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P Medina

Publications and source records attributed to P Medina.

At least 19 recordsLinked to original sources
PubMed2006

Association of increased fibrinogen concentration with impaired activation of anticoagulant protein C.

BACKGROUND: Low levels of activated protein C (APC) are a risk factor for venous thrombosis. The mechanisms leading to interindividual differences in APC are not totally elucidated. Protein C is activated by the thrombin-thrombomodulin complex. As thrombin binds to fibrinogen and thrombomodulin through a common region, it is conceivable that fibrinogen influences the activation of protein C. This would help to explain the association between high levels of fibrinogen and an increased thrombotic risk. METHODS: We analyzed the association between circulating APC levels and fibrinogen concentration in 382 healthy subjects. Subsequently, we studied the effect of increasing fibrinogen concentrations on the APC generation on cultured endothelial cells. RESULTS: An independent inverse association between circulating APC levels and fibrinogen was found [betacoefficient, -0.16; 95% confidence interval (95% CI) -0.26, -0.06; P = 0.001]. For each 100 mg dL(-1) increase in fibrinogen, the independent risk of having low APC levels (<0.7 ng mL(-1)) was almost three times higher (OR 2.8; 95% CI 1.1, 7.2; P = 0.04). Accordingly, a notable association between increasing fibrinogen concentrations and the reduction in the thrombin-thrombomodulin dependent activation of protein C on endothelial cells was found (r = -0.57; P = 0.002). CONCLUSIONS: We present evidence of an inverse association between circulating APC and fibrinogen levels. According to this finding together with the results of our in vitro experiments, we propose that the impairment in the generation of APC on endothelial cells constitutes a new prothrombotic mechanism of fibrinogen.

Adult↗
PubMed2006

Circulating activated protein C is reduced in young survivors of myocardial infarction and inversely correlates with the severity of coronary lesions.

BACKGROUND: Cardiovascular risk factors for myocardial infarction (MI) are less frequent in younger than in older MI survivors. Therefore, the thrombotic component of MI may play a more important role at a young age. As activated protein C (APC) provides systemic anticoagulant and anti-inflammatory protection, a low plasma APC level may be an arterial thrombotic risk factor. AIM: To determine whether there is an association between reduced APC levels and early MI and severe coronary lesions. METHODS: APC was measured in 231 young MI survivors and 231 controls. RESULTS: Low APC levels were significantly associated with MI. Compared with the fourth quartile, the odds ratio (OR) for APC values in the first quartile was 3.7 [95% confidence interval (CI) = 2.1-6.4], and 3.2 (1.5-7.0) after adjustment for cardiovascular risk factors. Moreover, each decrease of 0.43 ng mL(-1) (1 SD) in APC increased the OR 1.7 times (1.4-2.2), and 1.5 times (1.2-1.9) after adjustment for cardiovascular risk factors. Low APC levels were also associated with the number of coronary arteries affected and with the severity of coronary lesions (P < 0.001). CONCLUSIONS: There is a significant association between low circulating APC levels and both early MI and the extent and severity of coronary atherosclerosis, which might be related to the anticoagulant and anti-inflammatory properties of APC.

Adult↗
PubMed2005

The multifunctional protein C system.

The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.

Animals↗
PubMed2004

Contribution of different calcium channels to long-term potentiation in superior cervical ganglion of the rat.

We explored the contribution of different calcium channel types to the long-term potentiation (LTP) of superior cervical ganglion of the rat. Right after a conditioning train of 40 Hz for 5 s, the maximum amplitude of the postsynaptic response (maximum potentiation) increased 5.6+/-0.5-fold. Potentiation decreased to 20% of its initial value within the following 70.0+/-8.0 min (LTP decay time). The contribution of P/Q-, N- and L-type calcium channels to LTP was studied by blocking their activity with synthetic funnel-web spider toxin (10 or 100 microM), omega-conotoxin GVIA (5 microM) or nifedipine (10 microM), respectively. The three blockers reduced the amplitude of the postsynaptic compound action potential before the conditioning train. After the train, all of the toxins reduced the LTP decay time and the integral of the amplitude versus time curve, defined as the LTP extent. In addition, all three blockers increased the maximum potentiation. Our results demonstrate that different calcium channel types contribute to ganglionic LTP. These effects may be by coupling excitation-secretion from different types of synaptic vesicles.

