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DOES ADENOSINE MALFUNCTION PLAY A ROLE IN HYPERTENSION? ISABEL AZEVEDO and WALTER OSSWALD

Department of Pharmacology and Therapeutics, Faculty of Medicine, 4200 Porto, Portugal (Received in final form 14 October 1991)

TROPHIC EFFECTS OF SYMPATHETIC INNERVATION One of the oldest and most commonly used procedures in biological research in order to elucidate the physiological significance of an organ is its destruction [1]. In the case of the sympathetic nervous system, denervation experiments were of the utmost importance for the elucidation of its general homeostatic function, as well as of the sites of synthesis, storage and enzymatic degradation of the adrenergic transmitter [ 1]. Many years ago it was found that besides their short lived effects, adrenergic innervation also possesses long-term, 'trophic' actions on the effector organs [2, 3]. These 'trophic' effects became apparent through the so-called postjunctional denervation supersensitivity [4]. Although the results in various papers clearly showed that denervation affected the removal of catecholamines in a much more marked way than cocaine (see review by Azevedo and Osswald [5]), the conclusion that denervation affected the extraneuronal uptake system of catecholamines was not reached until some time later [6]. In fact surgical denervation of the lateral saphenous vein of the dog causes a decrease in the capacity of the tissue to accumulate and O-methylate noradrenaline and isoprenaline through the steroid-sensitive component of the extraneuronal uptake system. Similarly, a decrease in the O-methylating capacity of adult rabbit ear artery was produced by removal of the ipsilateral superior cervical ganglion [6]. Other rather specific reactions to sympathetic denervation are the increase in the number of fl-adrenergic receptors [4, 5] and the increase in the production of nerve growth factor by the effector organ [7]. Whereas all the trophic effects described above involve functional characteristics intimately correlated with specific neuroeffector interactions and thus could have been anticipated, hypertrophic and hyperplastic consequences of sympathetic denervation constituted unexpected results. The extensive morphological studies conducted in our laboratory, on various organs of adult dogs and on the ear artery of adult rabbits, denervated by surgical or chemical Correspondence to: Dr Isabel Azevedo. 1043-6618]92]030227-10]$03.00/0

© 1992 The Italian Pharmacological Society

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means, consistently showed changes indicating an increase in the synthetic activity of the effector cells. At the ultrastructural level, vascular smooth muscle cells and fibroblasts showed large nuclei rich in euchromatin and indentations of the nuclear membrane, prominent nucleoli and voluminous rough endoplasmic reticula, i.e. signs of dedifferentiation and increased synthetic activity [6]. Morphometric analysis at the light microscopic level confirmed increases in the size of the nuclei of smooth muscle cells, fibroblasts, endothelial and myocardial cells [6, 8, 9], in the size of smooth muscle cells [6, 8, 9], in the density of fibroblasts [6,10] and in the amount of extracellular material [6, 8]. In rat heart, denervation by 6-hydroxydopamine induced a marked increase in the production of atrial natriuretic peptide as well as the appearance of granules containing atrial natriuretic peptide in the ventriculum [ 11]. The consequences of sympathetic denervation performed during growth appear to be different: in rabbit ear artery DNA synthetic activity decreases, as well as the weight and total wall thickness of the vessel [12]; in rat portal vein the crosssectional area decreases in young [13] and increases in adult animals [14]. The overall conclusion of the studies conducted in our laboratory is that the sympathetic nervous system exerts a repressive effect on the nuclear activity of effector cells. The same type of results and conclusions were found by Campbell et al. [15] for chicken expansor secundariorum, by Fronek [16] for rabbit aorta and by Dimitriadou et al. [17] for rabbit cerebral artery. Thus, the long-term effects of sympathetic denervation on the nuclear activity of effector cells are so important that they result in a change in the morphological characteristics, dimensions and proliferative activity of the cells.

