Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of rolipram, a new generation antidepressant which is a selective inhibitor of phosphodiesterase, on the selectively bred Flinders Sensitive Line (FSL) of rats, a genetic animal model of depression, was studied. Acutely, rolipram produced comparable decreases in temperature and activity in the FSL and the Flinders Resistant Line (FRL) rats. Upon chronic treatment there was a trend for rolipram to counteract the shock-induced suppression of activity in the FSL rats, suggesting an antidepressant-like effect. However, both groups gained a significant amount of weight, which appeared to be associated with polydipsia and polyuria. In addition, both groups were significantly more affected by the muscarinic agonist, oxotremorine, than their vehicle-treated counterparts. Thus, the FSL rats, which are genetically supersensitive to cholinergic agonists, are even more sensitive following chronic treatment with rolipram. These unexpected findings suggest that rolipram may not be appropriate as an antidepressant for humans because of undesirable side effects.
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PMID:Antidepressant effects of rolipram in a genetic animal model of depression: cholinergic supersensitivity and weight gain. 262 26

A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of [8-arginine]vasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study to clarify the mechanism by which Li administered orally for several weeks induces polyuria and NDI in rats. Albino rats consuming a diet which contained Li (60 mmol/kg) for 4 wk developed marked polyuria and polydipsia; at the end of 4 wk the plasma Li was 0.7 +/- 0.09 mM (mean +/- SEM; n = 36). Li-treated rats had a significantly decreased (-33%) tissue osmolality in papilla and greatly reduced cortico-papillary gradient of urea (cortex--43%; medulla--64%; papilla--74%). Plasma urea was significantly (P less than 0.001) lower in Li-treated rats (5.4 +/- 0.2 mM) compared with controls (6.8 +/- 0.3 mM). Medullary collecting tubules (MCT) and papillary collecting ducts (PCD) microdissected from Li-treated animals had higher content of protein than MCT and PCD from the control rats. The cAMP accumulation in response to AVP added in vitro was significantly (delta = -60%) reduced. Also, the cAMP accumulation in MCT and PCD after incubation with forskolin was markedly lower in Li-treated rats. Addition of 0.5 mM 1-methyl,3-isobutyl-xanthine did not restore the cAMP accumulation in response to AVP and forskolin in MCT from Li-treated animals. In collecting tubule segments from polyuric rats with hypothalamic diabetes insipidus (Brattleboro homozygotes) the AVP-dependent cAMP accumulation was not diminished. The activity of adenylate cyclase (AdC) in MCT of Li-treated rats, both the basal and the activity stimulated by AVP, forskolin, or fluoride, was significantly (delta approximately equal to -30%) reduced, while the activity of cAMP phosphodiesterase (cAMP-PDIE) in the same segment showed no significant difference from the controls. Also, the content of ATP in MCT microdissected from Li-treated rats and incubated in vitro did not differ from controls. The rate of [14C]succinate oxidation to 14CO2 in MAL was inhibited (-77%) by 1 mM furosemide, which indicates that this metabolic process is coupled with NaCl cotransport in MAL. The rate of (14)CO(2) production from [14C]succinate in MAL was not significantly different between control and Li-treated rats. In MCT of control rats, the rate of [14C]succinate oxidation was approximately 3 times lower than in MAL. The rate of (14)CO(2) production from [(14)C]succinate in MCT of Li-treated rats was significantly (delta +33%) higher than in MCT dissected from control rats. Based on these results, we conclude that at least two factors play an important role in the pathogenesis of NDI consequent to chronic oral administration of Li: (a) decreased ability of MCT and PCD to generate and accumulate cAMP in response to stimulation by AVP; this defect is primarily due to diminished activity of AdC in these tubular segments caused by prolonged exposure to Li; and (b) lower osmolality of renal papillary tissue, due to primarily to depletion of urea, which decreases osmotic driving force for water reabsorption in collecting tubules. On the other hand, NaCI reabsorption in MAL is apparently not affected by chronic Li treatment.
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PMID:Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats. 298 35

