats during Chronic Angiotensin II Subtype 1 Receptor (AT(1)R) Blockade.

Jones ES, Black MJ, Widdop RE - Int J Hypertens (2012)

Bottom Line: Mean arterial pressure (MAP) and left ventricular volume were markedly decreased by candesartan cilexetil, however, simultaneous treatment with PD123319 had no additional effect on either parameter.Perivascular fibrosis was significantly reduced by candesartan cilexetil in aged animals only, and this effect was reversed by concomitant PD123319 administration.These results suggest that AT(2)R stimulation does not significantly influence the antihypertensive effect of chronic AT(1)R blockade, but plays a role in the regulation of vascular structure.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia.

ABSTRACT
Cardiac AT(2)R expression is upregulated in the normal process of aging. In this study we determined the contribution of AT(2)R to chronic antihypertensive and remodelling effects of AT(1)R blockade in aged hypertensive rats. Adult (20 weeks) and senescent (20 months) spontaneously hypertensive rats (SHRs) were treated with either the AT(1)R antagonist, candesartan cilexetil (2 mg/kg/day), the AT(2)R antagonist, PD123319 (10 mg/kg/day), or a combination of the 2 compounds. Mean arterial pressure (MAP) and left ventricular volume were markedly decreased by candesartan cilexetil, however, simultaneous treatment with PD123319 had no additional effect on either parameter. Perivascular fibrosis was significantly reduced by candesartan cilexetil in aged animals only, and this effect was reversed by concomitant PD123319 administration. Vascular hypertrophy was reduced by candesartan cilexetil, and these effects were reversed by simultaneous PD123319. These results suggest that AT(2)R stimulation does not significantly influence the antihypertensive effect of chronic AT(1)R blockade, but plays a role in the regulation of vascular structure. The severe degree of cardiac perivascular fibrosis in senescent animals was regressed by AT(1)R blockade and this effect was reversed by simultaneous AT(2)R inhibition, demonstrating an antifibrotic role of AT(2)R stimulation in the aging hypertensive heart.

No MeSH data available.


Related in: MedlinePlus

Mean data of interstitial collagen volume fraction of (a) left and (b) right ventricles of adult SHRs treated with vehicle (control, n = 6), candesartan cilexetil (2 mg/kg/day) alone (n = 7) or in combination with PD123319 (10 mg/kg/day, n = 7) or PD123319 alone. Interstitial collagen volume fraction of (c) left and (d) right ventricles of senescent SHRs treated with vehicle (control, n = 10), candesartan cilexetil alone (n = 9) or in combination with PD123319 (n = 9), PD123319 alone (n = 4), or hydralazine (30 mg/kg/day, n = 7).
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Related In: Results  -  Collection


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fig4: Mean data of interstitial collagen volume fraction of (a) left and (b) right ventricles of adult SHRs treated with vehicle (control, n = 6), candesartan cilexetil (2 mg/kg/day) alone (n = 7) or in combination with PD123319 (10 mg/kg/day, n = 7) or PD123319 alone. Interstitial collagen volume fraction of (c) left and (d) right ventricles of senescent SHRs treated with vehicle (control, n = 10), candesartan cilexetil alone (n = 9) or in combination with PD123319 (n = 9), PD123319 alone (n = 4), or hydralazine (30 mg/kg/day, n = 7).

Mentions: Representative light micrographs of perivascular and interstitial fibrosis of senescent SHRs are shown in Figure 3. Group data shows that neither left (Figures 4(a) and 4(c)) nor right (Figures 4(b) and 4(d)) ventricular interstitial fibrosis of adult and senescent SHRs were altered by any drug treatments. Likewise, perivascular fibrosis of adult SHRs was not influenced by AT1 or AT2R inhibition (Figure 5(a)). In contrast, perivascular fibrosis was significantly decreased by ~28% in senescent SHRs receiving candesartan cilexetil, and this effect was completely reversed by simultaneous AT2R blockade (Figure 5(b)).