THE ROLE OF ADENOSINE IN THE TROPHIC EFFECTS OF SYMPATHETIC INNERVATION

Noradrenaline accumulates in the cell nucleus [18], inducing a condensation of chromatin (Azevedo, unpublished results). This effect of noradrenaline is mimicked by isoprenaline, which decreases the incorporation of 3H-uridine into the smooth muscle cells of dog mesenteric arteries [19]. These facts suggest the possibility of noradrenaline being endowed with trophic effects upon the effector cells. In agreement with this hypothesis, Trendelenburg and Weiner [2] and Fleming [3] showed that reserpine treatment (which results in marked noradrenaline depletion) could induce post-junctional supersensitivity. Likewise, supersensitivity exhibited by blood vessels when placed in cell or organ culture conditions was abolished by the presence of noradrenaline in the culture medium [20]. On the other hand, a parallelism between the tissue content of noradrenaline and the O-methylating capacity of dog mesenteric artery [21] or the cord plasma content of noradrenaline and the O-methylating capacity of human umbilical arteries (Azevedo and Ferreira-de-Almeida, to be published) suggest a trophic effect of noradrenaline on the uptake and/or COMT activity of the cells. But, whereas noradrenaline seems to have trophic effects on specific adrenergic mechanisms of the effector cells, it is not responsible for the modulation of their basic phenotype.

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As a matter of fact, in our denervation experiments, neither did severe noradrenaline depletion induced by reserpine mimick the morphological changes observed after denervation [10]; nor did a continuous infusion of noradrenaline prevent the morphological alterations of denervation [6, 9]. If noradrenaline was shown not to be the main trophic factor of sympathetic innervation, adrenergic co-transmitters obviously constituted the next hypothesis to be considered. Since ATP has been repeatedly shown to be released from a. variety of sympathetic nerve varicosities during nervous activity [22], the effects of some purinergic agonists on the changes induced by sympathetic denervation were investigated. A continuous infusion of adenosine (10pg/kg/h) or of Nethylcarboxamidoadenosine (0.1/.zg/kg/h) prevented the morphological changes caused in the saphenous vein of the dog by denervation [9]; the effects of adenosine were not mimicked by inosine. Continuous i.v. infusions of adenosine (10/.tg/kg/h) to dogs also prevented the effects of denervation upon fibroblast and mast cell densities in the portal space connective tissue of the liver [10]. Adenosine thus appears to be the main factor responsible for the basic trophic effects of sympathetic innervation.

VASCULAR STRUCTURAL CHANGES AND HYPERTENSION ARE INDUCED BY CHRONIC BLOCKADE OF ADENOSINE RECEPTORS It is well known that human arterial hypertension is accompanied by structural changes in blood vessels. These changes are similar to those occurring in spontaneously hypertensive rats and mainly consist of hypertrophy of the vascular wall [23]. Since hypertrophy of the vascular wall has been repeatedly demonstrated by others and by ourselves (see above) to result from sympathetic denervation, lack of adenosine appearing to be the cause of hypertrophy, we decided to investigate the effects of a long-term blockade o f adenosine receptors on the blood vessel structure and on the blood pressure of Wistar rats [24]. Infusion of 1,3-dipropyl-8-sulphophenylxanthine (DPSPX), a water soluble, non-selective antagonist of adenosinoceptors, through an Alzet minipump implanted in the peritoneal cavity (30/.tg/kg/h for 7 days) induced~an increase in both diastolic and systolic blood pressure and striking structural changes in blood vessels. Different changes occurred in different blood vessels: small mesenteric arteries (N60 pm outer diameter) were occasionally occluded by proliferation of intimal cells or presented medial encroaching on the lumen due to asymmetric hyperplasia of smooth muscle cells (Fig. 1); small renal cortical arteries-(~60/.tin outer diameter) also showed asymmetric hyperplasia of smooth muscle and reduplication of internal elastic lamina (Fig. 2); both the renal and the tail arteries presented increased thickness of the media, hypertrophy of smooth muscle cells and, occasionally, buttons of smooth muscle appeared in the intima (Fig. 3). These buttons were of variable size, protruded into the lumen and sometimes occupied a large part of it. The size of myocardial cell nuclei was significantly increased [24].