Animals↗
PubMed2004

Influence of azadirachtin, a botanical insecticide, on Chrysoperla carnea (Stephens) reproduction: toxicity and ultrastructural approach.

A commercial formulation of azadirachtin (Align) was tested on Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae) adults to determine its effects on reproduction. Three methods of exposure were carried out in the laboratory (residual, direct contact and ingestion) with concentrations close to the maximum field recommended concentration in Spain (48 mg AI/liter). Align proved to be harmless to newly emerged adults irrespective of the mode of exposure. Nevertheless, fecundity was reduced in a reversible way in females that have ingested azadiracthin after the onset of oviposition. Fertility was not different from that of controls in all treatments. Additional tests showed that males were not involved in the reduction of oviposition. Electron microscopy studies pointed out that Align interfered with vitellogenin synthesis and/or its uptake by developing oocytes; thus, growing follicles in treated females were significantly smaller that those of the controls. The role of azadirachtin as a compound that may influence several hormonal and protein titers involved in reproduction is also discussed.

Animals↗
PubMed2003

Rupture of the lesser gastric curvature after a Heimlich maneuver.

BACKGROUND: We present a case of lesser gastric curvature injury after a Heimlich maneuver due to obstruction of the breathing tract that was repaired by laparoscopic surgery. METHODS: A patient with perforation of the lesser gastric curvature as a result of closed abdominal traumatism was operated on using the laparoscopic approach with the use of four trocars as work openings. With this technique, the diagnosis was confirmed, the injury repaired, and the abdominal cavity washed. RESULTS: The postoperative period was favorable and the patient was released from the hospital on day 7 without any complications. CONCLUSIONS: Laparoscopic surgery can be technically reproduced in the treatment of gastric injury as a result of closed abdominal traumatism.

Aged↗
PubMed2003

Topical toxicity of two acetonic fractions of Trichilia havanensis Jacq. and four insecticides to larvae and adults of Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae).

The toxicity of botanical origin compounds such as two acetonic fractions of the seed kernels of the Meliacea Trichilia havanensis Jacq with insecticide properties (azadirone (F12) and the mixture F18 [1,7+3,7-di-O-acethylhavanensin (4:1)], three insecticides commercially available (imidacloprid, natural pyrethrins+PBO, triflumuron) and phloxine B, were tested in the laboratory. Topical bioassays using third instar and newly emerged adults of the lacewing Chrysoperla carnea (Stephens) at the maximum field recommended rate in Spain for commercials and at 1,000 ppm of active ingredient for T. havanensis acetone fractions and phloxine-B, were carried out. Imidacloprid and triflumuron were very toxic to third instar larvae inhibiting adult emergence, being the rest of insecticides harmless. Fecundity and fertility were not affected by the non-toxic compounds. Concerning adults, only imidacloprid and natural pyrethrins killed them significantly 24 hours after treatment. Phloxine B, triflumuron and T. havanensis fractions were harmless and did not cause any effect on fecundity and fertility with the exception of triflumuron, which reduced considerably the egg hatch. It can be concluded that T. havanensis acetonic fractions and phloxine B were non-toxic to larvae and adults of C. carnea when treated topically, whereas triflumuron, natural pyrethrins and imidacloprid affected one or more of the evaluated parameters under our conditions.

Acetone↗
PubMed2001

Endothelin-1-induced potentiation of adrenergic responses in the rabbit pulmonary artery: role of thromboxane A(2).

