Preliminary investigation on effects of burantashi extract on liver enzymes of aibino male and female whistar rats

Thesis Overview

<p> INTRODUCTION<br>PHYSIOLOGY OF ERECTION<br>Penile Erection involves an integration of complex physiological<br>processes involving the central nervous system, peripheral nervous system,<br>hormonal and vascular systems. Any abnormality involving these systems<br>whether from medications or disease has a significant impact on the ability to<br>develop and sustain erection; ejaculate and experience orgasm. (Laumann et al.,<br>1999).<br>The physiological process of erection begins in the brain and involves the<br>nervous and vascular system. The chemicals that initiate erection are<br>neurotransmitters present in the brain. Any kind of stimulation physical or<br>psychological, causes nerves to send message to the vascular system which result<br>in significant blood flow to the penis. Two arteries in the penis supply blood to<br>erectile tissues and the corpora cavernous which become engorged and expand<br>as a result of increased blood flow and pressures. Because blood must stay in the<br>penis to maintain rigidity. An erectile tissue is enclosed by tunicae, which is<br>fibrous elastic sheathes cinch which prevents blood leaving he penis during<br>13<br>electron. When muscle in the penis contract to stop the inflow of blood and open<br>out flow channels and an electron is reserved.<br>HORMONAL INVOLVEMENT IN ERECTION<br>ï‚· Oestrogen/Progesterone: (These are female hormones that cause clitoral<br>erection. If the body has two much oestrogen and or too little testost erone, she<br>ca n get very wet but can not erect her clitoral and G-spot. ( Haimen et al.,<br>2002). Estrogen tends to increase the size of the bread, labia minors (inner lips)<br>and clitoral hood, but shrinks the glans clitoris into the clitoral hood making it<br>invisible. It also increases the thickness of the vaginal lining making the G-spot<br>inaccessible. The mechanism of the clitoral and G-spot erection is the same as<br>that of the penis. It is driven by the parasympathetic sexual nerve (The<br>neurotransmitter acetylcholine) through the neurotransmitter. Nitric oxide and<br>the erection dilator cGMP, which is continuously powered by the burning of<br>testosterone without a testosterone burst and burning. She cannot pop the glans<br>Clitoris and G-spot out. If she is on birth control pills there is a chance that her<br>body is over flooded by estrogens and low progesterone. Over loaded liver<br>cannot produce sufficient essential enzymes to synthesize sufficient NO, cGMP<br>and testosterone to support the clitoral and G-spot erection infact excessive<br>estrogen or progesterone in the body will shrink the penis, clitoral and G-spot,<br>but likely increase the breast size (under the excessive estrogen action).<br>14<br>ï‚· Testosterone:- Testosterone is a hormone produced by the testicles and is<br>responsible for the proper development of male sexual characters. The pump<br>helps the penis to become erect while band maintains the erection.<br>Circulating levels of testosterone correlate with NO, production.<br>Testosterone treatment can reduce central adiposity and insulin resistance, which<br>may contribute to its beneficial effects on vascular NO, and ED. Raising low<br>testosterone levels improves ED and can restore erectile function in response to<br>PDE-5 inhibitors.<br>MECHANISM OF ACTION OF PDE-5 INHIBITION IN ERECTILE<br>DYSFUNCTION.<br>A spinal reflex and the L-arginine nitric oxide guanglyl cyclase-cyclic<br>guanosine monophonsphate (cGMP) pathway mediate smooth muscle relaxation<br>that results in penile erection. Nerves and endothelial cells directly release nitric<br>oxide in the penis, where it stimulates guanylyl cyclase to produce cGMP and<br>lowers intracellular calcium level. This triggers relaxation of arterial and<br>trabecular smooth muscle, leading to arterial dilation, venous constriction, and<br>erection. Phosphodiesterases (PDEs) is the predominant phosphodiesterase in<br>the corpus cavernosum. The catalytic site of PDE-5 normally degrades cGMP<br>and PDE-5 inhibitors such as sildenafil potentiate endogenous increase in cGMP<br>by inhibiting its breakdown at the catalytic site. Phosphorylation of PDE-5<br>increases its enzymatic activity as well as the affinity of its allosteric<br>(noncatalytic/GAF domains) sites for cGMP. Binding of cGMP to the allosteric<br>15<br>site further stimulates enzymatic activity. Thus phosphorlation of PDE-5 and<br>binding of cGMP to the non catalytic site mediate negative feed back regulation<br>of the cGMP pathway.<br>In recent years a deeper understanding of the regulation of penile smooth<br>muscle has led to greater insight into the physiology of normal erectile function<br>and erectile dysfunction (ED), as well as the introduction of phosphodiesterase<br>(PDE) inhibitor for the treatment of ED. The oral PDE-5 inhibitors sidenafil has<br>proved to be a safe and effective treatment for this disorder and has fostered<br>further research into the underlying mechanisms of such drugs. This article will<br>review the biochemical pathways involved in erection. The role of PDE-5 in<br>these pathway and the molecular mechanisms involved in PDE activity.