ABSTRACT

This work was carried out to investigate the effects of Burantashi extract on liver enzymes of albino male and female whistar rats. Burantashi is a popular seasoning agent to barbecued meat (suya) in Nigeria,mostly found in the northern part of the Nigeria. Liver Enzymes are those enzymes that plays important role in the liver both in function and regulation. Erectile dysfunction (ED) is defined as the consistent or recurrent inability of a man to attain or maintain penile erection, sufficient for sexual activity (2nd) International consultation on sexual Dysfunction Paris, June 28th July 1st, 2003).  Following the discovery and introduction of Burantashi research on the mechanism underlying penile erection, has had an enormous boost and many preclinical and clinical papers have been published in the last five years on the peripheral regulation of, and the mediators involved in human penile erection. The most widely accepted risk factors for ED are discussed. The research is focused on human data and the safety and effectiveness of Burantasni Stem as a phosphodiesterase -5- Inhibitors (PDE-5) used to treat Erectile Dysfunctions.

CHAPTER ONE

INTRODUCTION

1.1 PHYSIOLOGY OF ERECTION

Penile Erection involves an integration of complex physiological processes involving the central nervous system, peripheral nervous system, hormonal and vascular systems. Any abnormality involving these systems whether from medications or disease has a significant impact on the ability to develop and sustain erection; ejaculate and experience orgasm. (Laumann et al., 1999).

The physiological process of erection begins in the brain and involves the nervous and vascular system. The chemicals that initiate erection are neurotransmitters present in the brain. Any kind of stimulation physical or psychological, causes nerves to send message to the vascular system which result in significant blood flow to the penis. Two arteries in the penis supply blood to erectile tissues and the corpora cavernous which become engorged and expand as a result of increased blood flow and pressures. Because blood must stay in the penis to maintain rigidity. An erectile tissue is enclosed by tunicae, which is fibrous elastic sheathes cinch which prevents blood leaving he    penis during electron. When muscle in the penis contract to stop the inflow of blood and open out flow channels and an electron is reserved.

1.2 HORMONAL INVOLVEMENT IN ERECTION

• Oestrogen/Progesterone: (These are female hormones that cause clitoral erection. If the body has two much oestrogen and or too little testost erone, she ca n get very wet but can not erect her clitoral and G-spot. ( Haimen et al., 2002). Estrogen tends to increase the size of the bread, labia minors (inner lips) and clitoral hood, but shrinks the glans clitoris into the clitoral hood making it invisible. It also increases the thickness of the vaginal lining making the G-spot inaccessible. The mechanism of the clitoral and G-spot erection is the same as that of the penis. It is driven by the parasympathetic sexual nerve (The neurotransmitter acetylcholine) through the neurotransmitter. Nitric oxide and the erection dilator cGMP, which is continuously powered by the burning of testosterone without a testosterone burst and burning. She cannot pop the glans Clitoris and G-spot out. If she is on birth control pills there is a chance that her body is over flooded by estrogens and low progesterone. Over loaded liver cannot produce sufficient essential enzymes to synthesize sufficient NO, cGMP and testosterone to support the clitoral and G-spot erection infact excessive estrogen or progesterone in the body will shrink the penis, clitoral and G-spot, but likely increase the breast size (under the excessive estrogen action).

• Testosterone:- Testosterone is a hormone produced by the testicles and is

responsible for the proper development of male sexual characters. The pump helps the penis to become erect while band maintains the erection.

Circulating levels of testosterone correlate with NO, production. Testosterone treatment can reduce central adiposity and insulin resistance, which may contribute to its beneficial effects on vascular NO, and ED. Raising low testosterone levels improves ED and can restore erectile function in response to PDE-5 inhibitors.

