General features of hibernation, h y p e r t e n s i o n ,
h y p e rc h o le s te ro le m ia and selective sensory d en erv atio n a r e described in this section. This section it is not intended to be a c o m p re h en siv e review or to cover and compare d i f f e r e n t animal models for each of these conditions, but rather to give a
p e rsp ec tiv e on features relevant to the r e s p e c t i v e
e x p e rim e n ta l chapter.
1 . 5 . 1 H ib e r n a t io n
H ibernation in m am m als has arisen in the course o f
evolution as an adaptation for the u n fav o u rab le conditions o f the environm ent and is a complicated, cyclic phenom enon. T h e
facultative hibernators, including Syrian h a m s t e r s
{Mesocricetus a u r a t u s ) are directly influenced by e x t e r n a l
am bient te m p era tu re and photoperiod (Kalsbukhov, 1 9 8 5 ).
They are bred in the laboratories, which make them a
desirable species to work on, how ever they do not always s i n k in to hib ern atio n in spite of the low te m p e ra tu re of t h e surro u n d in g environm ent, this peculiarity has been b r o u g h t about by heredity (Chaffee, 1966; Kalabukhov, 1985).
In vestigation of th erm o reg u latio n of h i b e r n a t i n g m am m als in natural and ex perim ental conditions showed t h a t these m am m als could reduce their body t e m p e r a tu r e |to just above 0 °C w ithout any pathological consequence for their vital f u n c tio n s .
Syrian h am ster's body tem p era tu re is reduced from 3 6 . 0 - 3 7 . 0 °C at active state to 4.0-6.0 °C at torpid state (Lust et aL, 1989).
To some m easure hibernation in m am m als can b e
considered as specially programmed changes in the system a n d
cells of organism. These changes put the animal in to a
depressed state with an energy saving. In the particular case of
the Syrian hamster, the heart rate falls from 3 0 0 - 5 0 0
beats/m in to below 5 beats/min (Merril et aL, 1981). The l e v e l of m etab o lism is 1-5 % of the eutherm ic p a ra m eters and t h e
rate of m etabolism drops from 0.2 cal/g /m in to 0 .0 0 2
cal/g/m in during torpor (see Pakhotin et aL, 1993).
During hibernation, all excitable tissues of the h i b e r n a t o r exhibit a m arked reduction in electrical activity. In p a r t i c u l a r , this has been shown for n eu ro m u scu lar transm ission in t h e
ground squirrel (Albuquerque et aL, 1978), and Syrian hamster
(M elichar et aL, 1973) and for the nerve conduction in h a m s t e r (Chatfield et aL, 1978). During the deep hib ern atin g s t a t e axonal tran sp o rt is slowed or nearly abolished in the sciatic
nerve of ground squirrel (Boegman & A lbuquerque, 1 9 8 0 ).
H ow ever if the nerve was crushed, the segm ent distal to t h e crush rem ain ed electrically excitable for several weeks a f t e r
the crush. The survival time of this nerve segm ent w a s
d e p e n d e n t on the m ain ten an ce of a deep state of h i b e r n a t i o n and also on the length of the nerve segm ent attached to t h e muscle (Kalia et aL, 1982).
Onset of hibernation is accompanied by a decline in h e a r t rate and consequent decrease in systolic and diastolic b lo o d
pressure. However, the mean arterial pressure is kept w i t h i n the range observed in the normal conscious animals, by a n increase in p eripheral resistance. This increase in p e r i p h e r a l
resistance was mainly attributed to the m ain ten a n ce o f
vascular tone and to a generalized vasoconstriction t h r o u g h o u t the periphery. In 1960, Lyman and O'Brien rep o rted that t h e peripheral resistance of the ground squirrel could be a b o li s h e d by sympatholytic and ganglionic blocking agents. The a u t h o r s suggested that the vascular tone is maintained, in large part b y sym pathetic v aso co n stricto r action.
At low tem p era tu re (11 °C), the responses to NA a r e
a ugm ented in the femoral arteries of ground squirrel, b u t
depressed in those of rat (Marker & Webb, 1987). I n c r e a s e d resp o n siv en e ss to NA was also seen in aorta, portal vein a n d renal vessels of hibernating com pared with n o n - h i b e r n a t i n g
w oodchucks (Marmota Monax., Miller et aL, 1986). T his
adaptive response is specific and has led to the hypothesis t h a t
the changes in vascular resp o n siv en ess contribute to t h e
regional control of blood flow in hibernating animals.