<br>A penile erection result from the relaxation of smooth muscle in the<br>penis .the process is mediated by a spinal reflex and incorporates sensory and<br>mental stimuli. The Balance between factors that stimulate contraction and<br>relaxation determines the tone of penile vasculature and the smooth muscle of<br>the corpus cavernosum.<br>In primates, including humans the L-arginine nitric oxide guanylyl cyclase<br>cyclic guanosine monophosphate (cGMP) pathway is the key mechanism of<br>penile erection. Nitric oxide is produced from oxygen and L-arginine under the<br>control of nitric oxide synthase (NOS). Sexual arousal stimulates neural<br>pathways that result in the release of NO from nerves and endothelial cells<br>directly into the penis. NO penetrates into the cytoplasm of smooth muscle cells<br>16<br>and binds to guanylyl cyclase. The interaction of NO with guanylyl cyclase<br>causes a conformational change in the enzyme, which results in the catalytic<br>production of 3,5 cyclic guanosine monophosphate from guanosine<br>5’triphosphate. Cyclic cGMP activities cGMP dependent protein kinase (PKG)<br>which in turn phosphorylates several proteins. These protein kinase interactions<br>results in reduced intraocular calcium levels and a consequent relaxation of<br>arterial and trabecular smooth muscle leading to arterial dilation. Venous<br>constriction and the rigidity of penile erection.<br>Since cGMP plays a key role in this process, potential interventions for<br>inadequate smooth muscle relaxation include increasing the level of<br>intracellular cGMP. PDE-5 normally inhibits penile erection by degrading<br>cGMP. This degradation occurs at the catalytic site in the presence of bound<br>zinc. PDE-5 inhibitors lower the activity of PDE-5 by competing with cGMP<br>and consequently raise the level of cGMP. In the absence of stimulation of the<br>NO pathway. PDE-5 inhibition is ineffective in isolated strips of corpus c<br>avernosum, sildenafil relaxes the smooth muscle by amplifying the effects of<br>the normal, endogenous cGMP- dependent relaxation mechanisms but<br>produces little effect in the absence of a NO donor. Since sexual arousal<br>stimulates this pathway specifically in the penis, PDE-5 inhibitor has a relatively<br>small effect on smooth muscle in other tissues.<br>PDE-5 is the predominant phosphodiesterase in the corpus carvernosum,<br>however, at least 11 families of PDE have been identified in mammals, some<br>17<br>PDE types are associated with more than one gene and some mRNA exhibit<br>two or more splice variants. The result is more than 50 species of PDE. Some<br>types of PDE are specific for either cyclic adenosine monophosphate (cGMP) or<br>cGMP, and some degrade both PDE, for example degrades both cGMP and<br>cGMP. Whereas PDE-4 is specific for Camp-5 and PDE-5 is specific for cGMP.<br>The cross reactivity of PDE inhibitors can be attributed largely to similarities of<br>their homologous catalytic domain. Messager RNA has been detected in human<br>corpus cavernosum tissue for the human PDE isoforms-PDE-1A, PDE-1B, PDE-<br>1C, PDE-2A, PDE-3A, PDE-4A, PDE-4B, PDE-4C, PDE-4D, PDE-5A, PDE-<br>7A, PDE-8A, and PDE-9A. Most mammalian PDEs are dimers but the<br>functional significance of this dimerization is unknown, some like PDE5, have<br>two identical submits (homodimers) and some like PDE-6 have two different<br>submits (heterodimers).<br>The PDE-5 also differs in the nature of the regulatory domain of the<br>enzyme and in the role of phosphorylation. In all cases, the catalytic domain is<br>located towards the carboxylterminus and the regulatory domain is located<br>towards the amino terminus. A PDE-5 monomeric fragment retains the essential<br>catalytic features of the domain full length enzyme.<br>NITRIC OXIDE REGULATION OF PENILE ERECTION<br>Biology And Therapeutic Implications<br>18<br>For approximately a decade now, substantial evidence has accrued supporting<br>nitric oxide (NO) as the central component of major signal transduction system<br>that ats in the penis to mediate the erectile response. This molecules subserve a<br>Unique biochemical cascade invading production of the potent second<br>messenger molecule, 3’5’ cyclic guanosine monophosphate (cGMP) and its<br>activation of protein kinase G (PKG) which induces physiologic penile erection<br>by regulating the state of penile smooth muscle contractility (Burnett, 1997). In<br>fact, current data support the notion that this NO based biochemical cascade<br>represent a convergence of cellular biochemical and molecular inputs, which on<br>the signal transduction regulatory level, is indispensable for the mechanism of<br>penile erection (Hedland et al., 2000). Consistent with the importance of NO<br>radiation of penile erection, its biology in the penis is quite complex, involving<br>multiple regulatory interactions, the molecule itself may target several<br>biochemical mechanisms that achieve erectile tissue relaxation but is also the<br>target of a host of modulatory influences that determines its release and mode of<br>action in erectile tissue. At the same time, premier signal transduction<br>mechanism has been exploited for therapeutic purposes, specifically in the<br>clinical management of erectile dysfunction. Discoveries pertaining to the field<br>of NO biology in the penis have, in recent years been rapidly translated into the<br>clinical management of the first orally effective pharmacotherapy for erectile<br>dysfunction, sildenafil citrate (Viagra) (Goldstein et al., 1998) <br></p>