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The results of these studies strongly suggest a role for adenosine in the modulation of effector cell phenotype. The hypertrophic and hyperplastic changes of DPSPX treatment are even greater than those observed in denervation experiments. This was perhaps to be expected, since in this case the effects of adenosine were blocked without distinction of its neural (sympathetic varicosities) or non-neuronal origin (all other sources of adenosine). The mechanism(s) of DPSPX-induced hypertension is not known. Adenosine is a potent vasodilator and appears to maintain a vasodilatory tone [25]; it also inhibits noradrenaline release [26-28]. Blockade of any of these effects could be involved in the hypertensive response to DPSPX. Thus, it could be argued that the vascular structural changes are not due to the direct effect of DPSPX, instead resulting from the stimulus that high intravascular pressure represents fdr the blood vessel wall [29]. Several facts, though, contradict this hypothesis: the duration of hypertension (a few days) seems too short for such marked changes to develop; the vascular changes consisted not only of hypertrophy of artery wall and smooth muscle cells but also of striking asymmetric hyperplastic events suggesting the presence of a strong growth factor or the lack of a strong repressive factor; moreover, the changes were not restricted to blood vessels, a proliferation of fibroblasts in the mesentery also being observed. Whereas the vascular structural changes induced by DPSPX are probably not responsible for the initial rise in blood pressure, they may be involved in the longterm rise and/or maintenance of high blood pressure. In this respect, the DPSPXinduced hypertension may constitute a new interesting model for the study of the

Fig. 1 Medial encroaching (*) on the lumen (L) in a small mesenteric artery from a DPSPXtreated rat; note asymmetric hyperplasia of smooth muscle cells (arrowheads). Scale bar = 100 pm.

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complex and elusive syndrome of essential hypertension. The potent repressive effects of adenosine on the nuclear activity of vascular cells make it an interesting candidate as a factor the absence of which induces vascular growth in hypertension. A growth-promoting agent has been consistently looked for in hypertension [23, 30-32]. The parallels between hypernoradrenergic innervation and the development of hypertension in the spontaneously hypertensive rat focused the attention on noradrenaline for a time [31]. Recent experiments [33] on the influence of exogenous nerve growth factor on the development of sympathetic innervation of blood vessels and blood pressure clearly showed that hypernoradrenergic innervation p e r s e is not able to induce hypertension. Thus, although the noradrenergic component of the sympathetic innervation in all probability contributes to the hypertensive syndrome, it does not seem to be the main factor. Angiotensin II, besides exhibiting potent direct and indirect vasoconstrictor effects, produces structural changes in blood vessels by a mechanism unrelated to pressure [32]. The availability of drugs that either block angiotensin II receptors or the angiotensin converting enzyme made it possible to analyze in detail the role eventually played by angiotensin II. In research devoted to the putative involvement of the vascular renin-angiotensin system in the determination of vascular structure in hypertension, Mulvany [32] came to a negative conclusion. However, in this study the trophic effects of angiotensin II have been studied with a single parameter, namely the media:lumen ratio of a small mesenteric artery. Our results on the trophic changes induced by DPSPX suggest a high variability in these changes,

Fig. 2 Reduplicationof internal elastic lamina (arrowhead) and asymmetricgrowth of media (*) in a small renal cortical artery from a DPSPX-treated rat. Scale bar = 100/.tm.

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Fig. 3 Button (B) of smooth muscle and connective tissue, with elastin (arrowheads), protruding into the lumen (L) of a tail artery from a DPSPX-treated rat. Scale bar = 100/.tm.

according to the type of vessel. On the other hand, the results of Owens [30] on aortic smooth muscle of spontaneously hypertensive rats gave evidence for exquisite nuances in hypertrophic and hyperplastic growth responses versus time as well as for the reversibility of those trophic changes. Thus, it appears that angiotensin II has not been excluded as a factor playing an important role in the appearance and maintenance of structural changes in the process of hypertension. In this context, the interactions of adenosine and angiotensin II appear of interest. Adenosine is a potent inhibitor of renin release [34], a recent study having demonstrated that even under basal physiological conditions endogenous adenosine tonically inhibits renin release; this inhibitory effect is augmented whenever the renin-angiotensin system is stimulated [35]. Considerable evidence has accumulated for the existence of a renin-angiotensin system in the blood vessel wall with local generation of both angiotensin I and angiotensin II [36]. It has been postulated that vascular cells can produce angiotensins and that its release may be regulated by drugs. For instance, it has been demonstrated that fl-adrenoceptor stimulation induces the release of angiotensin II from mesenteric arteries [37]. Given the role of adenosine in the control of renal renin release, it would be of great interest to know if adenosine also contributes to the regulation of vascular production of angiotensin. In any case, the inhibition of renal renin release by adenosine should interfere with vascular angiotensin production, since renin from renal origin is essential for this purpose [38]. Finally, it has been demonstrated that caffeine augments the slow pressor effect of chronic low-dose infusions of angiotensin II [39]. In conclusion, there are many interactions between adenosine and angiotensin

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II. As angiotensin II produces trophic changes similar to those described by us for DPSPX, it can not be excluded that the trophic effects of DPSPX are due to a putative interference of angiotensin II.

