Multidrug resistance proteins preferentially regulate natriuretic peptide-driven cGMP signalling in the heart and vasculature.

BACKGROUND AND PURPOSE: cGMP underpins the bioactivity of NO and natriuretic peptides and is key to cardiovascular homeostasis. cGMP-driven responses are terminated primarily by PDEs, but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo. EXPERIMENTAL APPROACH: Proliferation of human coronary artery smooth muscle cells (hCASMCs), vasorelaxation of murine aorta and reductions in mean arterial BP (MABP) in response to NO donors or natriuretic peptides were determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced heart failure was also explored. KEY RESULTS: MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and atrial natriuretic peptide (ANP). MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP per se but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental heart failure. These beneficial actions of MRP inhibition were associated with a greater intracellular:extracellular cGMP ratio in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS: MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

Kallmann syndrome patient with gender dysphoria, multiple sclerosis, and thrombophilia.

One of the challenging issues in patients with complex problems is that the various diseases and their treatment can influence each other and present unusual hurdles in management. We investigated one such complex case. A 34-year-old XY male presented with azoospermia, detected on semen analysis for pre-orchidectomy sperm banking. He had a 20-year history of gender dysphoria and bilateral breast swelling. The patient suffered a deep vein thrombosis at the age of 19 years. Examination confirmed clinical features of Kallmann syndrome including unilateral cryptorchidism, micropenis, congenital anosmia, and bimanual synkinesis (mirror movements), with reduced serum testosterone and normal gonadotropin levels demonstrating hypogonadotropic hypogonadism. MRI showed missing olfactory bulbs. Osteopenia and reduced vitamin D levels of 21 nmol/L were identified. He was found to harbor a heterozygous factor-V-Leiden mutation. The genetic basis of Kallmann syndrome remains unknown: his screening tests were negative for mutations in CHD7, FGF8, FGFR1, GNRH1, GNRHR, HS6ST1, KAL1, KISS1R, KISS1, NELF, PROK2, PROKR2, TAC3, and TACR3. The patient initially declined testosterone therapy with a view to undergo gender reassignment. Over the next 2 years, the patient experienced recurrent episodes of weakness and paresthesia, associated with classical MRI appearances of multiple sclerosis-related demyelination in the spinal cord and brain. Although it was difficult to elucidate an association between the patient's gender dysphoria and untreated congenital hypogonadism, his desire to become female together with his co-existing thrombophilia, presented challenges to the administration of hormone treatment. Furthermore, we have considered an association between multiple sclerosis and hypogonadotropic hypogonadism.