Influence of Angiotensin II Subtype 2 Receptor (AT(2)R) Antagonist, PD123319, on Cardiovascular Remodelling of Aged Spontaneously Hypertensive Rats during Chronic Angiotensin II Subtype 1 Receptor (AT(1)R) Blockade.

Jones ES, Black MJ, Widdop RE - Int J Hypertens (2012)

Mean data of interstitial collagen volume fraction of (a) left and (b) right ventricles of adult SHRs treated with vehicle (control, n = 6), candesartan cilexetil (2 mg/kg/day) alone (n = 7) or in combination with PD123319 (10 mg/kg/day, n = 7) or PD123319 alone. Interstitial collagen volume fraction of (c) left and (d) right ventricles of senescent SHRs treated with vehicle (control, n = 10), candesartan cilexetil alone (n = 9) or in combination with PD123319 (n = 9), PD123319 alone (n = 4), or hydralazine (30 mg/kg/day, n = 7).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303759&req=5

fig4: Mean data of interstitial collagen volume fraction of (a) left and (b) right ventricles of adult SHRs treated with vehicle (control, n = 6), candesartan cilexetil (2 mg/kg/day) alone (n = 7) or in combination with PD123319 (10 mg/kg/day, n = 7) or PD123319 alone. Interstitial collagen volume fraction of (c) left and (d) right ventricles of senescent SHRs treated with vehicle (control, n = 10), candesartan cilexetil alone (n = 9) or in combination with PD123319 (n = 9), PD123319 alone (n = 4), or hydralazine (30 mg/kg/day, n = 7).
Mentions: Representative light micrographs of perivascular and interstitial fibrosis of senescent SHRs are shown in Figure 3. Group data shows that neither left (Figures 4(a) and 4(c)) nor right (Figures 4(b) and 4(d)) ventricular interstitial fibrosis of adult and senescent SHRs were altered by any drug treatments. Likewise, perivascular fibrosis of adult SHRs was not influenced by AT1 or AT2R inhibition (Figure 5(a)). In contrast, perivascular fibrosis was significantly decreased by ~28% in senescent SHRs receiving candesartan cilexetil, and this effect was completely reversed by simultaneous AT2R blockade (Figure 5(b)).

Bottom Line: Mean arterial pressure (MAP) and left ventricular volume were markedly decreased by candesartan cilexetil, however, simultaneous treatment with PD123319 had no additional effect on either parameter.Perivascular fibrosis was significantly reduced by candesartan cilexetil in aged animals only, and this effect was reversed by concomitant PD123319 administration.These results suggest that AT(2)R stimulation does not significantly influence the antihypertensive effect of chronic AT(1)R blockade, but plays a role in the regulation of vascular structure.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia.

ABSTRACT
Cardiac AT(2)R expression is upregulated in the normal process of aging. In this study we determined the contribution of AT(2)R to chronic antihypertensive and remodelling effects of AT(1)R blockade in aged hypertensive rats. Adult (20 weeks) and senescent (20 months) spontaneously hypertensive rats (SHRs) were treated with either the AT(1)R antagonist, candesartan cilexetil (2 mg/kg/day), the AT(2)R antagonist, PD123319 (10 mg/kg/day), or a combination of the 2 compounds. Mean arterial pressure (MAP) and left ventricular volume were markedly decreased by candesartan cilexetil, however, simultaneous treatment with PD123319 had no additional effect on either parameter. Perivascular fibrosis was significantly reduced by candesartan cilexetil in aged animals only, and this effect was reversed by concomitant PD123319 administration. Vascular hypertrophy was reduced by candesartan cilexetil, and these effects were reversed by simultaneous PD123319. These results suggest that AT(2)R stimulation does not significantly influence the antihypertensive effect of chronic AT(1)R blockade, but plays a role in the regulation of vascular structure. The severe degree of cardiac perivascular fibrosis in senescent animals was regressed by AT(1)R blockade and this effect was reversed by simultaneous AT(2)R inhibition, demonstrating an antifibrotic role of AT(2)R stimulation in the aging hypertensive heart.

No MeSH data available.


Related in: MedlinePlus