The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus.
OBJECTIVE
Patients with diabetes mellitus exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide production. Elevated intracellular cyclic guanosine monophosphate (cGMP) levels contribute to an effective cardioprotection in different pathophysiological conditions. In this study, we investigated whether chronic treatment with the phosphodiesterase-5 inhibitor vardenafil could improve diabetic cardiovascular dysfunction by up-regulating the nitric oxide-cGMP pathway in the vessel wall and myocardium.


METHODS
Diabetes was induced in young rats by a single intraperitoneal injection of streptozotocin (60 mg x kg(-1)). In the treatment group, vardenafil (10 mg x kg(-1) x day(-1)) was given orally for 8 weeks. Diabetic control animals received vehicle for the same time. Left ventricular pressure-volume relations were measured by using a microtip Millar pressure-volume conductance catheter, and indexes of contractility, such as the slope of end-systolic pressure-volume relationship (E(max)) and preload recruitable stroke work (PRSW), were calculated. In organ bath experiments for isometric tension with rings of isolated aortae, endothelium-dependent and independent vasorelaxation was investigated by using acetylcholine and sodium nitroprusside.


RESULTS
When compared with the non-diabetic controls, diabetic rats showed increased myocardial and vascular transforming growth factor-beta1 expression, impaired left ventricular contractility (impairment of E(max) by 53%, PRSW by 40%; P < 0.05) and vascular dysfunction. Treatment with vardenafil resulted in higher cGMP levels, reduced transforming growth factor-beta1 expression, significantly improved cardiac function (improvement of E(max) by 95%, PRSW by 69%; P < 0.05) and greater vasorelaxation to acetylcholine and sodium nitroprusside in aortae from diabetic animals.


CONCLUSIONS
Our results demonstrate that impaired vascular cGMP signalling contributes to the development of diabetic vascular and cardiac dysfunction, which can be prevented by chronic phosphodiesterase-5 inhibition.
Radovits
T
T
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. radovitstamas@yahoo.com
Bömicke
T
T
Kökény
G
G
Arif
R
R
Loganathan
S
S
Kécsán
K
K
Korkmaz
S
S
Barnucz
E
E
Sandner
P
P
Karck
M
M
Szabó
G
G
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D006152:Cyclic GMP / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use; D000069058:Vardenafil Dihydrochloride; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology
D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D013450:Sulfones; D053773:Transforming Growth Factor beta1; D014227:Triazines; D014665:Vasodilator Agents; D000069058:Vardenafil Dihydrochloride; D006152:Cyclic GMP