1.3 MECHANISM  OF  ACTION  OF  PDE-5  INHIBITION  IN  ERECTILE DYSFUNCTION.

A spinal reflex and the L-arginine nitric oxide guanglyl cyclase-cyclic guanosine monophonsphate (cGMP) pathway mediate smooth muscle relaxation that results in penile erection. Nerves and endothelial cells directly release nitric oxide in the penis, where it stimulates guanylyl cyclase to produce cGMP and lowers intracellular calcium level. This triggers relaxation of arterial and trabecular smooth muscle, leading to arterial dilation, venous constriction, and erection. Phosphodiesterases (PDEs) is the predominant phosphodiesterase in the corpus cavernosum. The catalytic site of PDE-5 normally degrades cGMP and PDE-5 inhibitors such as sildenafil potentiate endogenous increase in cGMP by inhibiting its breakdown at the catalytic site. Phosphorylation of PDE-5 increases its enzymatic activity as well as the affinity of its allosteric (noncatalytic/GAF domains) sites for  cGMP. Binding of cGMP to the allosteric site further stimulates enzymatic activity. Thus phosphorlation of PDE-5 and binding of cGMP to the non catalytic site mediate negative feed back regulation of  the cGMP pathway.

In recent years a deeper understanding of the regulation of penile smooth muscle has led to greater insight into the physiology of normal erectile function and erectile dysfunction (ED), as well as the introduction of phosphodiesterase (PDE) inhibitor for the treatment of ED. The oral PDE-5 inhibitors sidenafil has proved to be a safe and effective treatment for this disorder and has fostered further research into the underlying mechanisms of such drugs. This article will review the biochemical pathways involved in erection. The role of PDE-5 in these pathway and the molecular mechanisms involved in PDE activity.

A penile erection result from the relaxation of smooth muscle in the penis .the process is mediated by a spinal reflex and incorporates sensory and mental stimuli. The Balance between factors that stimulate contraction and relaxation determines the tone of penile vasculature and the smooth muscle of the corpus cavernosum.

In primates, including humans the L-arginine nitric oxide guanylyl cyclase cyclic guanosine monophosphate (cGMP) pathway is the key mechanism of penile erection. Nitric oxide is produced from oxygen and L-arginine under the control of nitric oxide synthase (NOS). Sexual arousal stimulates neural pathways that result in the release of NO from nerves and endothelial cells directly into the penis. NO penetrates into the cytoplasm of smooth muscle cells and binds to guanylyl cyclase. The interaction of NO with guanylyl cyclase causes a conformational change in the enzyme, which results in the catalytic production of 3,5 cyclic guanosine monophosphate from guanosine 5’triphosphate. Cyclic cGMP activities cGMP dependent protein kinase (PKG) which in turn phosphorylates several proteins. These protein kinase interactions results in reduced intraocular calcium levels and a consequent relaxation of arterial and trabecular smooth muscle leading to arterial dilation. Venous constriction and the rigidity of penile erection.

Since cGMP plays a key role in this process, potential interventions for inadequate smooth muscle relaxation include increasing the  level  of intracellular cGMP. PDE-5 normally inhibits penile erection by degrading cGMP. This degradation occurs at the catalytic site in the presence of bound zinc. PDE-5 inhibitors lower the activity of PDE-5 by competing with cGMP and consequently raise the level of cGMP. In the absence of stimulation of the NO pathway. PDE-5 inhibition is ineffective in isolated strips of corpus c avernosum, sildenafil relaxes the smooth muscle by amplifying the  effects of the normal, endogenous cGMP- dependent relaxation mechanisms but produces little effect in the absence of a NO donor. Since sexual arousal stimulates this pathway specifically in the penis, PDE-5 inhibitor has a relatively small effect on smooth muscle in other tissues.