To examine whether low concentrations of endothelin-1 potentiate the vasoconstrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline. Endothelin-1 (10(-10) M) potentiated the contractions induced by electrical stimulation and noradrenaline. The endothelin ET(B) receptor antagonist (2,6-dimethylpiperidinecarbonyl-gamma-methyl-Leu-N(in)-[Methoxycarbonyl]-D-Trp-D-Nle) (BQ-788, 10(-6) M), but not the endothelin ET(A) receptor antagonist cyclo(D-Asp-Pro-D-Val-Leu-D-TRP) (BQ-123, 10(-6) M), inhibited the potentiating effects of endothelin-1. Pretreatment with the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor furegrelate and the thromboxane receptor antagonist [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[[[(1-oxoheptyl)amino]acetyl]amino] methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-30741) (all at 10(-5) M) prevented the potentiation induced by endothelin-1 on adrenergic stimulation. The Ca(2+) channel antagonist nifedipine (10(-6) M) did not affect the potentiation induced by endothelin-1. The results indicate that endothelin-1 potentiates the responses to electrical stimulation and noradrenaline by activating endothelin ET(B) receptors. This potentiation depends on the production of cyclooxygenase-generated factors, probably thromboxane A(2).

Animals↗
PubMed2001

U-46619-induced potentiation of noradrenergic constriction in the human saphenous vein: antagonism by thromboxane receptor blockade.

OBJECTIVE: We investigated the potentiating effect of U-46619, a synthetic analogue of thromboxane A(2) (TXA(2)), on the adrenergic responses in human saphenous vein. METHODS: Saphenous vein rings were obtained from 35 patients undergoing coronary artery bypass surgery. The rings were suspended in organ bath chambers for isometric recording of tension. RESULTS: U-46619 (10(-10)-3 x 10(-7) mol/l) produced concentration-dependent and endothelium-independent contractile responses. U-46619 (10(-10) mol/l) potentiated the contractions elicited by electrical stimulation and potassium chloride, and produced leftward shifts of the concentration-response curve for noradrenaline. The TXA(2) receptor antagonist SQ-30741 (10(-8) mol/l) prevented the potentiation evoked by U-46619. The dihydropyridine calcium antagonist nifedipine (10(-6) mol/l) did not affect the potentiation of electrical stimulation and noradrenaline induced by U-46619, but abolished the potentiation of U-46619 on KCl-induced contractions. CONCLUSIONS: U-46619 facilitates sympathetic neurotransmission and potentiates constrictor effects of noradrenaline in human saphenous veins through stimulation of TXA(2) receptors. These effects are independent of calcium entry through dihydropyridine calcium channels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

[PSA:alpha 1-antichymotrypsin ratio/total PSA in the diagnosis of prostatic cancer in the range of total PSA from 4 to 10 ng/ml].

OBJECTIVE: To evaluate the usefulness of the ratio PSA:alpha-1-antichymotrypsin/total PSA (C/T) in the diagnosis of prostate cancer in the range of total PSA between 4 and 10 ng/mL. MATERIAL AND METHODS: By using home-made ELISAs we have determined plasmatic concentrations of total PSA and complex PSA:alpha-1-ACT in 300 patients with total PSA between 4-10 ng/mL. All samples were obtained before any manipulation that could interfere the PSA levels. RESULTS: By prostatic biopsy 85 patients (28.3%) were diagnosed of prostate cancer (CaP) and 215 (71.6%) of benign prostatic hyperplasia (BPH). The mean values of the complex PSA:alpha-1-ACT (4.2 ng/mL in the BPH patients vs 5.0 ng/mL in the CaP patients) and of the C/T ratio (0.70 vs 0.82, respectively) showed significant differences between both groups (p = < 0.0001). The total PSA did not show differences (6.1 ng/mL vs 6.0 ng/mL; p = 0.79). From all three parameter evaluated, the ratio C/T had the biggest area under the ROC (0.884) and statistically significant differences in comparison with total PSA (0.490; p = < 0.001) and the complex PSA:alpha-1-ACT (0.696: p = < 0.001). Therefore, by using a ratio C/T > 0.62 to decide the performance of a biopsy, 27% of the patients with BPH could have avoided this procedure with a 100% sensitivity. Increasing the ratio to 0.68 the specificity is 47% and the sensitivity is 95.2%. Rectal examination did not have influence on the cut-off, sensitivity, specificity and area under the ROC of the ratio C/T. CONCLUSIONS: Our results confirm that the ratio C/T improve the diagnostic capacity of the total PSA between 4-10 ng/ml. Moreover, the rectal examination does not influence the selection of ratio C/T cut-off suggestives of CaP neither the diagnostic efficacy.

