Coronary Artery Diameter Increase Induced by a Phosphodiesterase 5 Inhibitor, E4021, in Conscious Pigs

Adachi, Hideyuki; Nishino, Mayu

doi:10.1254/jjp.77.99

Cited by 10 publications

(6 citation statements)

References 8 publications

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“…PDE isoenzymes in vascular smooth muscle. Previous studies using the PDE5 inhibitors zaprinast (23) or E4021 (29) demonstrated an increase in cGMP levels in isolated coronary artery segments and dose-dependent dilation of the large epicardial coronary arteries in awake pigs (1,29). Similarly, Wallis and co-workers (36) reported that sildenafil resulted in a significant increase of cGMP concentration in isolated canine coronary artery segments in vitro.…”

Section: Discussionmentioning

confidence: 96%

Effect of sildenafil on coronary active and reactive hyperemia

Chen

Traverse

et al. 2000

American Journal of Physiology-Heart and Circulatory Physiology

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Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.

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Section: Discussionmentioning

confidence: 96%

Effect of sildenafil on coronary active and reactive hyperemia

Chen

Traverse

et al. 2000

American Journal of Physiology-Heart and Circulatory Physiology

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“…cGMP-mediated vasodilation occurs preferentially in arterial vessels with less effect at the level of the coronary arterioles (9). Selective inhibition of PDE5 with sildenafil (29), E4021 (1,20), or zaprinast (17) significantly increased cGMP and caused relaxation of isolated normal epicardial coronary arteries. In normal animals, stimulation of endogenous coronary NO production with acetylcholine (13), intraarterial infusion of NO donors (7,11), or intraarterial infusions of ANP or BNP resulted in resistance vessel dilation with an increase of coronary blood flow (14,29).…”

Section: Discussionmentioning

confidence: 99%

Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure

Chen

Traverse

Hou

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure. Am J Physiol Heart Circ Physiol 284: H1513-H1520, 2003; 10.1152/ajpheart.00529.2001.-Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition with sildenafil in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/dtmax) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 Ϯ 1.4 to 23 Ϯ 1.4 mmHg. Sildenafil (2 and 10 mg/kg per os) caused a 5-to 6-mmHg decrease of aortic pressure (P Ͻ 0.05), with no change of heart rate, LV systolic pressure, or LV dP/dtmax. Sildenafil caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals, sildenafil did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF.phosphodiesterase; guanosine 3Ј,5Ј-cyclic monophosphate; blood flow; myocardial O2 consumption ACTIVATION OF GUANYLYL CYCLASE in vascular smooth muscle causes increases in cGMP and cGMP-dependent protein kinases that result in vasodilation through modulation of calcium channels and by decreasing the calcium sensitivity of vascular smooth muscle contractile proteins (18). Although the principal mechanism of cGMP production in the coronary vessels involves activation of soluble guanylyl cyclase by nitric oxide (NO) produced in the vascular endothelium, the natriuretic peptides can also cause coronary vasodilation by interacting with vascular smooth muscle natriuretic peptide receptor type A to cause activation of particulate guanylyl cyclase (14, 29). The vasodilator response to cGMP is terminated by several cyclic nucleotide phosphodiesterases. Phosphodiesterase type 5 (PDE5), which selectively degrades cGMP but does not catabolize cAMP (2,19,26), has recently received attention because of the availability of sildenafil, a selective inhibitor of PDE5, for treatment of erectile dysfunction (5). PDE5 is found in high concentrations in the corpus cavernosum; sildenafil increases cGMP levels and causes smooth muscle relaxation (5). PDE5 is also found in vascular smooth muscle of systemic and coronary arteries (26), and thus has the potential to produce effects on arterial pressure and coronary blood flow. In isola...

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“…However, their use is limited due to their non-selective activity. Recently, highly selective intracellular PDE5 inhibitors (E4021, SCH 51866) were introduced in clinical trials to control hypertension, pulmonary hypertension, respiratory distress, platelet aggregation and erectile dysfunction [156][157][158][159][160][161][162][163][164]. Increased 3', 5' cGMP in the cerebral arterial wall by selective inhibition of PDE5 may prevent development of delayed vasospasm after SAH [165,166].…”

Section: Prevention Of Vasospasm By Pde Selective Inhibitormentioning

confidence: 99%

Analysis of Nitric Oxide (NO) in Cerebral Vasospasm After Aneursymal Bleeding

Pluta

Oldfield²

2007

RRCT

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Nitric oxide (NO) is produced by the endothelial NOS (eNOS) in the intima and by the neuronal NOS (nNOS) in the adventitia of cerebral vessels. By activating soluble guanylyl cyclase, NO increases the production of 3'-5'cGMP, which relaxes smooth muscle cells and dilates the arteries in response to shear stress, metabolic demands and changes of pCO(2) (chemoregulation). 3'-5'cGMP is then metabolized by phosphodiesterases (PDEs). Aneurysmal subarachnoid hemorrhage (SAH) interrupts this regulation of cerebral blood flow (CBF). Oxyhemoglobin, gradually released from the subarachnoid clot enveloping the conductive arteries, scavenges NO and destroys nNOS-containing neurons. This deprives the arteries of NO, leading to vasoconstriction which initiates delayed vasospasm. This arterial narrowing increases shear stress and stimulates eNOS, which under normal conditions would lead to increased production of NO and dilation of arteries. However, this does not occur because of transient eNOS dysfunction evoked by increased levels of an endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA). Increased ADMA levels result from decreased elimination due to inhibition of the ADMA-hydrolyzing enzyme (DDAH 2) in arteries in spasm by hemoglobin metabolites, bilirubin-oxidized fragments (BOXes). This eNOS dysfunction sustains vasospasm until ADMA levels decrease and NO release from endothelial cells increases. This NO-based pathophysiological mechanism of vasospasm suggests that exogenous delivery of NO, modification of PDE activity, inhibition of the L-arginine-methylating enzyme (I PRMT 3) or stimulation of DDAH 2 may provide new therapies to prevent and treat vasospasm. This paper summarizes experimental and early clinical data that are consistent with the involvement of NO in delayed cerebral vasospasm after SAH and which suggests new therapeutic possibilities.

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Coronary Artery Diameter Increase Induced by a Phosphodiesterase 5 Inhibitor, E4021, in Conscious Pigs

Cited by 10 publications

References 8 publications

Effect of sildenafil on coronary active and reactive hyperemia

Effect of sildenafil on coronary active and reactive hyperemia

Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure

Analysis of Nitric Oxide (NO) in Cerebral Vasospasm After Aneursymal Bleeding

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