sildenafil-citrate and Hypercapnia

Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean ± SD age 38.5 ± 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular.

Topics: Adult; Brain; Brain Mapping; Double-Blind Method; Humans; Hypercapnia; Magnetic Resonance Imaging; Middle Aged; Muscular Dystrophy, Duchenne; Phosphodiesterase 5 Inhibitors; Physical Stimulation; Psychomotor Performance; Sildenafil Citrate; Touch Perception; Treatment Outcome

Sildenafil (Viagra), a cyclic guanosine monophosphate-degrading phosphodiesterase 5 inhibitor, induces headache and migraine. Such headache induction may be caused by an increased neuronal excitability, as no concurrent effect on cerebral arteries is found. In 13 healthy females (23+/-3 years, 70.3+/-6.6 kg), the effect of sildenafil on a visual (reversing checkerboard) and a hypercapnic (6% CO2 inhalation) response was evaluated using functional magnetic resonance imaging (fMRI, 3 T MR scanner). On separate occasions, visual-evoked potential (VEP) measurements (latency (P100) and maximal amplitude) were performed. The measurements were applied at baseline and at both 1 and 2 h after ingestion of 100 mg of sildenafil. Blood pressure, heart rate and side effects, including headache, were obtained. Headache was induced in all but one subject on both study days. Sildenafil did not affect VEP amplitude or latency (P100). The fMRI response to visual stimulation or hypercapnia was unchanged by sildenafil. In conclusion, sildenafil induces mild headache without potentiating a neuronal or local cerebrovascular visual response or a global cerebrovascular hypercapnic response. The implication is that sildenafil-induced headache does not include a general lowering of threshold for a neuronal or cerebrovascular response, and that sildenafil does not modulate the hypercapnic response in healthy subjects.

Topics: Adult; Cerebrovascular Circulation; Evoked Potentials, Visual; Female; Headache; Hemodynamics; Humans; Hypercapnia; Magnetic Resonance Imaging; Photic Stimulation; Piperazines; Purines; Sildenafil Citrate; Sulfones; Young Adult

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cerebrovascular Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hypercapnia; Models, Biological; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Subarachnoid Hemorrhage; Sulfones; Vasodilation; Vasodilator Agents; Vasospasm, Intracranial