PDE-5 is the predominant phosphodiesterase in the corpus carvernosum, however, at least 11 families of PDE have been identified in mammals, some

PDE types are associated with more than one gene and some mRNA exhibit two or more splice variants. The result is more than 50 species of PDE. Some types of PDE are specific for either cyclic adenosine monophosphate (cGMP) or cGMP, and some degrade both PDE, for example degrades both cGMP and cGMP. Whereas PDE-4 is specific for Camp-5 and PDE-5 is specific for cGMP. The cross reactivity of PDE inhibitors can be attributed largely to similarities of their homologous catalytic domain. Messager RNA has been detected in human corpus cavernosum tissue for the human PDE isoforms-PDE-1A, PDE-1B, PDE- 1C, PDE-2A, PDE-3A, PDE-4A, PDE-4B, PDE-4C, PDE-4D, PDE-5A, PDE-

7A, PDE-8A, and PDE-9A. Most mammalian PDEs are dimers but the functional significance of this dimerization is unknown, some like PDE5, have two identical submits (homodimers) and some like PDE-6 have two different submits  (heterodimers).

The PDE-5 also differs in the nature of the regulatory domain of the enzyme and in the role of phosphorylation. In all cases, the catalytic domain is located towards the carboxylterminus and the regulatory domain is located towards the amino terminus. A PDE-5 monomeric fragment retains the essential catalytic features of the domain full length enzyme.

1.4 NITRIC OXIDE REGULATION OF PENILE ERECTION

Biology And Therapeutic Implications

For approximately a decade now, substantial evidence has accrued supporting nitric oxide (NO) as the central component of major  signal transduction system that ats in the penis to mediate the erectile response. This molecules subserve a Unique           biochemical   cascade              invading   production of   the   potent      second messenger  molecule,  3’5’  cyclic  guanosine  monophosphate  (cGMP)  and  its activation of protein kinase G (PKG) which induces physiologic penile erection by regulating the state of penile smooth muscle contractility (Burnett, 1997). In fact, current data support the notion that this NO based biochemical cascade represent a convergence of cellular biochemical and molecular inputs, which on the signal transduction regulatory level, is indispensable for the mechanism of penile erection (Hedland et al., 2000). Consistent with the importance of NO radiation of penile erection, its biology in the penis is quite complex, involving multiple                 regulatory interactions,     the   molecule   itself   may  target   several biochemical mechanisms that achieve erectile tissue relaxation     but is also the target of a host of modulatory influences that determines its release and mode of action  in  erectile  tissue. At              the  same time,  premier  signal  transduction mechanism  has  been  exploited  for  therapeutic  purposes,  specifically  in  the clinical management of erectile dysfunction. Discoveries pertaining to the field of NO biology in the penis have, in recent years been rapidly translated into the clinical management of the first orally effective pharmacotherapy for erectile dysfunction, sildenafil citrate (Viagra) (Goldstein et al., 1998).

NO BIOLOGY IN THE PENIS

Traditional understanding of the action of NO in the penis invokes the constitutive formation of this molecule under normal physiologic conditions with the expression and activities of the enzyme, sources localized to neural and endothelial components of the corporal tissue. The verification that NO derives from the autonomic innervations supplying the penis has directly supported the description of this molecule as a peripheral neurotransmitter of non adrenergic, no cholinergic-1992 mediated penile erection (Kim et al.,1991) the confirmation that the molecule also is produced within vascular and trabecular endothelium comprising the penile vascular supply, has offered additional support for the role of NO serving as an endothelial  relaxation factor of penile erection (kimoto et al., 1990, knispel et al., 1991, azadzoic et al., 1992, Hedlund et al., 2000).

1.5 ATIEOLOGY OF ERECTILE DYSFUNCTION

Erectile dysfunction (ED) is a sexual dysfunction that affects the reproductive systems of both men and women.

According to the definition by national Institute of Health consensus Development (NIHCD) panel on importance (1993) in males. It is sexual dysfunction characterized with the inability to develop or maintain an erection of the penis sufficient for satisfactory sexual performance. It is also known as male impotence or Baby D syndrome. While in women according to American psychiatric Association (APA) (1994), it is characterized with the persistant or recurrent inability to attain, or maintain until completion of the sexual activity, an adequate lubrication. Swelling response that otherwise is present during fem ale sexual arousal and sexual activity is thus prevented. Hence it is called woman impotence or female erectile dysfunction. (NIH, 2005).

