Abstract
Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3′ 5′-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng•min) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (Emax168%±8% vs 136%±4%) and small mesenteric arteries (SMA; Emax170%±6% vs 143%±3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 μmol/L) reduced PE-induced contraction in aortas from Ang II rats (E max94%±12%) but not in controls (154%±7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1±0.1 vs 5.9±0.06), but not in controls (6.0±0.03 vs 6.1±0.04). Sildenafil (10 μmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 μmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (Emax82%±12% vs 445±5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1±0.3 vs 5.3±0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 655-663 |
| Number of pages | 9 |
| Journal | Hypertension |
| Volume | 57 |
| Issue number | 3 PART 2 |
| DOIs | |
| State | Published - Mar 1 2011 |
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Keywords
- angiotensin II
- cGMP
- hypertension
- vinpocetine
ASJC Scopus subject areas
- Internal Medicine
Cite this
Decreased cGMP level contributes to increased contraction in arteries from hypertensive rats : Role of phosphodiesterase 1. / Giachini, Fernanda R.; Lima, Victor V.; Carneiro, Fernando S.; Tostes, Rita C.; Webb, R. Clinton.
In: Hypertension, Vol. 57, No. 3 PART 2, 01.03.2011, p. 655-663.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Decreased cGMP level contributes to increased contraction in arteries from hypertensive rats
T2 - Role of phosphodiesterase 1
AU - Giachini, Fernanda R.
AU - Lima, Victor V.
AU - Carneiro, Fernando S.
AU - Tostes, Rita C.
AU - Webb, R. Clinton
PY - 2011/3/1
Y1 - 2011/3/1
N2 - Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3′ 5′-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng•min) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (Emax168%±8% vs 136%±4%) and small mesenteric arteries (SMA; Emax170%±6% vs 143%±3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 μmol/L) reduced PE-induced contraction in aortas from Ang II rats (E max94%±12%) but not in controls (154%±7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1±0.1 vs 5.9±0.06), but not in controls (6.0±0.03 vs 6.1±0.04). Sildenafil (10 μmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 μmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (Emax82%±12% vs 445±5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1±0.3 vs 5.3±0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness.
AB - Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3′ 5′-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng•min) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (Emax168%±8% vs 136%±4%) and small mesenteric arteries (SMA; Emax170%±6% vs 143%±3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 μmol/L) reduced PE-induced contraction in aortas from Ang II rats (E max94%±12%) but not in controls (154%±7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1±0.1 vs 5.9±0.06), but not in controls (6.0±0.03 vs 6.1±0.04). Sildenafil (10 μmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 μmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (Emax82%±12% vs 445±5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1±0.3 vs 5.3±0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness.
KW - angiotensin II
KW - cGMP
KW - hypertension
KW - vinpocetine
UR - http://www.scopus.com/inward/record.url?scp=79953215598&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953215598&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.110.164327
DO - 10.1161/HYPERTENSIONAHA.110.164327
M3 - Article
C2 - 21282562
AN - SCOPUS:79953215598
VL - 57
SP - 655
EP - 663
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 3 PART 2
ER -