Aged↗
PubMed2001

Inhibition of nitric oxide activity by arginine analogs in human renal arteries.

BACKGROUND: Plasma levels of endogenous guanidine compounds are increased in various pathologic conditions, including chronic renal failure. In the present study we tested the effects of some of these compounds on basal and stimulated nitric oxide activity in human renal arteries. METHODS: Rings from human renal arteries were obtained from 22 patients undergoing nephrectomy. The rings were suspended in organ baths for isometric recording of tension. We then studied the effects of N(G)-monomethyl-L-arginine (L-NMMA), N(G),N(G)-dimethyl-L-arginine (asymmetrical dimethylarginine [ADMA]), aminoguanidine (AG), and methylguanidine (MG) on artery rings under basal and stimulated conditions. RESULTS: In precontracted arteries, L-NMMA (1 micromol/L to 1 mmol/L) and ADMA (1 micromol/L to 3 mmol/L) caused concentration- and endothelium-dependent contractions (median effective concentrations [EC50] = 13.3 micromol/L and 17.5 micromol/L, respectively; Emax = 15+/-4% and 17+/-4% of the response to 100 mmol/L KCl, respectively). Aminoguanidine (0.01 to 3 mmol/L) and MG (0.01 to 3 mmol/L) produced endothelium-independent contractions (Emax = 9+/-3% and 16+/-2% of the response to 100 mmol/L KCl, respectively). L-arginine (1 mmol/L) but not D-arginine (1 mmol/L) prevented the contractions by L-NMMA and ADMA, but did not change contractions induced by AG and MG. In precontracted arteries, the relaxation to acetylcholine was decreased but not abolished by L-NMMA and ADMA. The remaining relaxation was reduced by charybdotoxin (0.1 mol/L) and tetraethylammonium (1 mmol/L). CONCLUSIONS: The results demonstrate that L-NMMA and ADMA reduce basal and stimulated nitric oxide activity in human renal arteries. An increase in the plasma concentrations of methylarginines associated with renal disease should be considered as a risk factor for endothelial dysfunction and abnormal vasomotor tone in human renal arteries.

Acetylcholine↗
PubMed2001

Increased activation of protein C, but lower plasma levels of free, activated protein C in uraemic patients: relationship with systemic inflammation and haemostatic activation.