The word importance may also be used to describe other problems that interfere with sexual intercourse and reproduction, such as lack of sexual desire and problems with ejaculation or orgasm. Using the term “erectile dysfunction however, makes it clear that those other problems are not involved (NIH, 2005)

An erection occurs as a hydraulic effect due to blood entering and being retained in sponge-like bodies within the penis and clitoris. The process is most often than not initiated as a result of sexual arousal, when signals are transmitted from the brain to nerves in the pelvis erectile dysfunction  is therefore, indicated when an erection is consistently difficult or impossible to produce despite arousal (Laumann  et al., 1999).

1.6 PREVALENCE OF ERECTILE DYSFUNCTION IN MEN.

Erectile dysfunction ED, varies in severity; some men have a total inability to achieve an erection others have inconsistent ability to achieve an erection, and still others can sustain only brief erection. The variation in severity of erectile dysfunction makes estimating its frequency difficult. Many men also are reluctant to discuss erectile dysfunction with their doctors, and thus, the condition is under diagnosed nevertheless experts have estimated that ED affects 30 million men   in united sates, Again, according to the   statistical research carried out by Adegunloye and Eze in 2002 and 1994 respectively in Nigeria, results show that about 23-26.5% of men suffer from this condition while according to carey in 1990, discovered that about 4.9% of men suffer from the condition in the united states.

While erectile dysfunction can occur at any age, it is uncommon among young men and more common in the elderly. By the age of 45, most men have experienced erectile dysfunction at least some of the time. According to Massachusetts, male Aging study, complete impotence increase from 5% among men 40 years of age to 15% men 70 years and older. Population studies conducted in Netherlands found out that some degree of ED occurred in 20% men between 50-54 and in 50% of men between ages 70-78. In 1998, the National Ambulatory Medical care survey (NAMCS) counted 1,520,000 doctor offices visited  for erectile dysfunction (ED).

1.7 PREVALENCE OF ERECTILE DYSFUNCTION IN WOMEN.

Erection dysfunction which is known as female erectile dysfunction in woman occurs about 43% of American women (NIH consensus conference, 1993). And this medical condition is a persistent or recurrent inability to attain or maintain clitoral erection until completion of the sexual activity, an adequate lubrication. Swelling response that is normally present during female sexual arousal and sexual activity is therefore absent. The individual having the condition  is  said  to  experience  frigidity  (American  Psychiatric  Association, 1994). Again according to Otuba et al in 1989, about 8.7% of women suffer from this very condition in the United States while between 35.3-40%, according t o Adegunloye in 2002 and Eze in 1994 of women in Nigeria suffer from this condition. Spector and carey in 1994 reported 5-10% in the united states.

In addition, female erectile dysfunction occurs at any age but majorly in old age. Hence, the most significant age related change is menopause (Karen, 2002) and (Rod et al., 2008).

However erectile dysfunction may be caused by diabetes, a atherosclerosis, hormonal imbalance, neurological problems e.t.c (Organic causes) or stress depression e.t.c (Psychological causes).

Besides treating the underlying causes (Organic or Psychological), the first line treatment of ED consist of a trail of phosphodiesterase 5’(PDE-5) inhibitor (The first of which was sildenafil or Viagra). In some cases, treatment can involve prostaglandin tablets in the urethra, intracarvenous injection with a fine needle into the penis or clitoris that causes swelling, a penis or Clitoris prosthesis, a penis or clitoris pump or vascular surgery, estrogens replacement therapy for the women e.t.c (Kendric et al., 2005)

1.8 AIM OF STUDY

The aim of this research is to find out the effects of Barantashi. (pausinystalia yohimbe). Extract on the liver enzymes of albino male and female whistar rats.