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
CHAPTER ONE
INTRODUCTION
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
13electron. When muscle in the penis contract to stop the inflow of blood and open
out flow channels and an electron is reserved.HORMONAL INVOLVEMENT IN ERECTION
ï‚· 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).
14ï‚· 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.
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
15site 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
16and 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
17PDE 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.NITRIC OXIDE REGULATION OF PENILE ERECTION
Biology And Therapeutic Implications
18For 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
19Traditional 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).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,
20an 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).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
21carried 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).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,
221994). 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)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.