Atorvastatin enhances sildenafil-induced vasodilation through nitric oxide-mediated mechanisms.
Statins have cholesterol-independent effects including an increased vascular nitric oxide (NO) activity and are commonly used by patients with cardiovascular disease. Such patients frequently have erectile dysfunction, which may be treated with sildenafil, a selective inhibitor of phosphodiesterase type 5. Since statins and sildenafil can activate the NO-cGMP pathway, we investigated whether pre-treatment with atorvastatin (0, 5 and 30 mg/kg/day) for 2 weeks affects sildenafil (1 pM-100 mM)-induced relaxation of aortic rings isolated from Wistar rats. We also examined the hemodynamic consequences of this interaction in Wistar rats. Plasma nitrite/nitrate (NOx) concentrations were determined using an ozone-based chemiluminescence assay. While pre-treatment with atorvastatin increased the potency of sildenafil-induced vasorelaxation (P<0.01), no differences were observed in the maximum sildenafil-induced relaxation. Pre-incubation of aortic rings with NG-nitro-L-arginine methyl ester (L-NAME) reversed atorvastatin-induced increase in the potency of sildenafil relaxation. In addition, pre-treatment with atorvastatin enhanced plasma NOx concentrations and sildenafil-induced hypotension and tachycardia (all P<0.05). These results suggest that atorvastatin increases the vascular sensitivity to sildenafil through NO-mediated mechanisms.
Castro
Michele M
MM
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, Brazil, 14049-900.
Rizzi
Elen
E
Rascado
Ricardo R
RR
Nagassaki
Sabrina
S
Bendhack
Lusiane M
LM
Tanus-Santos
Jose E
JE
D000704:Analysis of Variance; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D017942:Nitric Acid / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D009566:Nitrates; D009573:Nitrites; D010879:Piperazines; D011687:Purines; D011758:Pyrroles; D013450:Sulfones; D014665:Vasodilator Agents; D017942:Nitric Acid; D000069059:Atorvastatin; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester