The apex is the part of the bladder that is directed forward, and it is connected to the umbilical cord by ligaments. It is also found in ureters, in the lining membrane of the renal tubules and in urethra. The urothelium of the urinary bladder consists of 3 different layers: the basal, intermediate and the superficial layers that directly line the surface of the bladder.
CHAPTER TWO
Protein kinases use ATP as a source of phosphate groups to phosphorylate proteins' serine and threonine residues. In bladder smooth muscle, protein kinase phosphorylates an enzyme involved in muscle contraction known as myosin light chain kinase. When the receptor coupled to Gi is activated, they inhibit adenylate cyclase, leading to the reduction in cAMP synthesis.
For example, stimulation of M2-receptors of the bladder detrusor muscle with acetylcholine results in inhibition of adenylate cyclase (Rang, 2003).
Inositol phosphate and phospholipase C
In the urinary bladder, ATP is responsible for the bladder contractions initiated by parasympathetic nerves. When urinary bladder urothelium is stimulated by stretch, hydrostatic pressure or pH change, it releases ATP, which binds to purinergic receptors P2X, and mediates mechanosensory transduction in bladder afferent nerves (Rang et al, 2003; Benko et al, 2003). On the contrary, it releases a second messenger such as PG (F2a; F2) and other non-prostanoic compounds that participate in the bladder function.
When the bladder is empty, the intravesical pressure is zero, and the pressure increases as the bladder progressively receives urine. As the bladder fills with urine, juvenile contractions begin to occur as a result of stretching of the urinary bladder that stimulates the sensory receptor of the bladder wall. These sensory signals are carried to the spinal cord by the pelvic nerves and returned to the bladder via parasympathetic fibers.
The first contraction, created by itself, induces further activation of receptors which cause an increase in the reflex contraction of the bladder; the scenario is repeated until the bladder has reached a high degree of contraction. Bladder smooth muscle works like other smooth muscles found elsewhere in the body, with a slight difference in how it is stimulated.
CHAPTER THREE
Diseases of the urinary bladder
Cystitis
Ureterocele is a congenital abnormality of the urinary bladder that involves the distal ureter at the opening to the bladder. If left untreated, however, it can lead to kidney stone formation, increased uric acid stones and poor kidney function (Gotta et ah, 1998).
Urinary bladder incontinence
When the bladder is full of urine, it may leak due to the weakness of the urinary bladder detrusor muscle which is unable to completely empty the bladder.
CHAPTER FOUR Diabetes mellitus
A patient is classified as diabetic when his/her fasting blood glucose test results in a concentration greater than 7.0 mmol/L or when his/her random blood glucose test results in a concentration greater than 11.0 mmol/L. The higher concentration of the patient's blood glucose must be obtained more than once to qualify him/her as a diabetic patient. Increased blood glucose expels water from cells into blood stream and eventually reaches the kidney where it is eliminated through the urine.
High blood glucose concentration will worsen dehydration, increased blood osmolarity, electrolyte imbalance and coma (Shargel et ah, 1997). Insulin reduces the amount of glucose in the blood by inhibiting its production by the liver, stimulating its uptake and metabolism in skeletal and adipose tissues (Vinik et al., 2003). In the fasting state, the concentration of glucose decreases, the pancreatic a-cells release glucagon and the /?-pancreatic cells reduce the amount of secreted insulin.
The amount of insulin released is proportional to the concentration of glucose in the blood. When /?-pancreatic cells are in contact with glucose, there is an increase in the ATP/ADP ratio that stimulates the release of insulin.
Treatment of Diabetes mellitus
- Microvascular diseases
- Protein kinase C (PKC)
- Advanced glycated end-products
- Polyol pathway
Factors involved in the development of diabetic neuropathy are: microvascular disease, protein kinase C, the polyol pathway, and the advanced glycation end product (Vinik et al., 2003). There is usually an increase in the amount of muscarinic receptors present in the diabetic bladder. This change was attributed to an increase in muscarinic receptors in the dome of the urinary bladder of diabetic rats compared with age-matched controls.
Vanilloid receptors are involved in the sensory activity of the urinary bladder to pH and temperature changes. This impairment leads to hypersensitivity of bladder full sensations, even with less urine in the bladder. Most of the drugs used to treat bladder dysfunction are chosen because of their mode of action and are not specifically designed for bladder dysfunction.
Some of the anticholinergic drugs used to treat urinary incontinence are tolterodine and oxybutynin, and they work by binding to muscarinic receptors. It has a higher potency than oxybutynin in the treatment of bladder incontinence (Michel et ah, 2005). Nevertheless, these agents are used to treat autonomic hyperreflexia, particularly in patients with upper spinal cord injuries that cause excessive sympathetic outflow (Golan et al., 2005).
Sympathomimetic drugs have limited use in the treatment of incontinence because of their serious side effects on the heart and blood vessels.
CHAPTER FIVE
BASIS OF THE PROJECT
Therefore, the present study was prompted by the controversies and inconsistencies existing in the biomedical literature on the responses of the diabetic bladder to muscarinic agonists.
STUDY OBJECTIVE
The animals were kept and maintained under laboratory conditions of temperature, humidity, and light; and were given free access to food and water ad libitum one week before the start of my experiments. Diabetes was induced in the diabetic group of rats by intraperitoneal injections of STZ (75 mg/kg). The STZ-treated rats were kept in their cages under laboratory conditions for 7-10 days to allow the development of diabetes in the animals.
Tissues were washed 3–5 times after the maximal contractile response to each concentration of ACh was obtained, and then allowed to equilibrate for 5–10 min before the sequence of the next higher concentration of acetylcholine was added. Isolated bladder strips from diabetic and normal, age-matched control animals were always placed in parallel under the same experimental conditions to allow adequate comparison of tissue contractile responses to acetylcholine. ACh-evoked tissue contractile responses were recorded isometrically using Ugo Basile force-displacement transducers and Gemini pen-type recorders (model 7070).
Data obtained are presented as means (±SEM) of the contractile responses of the bladder tissues to the different ACh concentrations. Statistical evaluation of the data was done by means of 'Student t-test' for unpaired data.
RESULTS
Diabetic bladder (DRB) -±— Normal bladder (NRB)
Fasting blood glucose (FBG) levels, body weight and bladder wet weight of isolated normal diabetic (non-diabetic) and STZ-treated rats at week 10 of the study period. Acetylcholine (ACh M) induced concentration-dependent contractions of the bladder isolated from non-diabetic and STZ-treated diabetic rats. However, acetylcholine always induced stronger, more vigorous, and larger contractions in diabetic bladders compared with bladders from age-matched nondiabetic control rats.
Enhanced contractile responses of diabetic bladder strips to bath-applied ACh were detected immediately after induction of diabetes, and the magnitude or. Atropine (ATR M), a muscarinic antagonist, inhibited the contractile responses of isolated bladder preparations to bath-applied acetylcholine in a concentration-dependent manner.
DISCUSSION
Previous investigators have shown that in diabetic animals the contractile response of the urinary bladder to muscarinic agonists is inconsistent. However, the duration of hyperglycemia, the segment of the bladder used by the animals' breeders, and the experimental conditions used could contribute significantly to the differences in the previous researchers' findings. 1986) also noted no change in the affinity for 3H-QNB with hypertrophic bladders after peripheral parasympathetic denervation of the urinary bladders.
1988) have also shown that the STZ-induced diabetic state causes an increased maximal contractile response to the muscarinic agonist, an increased density of muscarinic receptors, and no change in the affinity of bladder dome smooth muscle for 3H-QNB. The findings of this study are consistent with the works of Kolta et al. 1995) who observed enhanced and significantly larger responses of bladder strips from diabetic rats to acetylcholine and carbachol respectively, immediately after induction of diabetes with STZ. Tammela et al, 1995) further observed that the magnitude and/or intensity of acetylcholine- and. Carbachol-induced contractile responses of diabetic bladder strips continued to increase as the diabetic condition of the animals progressed.
In conclusion, the results of this study have shown that urinary bladders from STZ-treated diabetic rats exhibit an increased contractile response to bath-applied acetylcholine. Although the present study could not establish the mechanism of the increased contractile responsiveness of the diabetic bladders to the muscarinic agonist (ACh) used, my results tend to suggest that the changes in diabetic urinary bladder synaptosomal, vesicle-bound neurotransmitter (ACh) concentrations reported by Tong et al. 1996), and the compensatory increase in muscarinic M3 receptor population density reported by Latifpour et al. 1988) appear to be two of the most plausible mechanisms for the increased diabetic bladder response to acetylcholine.
CHAPTER SIX
On the functional role of muscarinic M2 receptors in cholinergic and purinergic responses in the rat urinary bladder. Changes in muscarinic responsiveness, muscarinic receptor density, and urinary bladder Ca2+ mobilization in streptozotocin-induced diabetic rats. Loss of caveolin-1 expression associated with disruption of muscarinic cholinergic activities in the urinary bladder.
Effects of experimental diabetes on biochemical and functional properties of bladder muscarinic receptors, Journal of Pharmacology and Experimental Therapeutics. The effect of streptozotocin-induced diabetes on cholinergic motor transmission in the rat urinary bladder. The changes of norepinephrine and acetylcholine concentration in immature rat urinary bladder caused by streptozotocin-induced diabetes.
Transient changes in voiding and bladder contractility after sucrose diuresis and streptozotocin-induced diabetes mellitus in rats. Changes in urinary bladder M2 muscarinic receptor protein and mRNA in 2-week streptozotocin-induced diabetic rats, Neuroscience Letters.