The DI +/+ Severe hereditary nephrogenic diabetes insipidus mouse is resistant to the antidiuretic action of vasopressin (VP) because of failure to accumulate cAMP and subsequent inability to form intramembranous particles on the apical (luminal) surface of kidney cells that normally respond to VP. The defect is primarily, if not exclusively, due to excessive activity of specific cAMP-phosphodiesterases. The abnormality can be overcome in vitro and in vivo by the phosphodiesterase inhibitor, rolipram. Most cases of hereditary NDI in man have sex-linked recessive inheritance, which appears to be due to an abnormality of the V2 receptor. The chromosomal locus of the defect is Xq28. Sporadic cases of congenital NDI have been described in females who appear to have a defect beyond the V2 receptor and the guanine nucleotide-binding stimulatory protein. There is no information on the biochemical defect in very rare cases with other types of inheritance patterns. No abnormalities of V1a and V1b receptor function have been found in patients with NDI. Mice and patients with NDI have evidence of increased AVP synthesis. AVP release in relation to plasma osmolality is increased in patients during infusion of hypertonic saline. This is the opposite of what has been described in patients with primary polydipsia (dipsogenic diabetes insipidus) who are chronically overhydrated. Together, these studies indicate that chronic dehydration and overhydration can cause up- and downregulation of the osmotic release of AVP.
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PMID:Hereditary vasopressin resistance in man and mouse. 837 15

The possible antiallodynic effect of phosphodiesterase 5 inhibitor sildenafil and nitric oxide donor glyceryl trinitrate as well as the changes in phosphodiesterase 5A2 mRNA expression in dorsal root ganglion and spinal cord of allodynic diabetic rats was assessed. Diabetes was induced by streptozotocin (50mg/kg, i.p.) in male Wistar rats. Streptozotocin injection produced hyperlglycemia, polydipsia, polyphagia and polyuria as well as long-term tactile allodynia (12 weeks) and a reduction of phosphodiesterase 5A2 mRNA expression in spinal cord of diabetic rats. Systemic administration of sildenafil (1-5.6 mg/kg, i.p.) reduced tactile allodynia in a dose-dependent manner in diabetic rats. Likewise, glyceryl trinitrate patches (0.2mg/h) also reduced tactile allodynia in diabetic rats. Moreover, both drugs reversed streptozotocin-induced phosphodiesterase 5A2 mRNA expression reduction. Our results indicate that glyceryl trinitrate and sildenafil reduce tactile allodynia in diabetic rats suggesting that nitric oxide and cyclic GMP supply is an important step in their mechanism of action of these drugs in diabetic animals. Data suggest that nitric oxide donors (as glyceryl trinitrate) and drugs which increase cyclic GMP levels (as sildenafil) could have a role in the pharmacotherapy of tactile allodynia in diabetic patients.
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PMID:Sildenafil and glyceryl trinitrate reduce tactile allodynia in streptozotocin-injected rats. 2007 49

Nephrogenic diabetes insipidus (NDI) is characterized by renal resistance to the antidiuretic hormone arginine vasopressin (AVP), which leads to polyuria, plasma hyperosmolarity, polydipsia, and impaired quality of living. Inherited forms are caused by X-linked loss-of-function mutations in the gene encoding the vasopressin 2 receptor (V2R) or autosomal recessive/dominant mutations in the gene encoding aquaporin 2 (AQP2). A common acquired form is lithium-induced NDI. AVP facilitates reabsorption of water through increased abundance and insertion of AQP2 in the apical membrane of principal cells in the collecting ducts. In X-linked NDI, V2R is dysfunctional, which leads to impaired water reabsorption. These patients have functional AQP2, and thus the challenge is to achieve AQP2 membrane insertion independently of V2R. The current treatment is symptomatic and is based on distally acting diuretics (thiazide or amiloride) and cyclooxygenase inhibitors (indomethacin). This mini-review covers published data from trials in preclinical in vivo models and a few human intervention studies to improve NDI by more causal approaches. Promising effects on NDI in preclinical studies have been demonstrated by the use of pharmacological approaches with secretin, Wnt5a, protein kinase A agonist, fluconazole, prostaglandin E2 EP2 and EP4 agonists, statins, metformin, and soluble prorenin receptor agonists. In patients, only casuistic reports have evaluated the effect of statins, phosphodiesterase inhibitors (rolipram and sildenafil), and the guanylate cyclase stimulator riociguat without amelioration of symptoms. It is concluded that there is currently no established intervention that causally improves symptoms or quality of life in patients with NDI. There is a need to collaborate to improve study quality and conduct formal trials.
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PMID:A mini-review of pharmacological strategies used to ameliorate polyuria associated with X-linked nephrogenic diabetes insipidus. 3292 47