1 .5 .2 H y p e r c h o l e s t e r o l e m i a
Cholesterol plays a vital role in m em b ran e function, b y its absorption into the hydrophobic portion of the p h o s p h o l i p i d bilayer, it tends to interfere with the motion of the acyl c h a in s of the phospholipid molecules and thereby alter the p h y s i c a l state of the m em brane. Such alterations have been shown to alter m em b ran e p erm eability, m em brane protein activity a n d m em b ran e receptor function (see Tulenko & Broderick, 1 9 8 6 ).
Early studies have established a decrease in t r a n s m e m b r a n e ion fluxes as the cholesterol content of artificial m em b ran e is increased (Papahadjopoulos & Watkins, 1967; P a p a h a d j o p o u lo s et aL, 1972; Owen & McIntyre, 1978). These studies have b e e n extended to include an evaluation of a cholesterol effect o n protein ion channels and have d em o n strated that an i n c r e a s e d cholesterol content alters both the expression and half life o f
ion channels in natural and synthetic m em b ran es (Renaud e t
al., 1982; Pope et al., 1982). In addition, function of a - and (3- adrenergic and m uscarinic receptors are altered in response to
altered m em b ran e cholesterol content (Insel et al., 1 9 7 8 ;
Dalziel et al., 1980; Criado et al., 1982; Renaud et al., 1982).
Although the exact role of cholesterol in d e v elo p m e n t o f
vascular disorders is presently unclear, it has b e e n
d e m o n stra te d that the cholesterol and low density l i p o p r o t e i n (LDL), accum ulate in the arterial walls in proportions to t h e i r
co ncentrations in the plasma (Hoff et al., 1 9 7 7 ).
H y p e rch o lestero lem ic plasm a has been shown to alter t h e contractile properties of arterial smooth muscle in vitro and in
vivo using a variety of techniques and animal m o d e ls.
Perfusion of h y p e rc h o leste ro le m ic hum an plasma, c a u s e d m arked poten tiatio n of contractile responses to NA in r a b b i t
perfu sed isolated femoral artery p rep aratio n s (Bloom et al.,
1975). D ietary -in d u ced h y p e rc h o le s te ro le m ia was f u r t h e r rep o rted to increase sensitivity to NA in the renal c o rtic a l blood vessels from baboons (Bomzon et al., 1978), and i n c r e a s e the coronary vascular resistance, during NA infusion in the d o g (R osendorff et al., 1981).
P erivascular n e u ro tra n sm issio n is thought to be a f f e c t e d in h y p e rlip id e m ia and consequent atherosclerosis ( A l - J u b o u r i & Al-Bayati, 1981; Panek et al., 1985; Lichtor et ai., 1 9 8 7 ; B urnstock et al., 1991; Stew art-L ee et al., 1991a; 1 9 9 2 ). H y p e rre s p o n siv e n e ss to electrical field sim ulation and to exogenous NA of the m esenteric arterial bed was observed i n rats fed an atherogenic diet (Al-Jubouri & Al-Bayati, 1 9 8 1 ). Ralevic and colleagues reported no alteration in n o r a d r e n e r g i c , but an im paired response to a ,p -m e th y le n e ATP in m e s e n t e r i c arterial beds in rats fed a high cholesterol diet (Ralevic et al.,
1996a). Additionally, Panek and coworkers have shown that in the tail artery of rats receiving a diet enriched in s a t u r a t e d
fats, displayed reduced perfusion pressure responses to
tran sm u ra l nerve stim ulation (Panek et al., 1985). There a r e
conflicting reports concerning the changes that occur in
response of tail artery of rats on high lipid diet to e x o g e n o u s NA during hyperlipidem ia; no change (Panek et al., 1985) a n d
elevation (Trzeciak et al., 1993) of responses to exogenous NA
have both been reported.
A few animal models of endogenous h y p e r l i p i d e m i a
w ithout form ation of atherosclerotic lesions have b e e n
developed so far, to study the effect of h y p e r l i p i d e m i a . Inoculation of the Donryu rats with Yoshida sarcom a cells h a s been used to develop inbred hyp erlip id ém ie rats that do n o t
develop typical ath ero m ato u s lesions or functional a n d
m orphological damage of smooth muscle cell despite h ig h
serum cholesterol levels (Fantappie et al., 1992; Chinellato e t
strain of rat is attributed to hepatic o v erp ro d u c tio n o f lipoproteins (Fantappie et aL, 1992).