FACTS AND THEORIES ON THE INVOLVEMENT OF ADENOSINE MALFUNCTION IN ESSENTIAL HYPERTENSION Adenosine was shown to be a potent repressive factor upon cell nucleus activity in blood vessels [9, 24]. On the other hand it has marked vasodilator properties being responsible, in the rat, for a physiological vasodilatatory tone [25]; it is a potent inhibitor of renin release [34, 35]; it inhibits noradrenergic transmission [26-28]; it decreases both heart rate and blood pressure through a central effect in the rat [40]. This panel of effects led us to think that chronic blockade of adenosine receptors would possibly increase blood pressure. The results of Matias et al. [24] confirmed this hypothesis: continuous treatment with DPSPX (30/2g/kg/h) induced hypertrophic vascular changes and hypertension in the rat. Do these experimental results have any implication on the clinical situation of essential hypertension? Of the various mechanisms possibly involved in the development of essential hypertension, vascular hypertrophy has lately received much attention. That is due to various factors: (a) the role that vascular hypertrophy is considered to play in the maintenance or reinforcement of hypertension, as initially proposed by Folkow [29]; (b) the appearance of structural changes in arteries and arterioles of spontaneously hypertensive rats before the appearance of hypertension [23]; and (c) the growth-promoting properties of angiotensin II [41] and the prolonged effect of treatment with angiotensin-converting enzyme inhibitors on the blood pressure of spontaneously hypertensive rats [32]. In the search for a growth factor causally involved in essential hypertension, angiotensin II seems not to fulfill all conditions (see for example refs 32 and 42). Other putative growth factors have been discussed (e.g. catecholamines, growth hormone, insulin and insulin-like growth factor) but were not proven to have more than ancillary roles [42]. Adenosine has trophic effects upon the cardiovascular system of rat [24] and dog [9] and is a potent modulator of the renin-angiotensin system [34, 35]. To our knowledge it has never been discussed as atrophic factor in hypertension. Hence, the hypothesis that adenosine malfunction is a rather primary event in essential hypertension should be discussed. If, due to a genetic, autoimmune or ambiental factor, adenosine transmission would be impaired, what would be the consequences which could be expected? (1) impairment of the adenosinergic vasodilating tone [25]; (2) increase in the activity of the renin-angiotensin system [34, 35]; (3) augmentation of noradrenergic transmission [26-28]; (4) hypertrophic changes of blood vessels and of the heart [9, 24]; (5) increase in central nervous system sympathetic drive to the cardiovascular system [40];

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(6) insulin resistance [43, 44]; (7) augmented platelet aggregation [45, 46]; (8) damage to the endothelium [47]. All but the first of these events have been somehow associated with essential hypertension (see for example refs 42, 48, 49, 50). Although this long list of possible consequences of adenosine malfunction is of course speculative, it represents a logical background for further research in this area. Moreover, some evidence suggesting an impairment of adenosinergic mechanisms in hypertension has already been advanced. For example, Kamikawa et al. [27] and Illes et al. [28] described a diminished purinergic modulation of the vascular adrenergic neurotransmission in spontaneously hypertensive rats. Robertson et al. [40] similarly described an altered purinergic function in the control of cardiovascular activity by the area postrema and solitary tract of spontaneously hypertensive rats. Recently, Green et al. [44] verified that there is a decrease in A1 adenosine receptors in adipocytes from spontaneously hypertensive rats. The answer to the initial question concerning a role for adenosine malfunction in essential hypertension is clearly not at hand; but the proposed hypothesis of a key role for adenosine in the regulation of cardiovascular events which, when disturbed, lead to hypertension, appears to be not only tenable but deserving of much investigational effort.

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Does adenosine malfunction play a role in hypertension?

Pharmacological Research, Vol. 25, No. 3, 1992 227 DOES ADENOSINE MALFUNCTION PLAY A ROLE IN HYPERTENSION? ISABEL AZEVEDO and WALTER OSSWALD Depart...
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