Chronic renal failure (CRF) courses with both systemic inflammatory reaction and haemostatic activation. We explored the relationship of these processes with plasma levels of free, activated protein C (APC) and complexes of APC with its inhibitors in patients with CRF under conservative treatment. Plasma concentrations of inflammatory cytokines [tumour necrosis factor alpha (TNFalpha) and interleukin 8], acute-phase proteins (C-reactive protein, fibrinogen, alpha1-anti-trypsin and von Willebrand factor), and markers of haemostatic activation (thrombin-anti-thrombin complexes, plasmin-anti-plasmin complexes, and fibrin and fibrinogen degradation products) were higher in patients than in controls. Inflammatory and haemostatic markers were significantly and positively correlated. Total plasma APC and APC:alpha1-anti-trypsin (alpha1AT) complexes were 44% and 75% higher in patients than in controls (P = 0.0001), whereas free APC was 20% lower (P < 0.015). No significant difference was observed in APC:protein C inhibitor (PCI) complexes between both groups. The free/total APC ratio was significantly lower in patients than in controls (P < 0.0001). Total plasma APC and APC:alpha1AT were positively correlated with activation markers of haemostasis and acute-phase proteins, whereas free APC was inversely correlated with plasma levels of creatinine, acute-phase proteins and fibrin degradation products (FnDP). Systemic inflammation and activation of haemostasis are interrelated processes in CRF. APC generation was increased in response to elevated thrombin production, but the inflammatory reaction, associated with increased synthesis of alpha1AT, reduced its anticoagulant effect. Lower free plasma APC in CRF may be pathogenically associated with atherothrombosis, a major cause of death in this disease.

Adult↗
PubMed2001

Low level of circulating activated protein C is a risk factor for venous thromboembolism.

The levels of circulating activated protein C (APC) reflect in vivo protein C activation. The aim of this study was to determine whether a low APC level is an independent risk factor for venous thromboembolism (VTE). We measured APC in 160 patients with a history of VTE and without recognized thrombophilic defects, and in 199 healthy individuals. The mean (+/- SD) APC level was lower in patients (0.99 +/- 0.44 ng/ml) than in controls (1.19 +/- 0.41 ng/ml) (p < 0.0001), and showed a different distribution in the two groups. Thirty-eight patients (23.7%) had APC levels below the 5th percentile of the control group (<0.69 ng/ml) and 57 patients (35.6%) had APC levels below the 10th percentile (<0.77 ng/ml). APC levels <0.69 ng/ml increased the risk of a single or recurrent episode of VTE 4.2-fold (95% confidence interval, 2.0-9.0) or 6.9-fold (2.6-17.9). respectively, and APC levels <0.77 ng/ml increased these risks 3.4-fold (1.9-6.2) or 5.1-fold (2.3-11.2), respectively, compared with controls. Familial studies revealed that in some cases the low APC phenotype seems to be hereditary. We conclude that a low level of circulating APC in individuals without any of the most recognized thrombophilic defects is a prevalent, independent risk factor for VTE, and that it predisposes to recurrent VTE.

Adult↗
PubMed2000

Effects of sildenafil on human penile blood vessels.

OBJECTIVES: To investigate the effects of sildenafil on human penile blood vessels and evaluate the interaction of sildenafil with neurogenic-mediated responses. Sildenafil is currently used in the treatment of erectile dysfunction. METHODS: Penile dorsal arteries and deep dorsal veins were obtained from 14 multiorgan donors. Vascular rings were suspended in organ bath chambers, and the isometric tension was recorded. We then studied the effects of sildenafil on precontracted vessels and the neurogenic (noradrenergic and nitrergic) responses. RESULTS: Sildenafil (10(-9) to 3 x 10(-6) M) caused concentration-dependent relaxation and amplified the relaxation induced by sodium nitroprusside. Relaxation was unaffected by the inhibitor of nitric oxide synthase N(G)-monomethyl-L-arginine (10(-4) M). Compared with zaprinast, sildenafil was 8 to 10 times more potent in terms of the median effective concentration (EC(50)) values. Electrical field stimulation of the vessels under resting tension caused frequency-dependent contractions that were attenuated in the presence of sildenafil. When penile vessels were contracted after blockade of norepinephrine release with guanethidine (10(-6) M), electrical stimulation induced frequency-dependent, nitric oxide-dependent relaxations that were enhanced by sildenafil. CONCLUSIONS: These results indicate that the relaxation of human penile arteries and veins induced by sildenafil involves inhibition of noradrenergic contraction, enhancement of neurogenic nitric oxide-mediated relaxation, and inhibition of smooth muscle contraction.

Adolescent↗
PubMed2000

Relaxation induced by cGMP phosphodiesterase inhibitors sildenafil and zaprinast in human vessels.