1 .5 .3 H y p e r t e n s io n
H ypertension is a disorder of the c ir c u la tio n
characterized by an increased peripheral vascular r e s i s t a n c e which may be the result of structural and functional changes o f the blood vessel wall. It is now comm only accepted that t h e etiology of essential hypertension is due to a complex i n t e r p l a y of genetic and env iro n m en tal factors. Since h y p e rte n sio n is a
m u ltifactorial disease, it is unlikely that a single sp ecific
dysfunction is responsible for developm ent and m aintenance of
hy pertension. Structural changes in the m edia have b e e n
described, namely hy p erp lasia and h y p e rtro p h y (W inquist e t aL, 1982; Head, 1991), which would tend to promote the e ff e c ts
of vasoconstrictor substances and attenuate the effects o f
vasodilator substances. In addition, h y p e rte n sio n is a s s o c i a t e d with changes in both periv ascu lar nerves and endothelial cells. As a general rule, the combined effect of these changes is to
increase the response of vascular beds and isolated b lo o d
vessels to vasoconstrictor substances and decrease response to
vasodilator substances (Luscher et aL, 1987).
The inv o lv em en t of sym pathetic nervous system in
h y p e rte n sio n is well established. An increase in the n u m b e r and density of NA-containing nerves has been d e m o n s t r a t e d histochem ically in various blood vessels from h y p e r t e n s i v e
animals (Abboud, 1982; Head, 1989). |Consistent with t h e s e
findings, vascular resp o n siv en ess to sym pathetic n e r v e
stim ulation is enhanced in spontaneously h y p e rte n siv e r a t s
(SHR), widely utilized as a genetic model for h y p e r t e n s i o n ,
com pared with the n o rm otensive genetic control W istar Kyoto
(WKY) rats. This augm ented state of sym pathetic t r a n s m i s s i o n in SHR is due to both an enhanced release of s y m p a t h e t i c tran sm itte rs and an enhanced sensitivity at the p o s t j u n c t i o n a l receptor (Head, 1989; Westfall & Meldrum, 1985). An i n c r e a s e s in the activity of the enzymes associated with the s y n t h e t i c ( d o p a m in e - p - h y d r o x y la s e ) and catabolic ( c a t e c h o l- O - m e th y l tran sferase) process of cathecholam ines in e x p e r i m e n t a l
hypertension has also been observed (Trajkov et al., 1974).
Adenosine is a potent regulator of vascular tone, e x e r t in g its effects both directly on vascular smooth muscle cells o r through prejunctional m odulation of p eriv ascu lar s y m p a t h e t i c n e u ro tra n sm is sio n (Burnstock & Kennedy, 1986; Olsson & Pearson, 1990). The regulatory actions of adenosine include; i) a rep ressiv e action upon cell nucleus activity in blood v e s s e l s (A lbino-T eixeira et al., 1991; Matias, et al., 1991), ii) a p o t e n t inhibitory action on renin release (Spielman & T h o m p s o n ,
1982; Kuan, et al., 1990), iii) inhibitory action o n
noradrenergic transmission (Su, 1978a; Kamikawa, et al., 1 9 8 0 ; Tiles et al., 1989), iv) decrease of both heart rate and b lo o d
p ressu re through central affects (Robertson et al., 1988), v )
physiological vasodiatory tone (Orlandi, 1996; review).
These findings have led Matias and co-w orkers to set u p
an animal model of h y p erten sio n induced by c h ro n ic
ad m in istratio n of the adenosine antagonist 1, 3 - d i p r o p y l - 8 -
su lfo p h e n y lx a n th in e (DPSPX). The authors have shown a
increased thickness of the media, hyperplasia and h y p e r t r o p h y of smooth muscle cells in tail and m esenteric arteries of r a t (Matias et aL, 1991).
1 .5 .4 S e le c t iv e s e n s o r y - m o t o r d e n e r v a tio n
Perivascular nerves are known to have im p o rtan t t r o p h ic effects on the blood vessel wall such that selective d e n e r v a t i o n produces m arked changes in the neurotransm itter levels in t h e
rem aining nerves and structural and functional changes in
vascular smooth muscle and endothelium (A berdeen et aL,
1990; Burnstock, 1991). Many studies have shown t r o p h ic
changes in the vasculature after selective d en erv atio n a n d
changes in the tran sm itte r content of the nerves r e m a i n i n g
after long-term denervation of prim ary afferents have also
been described. For instance, chronic sensory denervation leads to an increase in the level of NA in rat iris (Luthm an et aL,
1989) and an increase in tyrosine h y d r o x y l a s e
im m u n o re a c tiv ity (a m arker of sym pathetic nerves) in t h e perivascular nerves of the oral cavity of the rat and guinea p ig
(Terenghi et aL, 1986). Sensory nerves have also b e e n
suggested to impair sym pathetic rein n e rv atio n in rat t a r s a l smooth muscle (Pike et aL, 1992).
The ad m in istratio n of the neurotoxin capsaicin ( 8 -
m e th y l-N - v a n illy l- 6 - n o n e n a m id e ) to neonatal rats induces a selective, d o se -d e p e n d e n t destruction of sensory n e u r o n s giving rise to u n m y elin ated (C) and m yelinated (AÔ) fibers as