cyclic-gmp and aluminum-sulfate

Some heavy metals show adverse vascular and neurological effects, however, their effect on erection is underestimated. This study aims to investigate the effect of Pb, Cd and Al on erectile function and their potential mechanism of action in rats.. Measurement of intracavernosal pressure/mean arterial pressure (ICP/MAP) changes elicited by electrical stimulation of cavernous nerve in anesthetized rats treated with Pb-acetate, Al-sulfate, or Cd-sulfate acutely, and subacutely for 7 days. Serum creatinine, testosterone, TBARs, GSH levels and metal accumulation in corpus cavernosum were measured.. Pb, Al and Cd significantly reduced ICP/MAP in rats after acute (2,10-2,10 and 1,3 mg/kg respectively) and sub-acute (3, 3, and 1mg/kg/day respectively) treatments. They selectively accumulated in the corpus cavernosum reaching 25.107 ± 2.081 μg/g wet weight for Pb, 1.029 ± 0.193 for Cd, 31.343 ± 1.991 for Al, compared to 7.084 ± 1.517, 0.296 ± 0.067, and 8.86 ± 1.115 as controls respectively. Serum creatinine levels were not altered. Cd and Al significantly reduced testosterone level to 0.483 ± 0.059 and 0.419 ± 0.037 ng/ml respectively compared to 0.927 ± 0.105 ng/ml as control. Aluminum elevated TBARs significantly by 27.843%. The acute anti-erectile action of Pb was blocked by non-selective NOS and GC inhibitors and potassium channel blocker. Lead also masked the potentiatory effect of l-arginine and diazoxide on ICP/MAP. No interaction with muscarinic or nicotinic modulators was observed.. Pb, Cd and Al show anti-erectile effect independent on renal injury. They don not modulate cholinergic nor ganglionic transmission in corpus cavernosum. Pb may inhibit NO/cGMP/K+channel pathway. The effect of Cd and Al but not Pb seems to be hormonal dependent.

Topics: Alum Compounds; Animals; Arterial Pressure; Cadmium Compounds; Creatinine; Cyclic GMP; Dose-Response Relationship, Drug; Electric Stimulation; Glutathione; Injections, Intraperitoneal; Injections, Intravenous; Male; Neurotransmitter Agents; Nitric Oxide; Organometallic Compounds; Penile Erection; Penis; Potassium Channels; Rats, Wistar; Signal Transduction; Sulfates; Testosterone; Thiobarbituric Acid Reactive Substances; Time Factors

Cyclic diguanylate (c-di-GMP) is a novel immunomodulator and immune enhancer that triggers a protective host innate immune response. The protective effect of c-di-GMP as a vaccine adjuvant against Staphylococcus aureus infection was investigated by subcutaneous (s.c.) vaccination with two different S. aureus antigens, clumping factor A (ClfA) and a nontoxic mutant staphylococcal enterotoxin C (mSEC), then intravenous (i.v.) challenge with viable methicillin-resistant S. aureus (MRSA) in a systemic infection model. Mice immunized with c-di-GMP plus mSEC or c-di-GMP plus ClfA vaccines then challenged with MRSA produced strong antigen-specific antibody responses demonstrating immunogenicity of the vaccines. Bacterial counts in the spleen and liver of c-di-GMP plus mSEC and c-di-GMP plus ClfA-immunized mice were significantly lower than those of control mice (P<0.001). Mice immunized with c-di-GMP plus mSEC or c-di-GMP plus ClfA showed significantly higher survival rates at day 7 (87.5%) than those of the non-immunized control mice (33.3%) (P<0.05). Furthermore, immunization of mice with c-di-GMP plus mSEC or c-di-GMP plus ClfA induced not only very high titers of immunoglobulin G1 (IgG1), but c-di-GMP plus mSEC also induced significantly higher levels of IgG2a, IgG2b and IgG3 compared to alum adjuvant (P<0.01 and P<0.001, respectively) and c-di-GMP plus ClfA induced significantly higher levels of IgG2a, IgG2b and IgG3 compared to alum adjuvant (P<0.001). Our results show that c-di-GMP should be developed as an adjuvant and immunotherapeutic to provide protection against systemic infection caused by S. aureus (MRSA).