BACKGROUND: Sildenafil is currently used in the treatment of erectile dysfunction. However, assessment of direct effects of sildenafil on coronary arteries and on arteries used as coronary grafts is unknown. This study was designed to investigate the effects of sildenafil on contracted human coronary, internal mammary, and radial arteries obtained from multiorgan donors. The observations were extended to forearm veins. Zaprinast was included in this study for comparison. METHODS: Segments of left coronary, internal mammary, and radial arteries, and forearm veins were obtained from 16 multiorgan donors. Vascular rings were suspended in organ bath chambers and isometric tension was recorded. Then the effects of sildenafil, zaprinast, and sodium nitroprusside on precontracted vessels were studied. RESULTS: Sildenafil (10(-8) - 3 x 10(-5) mol/L) caused concentration-dependent relaxation in the internal mammary arteries, radial arteries, and forearm veins. In the coronary arteries, sildenafil had a modest relaxant effect. In addition, sildenafil amplified the relaxation induced by sodium nitroprusside in all four vessels. Relaxation was unaffected by the inhibitor of nitric oxide synthase NG-monomethyl-L-arginine (10(-4) mol/L). Compared with zaprinast, sildenafil was eight to ten times more potent in terms of EC50 values. CONCLUSIONS: The direct relaxant effects of sildenafil together with its synergistic interaction with nitric oxide donors should be considered in patients undergoing coronary bypass surgery, patients with low blood pressure, and patients receiving antihypertensive regimes.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Effects of antidepressants in adrenergic neurotransmission of human vas deferens.

OBJECTIVES: To evaluate the effects of sertraline, fluoxetine, and amitriptyline on the contractile responses of the human vas deferens muscle elicited by norepinephrine, electrical field stimulation, and KCl, because the therapeutic action of antidepressants may be accompanied by sexual dysfunction related to the contractility of the vas deferens smooth muscle. METHODS: Ring segments of the epididymal part of the vas deferens were taken from 32 elective vasectomies and mounted in organ baths for isometric recording of tension. We then studied the effects of sertraline, fluoxetine, and amitriptyline on the neurogenic and agonist-induced contractile responses. RESULTS: Amitriptyline caused concentration-dependent inhibition of neurogenic and norepinephrine-induced contractions. In contrast, only the highest concentration (10(-5) M) of sertraline and fluoxetine reduced the adrenergic contractions. The dihydropyridine calcium antagonist nifedipine (10(-6) M) completely prevented the inhibitory effect of sertraline and fluoxetine on neurogenic and norepinephrine-induced contractions but did not change the inhibition caused by amitriptyline. Sertraline, fluoxetine, and amitriptyline (all at 10(-5) M) attenuated contractions elicited by KCl and reduced contractions induced by CaCl(2) in KCl-depolarized preparations. CONCLUSIONS: The results indicate that sertraline and fluoxetine inhibit vas deferens motility through inhibition of Ca(2+) entry, with no effect on the adrenergic receptors, and amitriptyline acts as an adrenoceptor antagonist and inhibitor of the entry of calcium.

Amitriptyline↗
PubMed2000

Inhibition of neuroeffector transmission in human vas deferens by sildenafil.

Sildenafil (0.1 - 30 microM), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1 - 100 microM), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1 - 100 microM) had no effect on neurogenic contractions. The inhibition induced by sildenafil was not modified by the inhibitor of guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) (1 - 30 microM) but it was abolished by the K(+) channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM). Sildenafil, zaprinast and SNP did not affect the contractions induced by noradrenaline. SNP (10 microM) caused elevation of cyclic GMP levels that was potentiated by sildenafil (10 microM) and zaprinast (100 microM). ODQ (10 microM) inhibited the increase in cyclic GMP. Sildenafil inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large-conductance Ca(2+)-activated K(+) channels.

Adult↗