Topics: Adjuvants, Immunologic; Alum Compounds; Animals; Antibodies, Bacterial; Antigens, Bacterial; Coagulase; Colony Count, Microbial; Cyclic GMP; Enterotoxins; Female; Immunoglobulin G; Injections, Subcutaneous; Liver; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred C57BL; Spleen; Staphylococcal Infections; Staphylococcal Vaccines

Cyclic diguanylate (c-di-GMP) is a unique bacterial intracellular signaling molecule capable of stimulating enhanced protective innate immunity against various bacterial infections. The effects of intranasal pretreatment with c-di-GMP, or intraperitoneal coadministration of c-di-GMP with the pneumolysin toxoid (PdB) or pneumococcal surface protein A (PspA) before pneumococcal challenge, were investigated in mice. We found that c-di-GMP had no significant direct short-term effect on the growth rate of Streptococcus pneumoniae either in vitro or in vivo. However, intranasal pretreatment of mice with c-di-GMP resulted in a significant decrease in bacterial load in lungs and blood after serotypes 2 and 3 challenge, and a significant decrease in lung titers after serotype 4 challenge. Potential cellular mediators of these enhanced protective responses were identified in lungs and draining lymph nodes. Intraperitoneal coadministration of c-di-GMP with PdB or PspA before challenge resulted in significantly higher antigen-specific antibody titers and increased survival of mice, compared to that obtained with alum adjuvant. These findings demonstrate that local or systemic c-di-GMP administration stimulates innate and adaptive immunity against invasive pneumococcal disease. We propose that c-di-GMP can be used as an effective broad spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases.

Topics: Adjuvants, Immunologic; Administration, Intranasal; Alum Compounds; Animals; Antibodies, Bacterial; Bacterial Proteins; Blood; Colony Count, Microbial; Cyclic GMP; Female; Immunologic Factors; Injections, Intraperitoneal; Lung; Lymph Nodes; Male; Mice; Mice, Inbred BALB C; Pneumococcal Infections; Pneumococcal Vaccines; Streptococcus pneumoniae; Streptolysins; Survival Analysis

Oral administration of 0.3% aluminum (citrate or sulfate salt) for 4 weeks significantly elevated adenosine 3',5'-monophosphate (cyclic AMP) levels in rat cortex, hippocampus, striatum and cerebellum. The largest effect observed was a 60% increase in cortical cyclic AMP levels in rats administered aluminum sulfate. The effects of orally administered aluminum on guanosine 3',5'-monophosphate (cyclic GMP) levels were less widespread. Dietary aluminum citrate only elevated cyclic GMP levels in the hippocampus, while aluminum sulfate caused significant increases in the cerebellum, hippocampus and striatum. Aluminum citrate administered i.c.v. (1 mumol, 2 weeks postadministration) elevated cyclic AMP levels in the cortex, but had no effect on cyclic GMP levels. Aluminum administered either orally or i.c.v. had no effect on in vivo acetylcholine levels. However, dietary aluminum citrate significantly reduced choline levels in the cortex, hippocampus and striatum. Aluminum administered i.c.v. had no effect on choline acetyltransferase activity or on high-affinity choline transport. These results indicate that: the metabolism of cyclic AMP and of cyclic GMP are more sensitive to aluminum than are presynaptic cholinergic processes; the metabolism of cyclic AMP is more sensitive to the effects of aluminum than is the metabolism of cyclic GMP; and cortical cAMP metabolism is the most sensitive to the presence of aluminum. Possible consequences of elevated levels of cyclic nucleotides induced by aluminum in the brain are proposed.

Topics: Administration, Oral; Alum Compounds; Aluminum; Animals; Brain; Choline; Choline O-Acetyltransferase; Citrates; Citric Acid; Cyclic AMP; Cyclic GMP; Injections, Intraventricular; Male; Rats; Rats, Inbred Strains; Sulfates