Pharmacology & Toxicology 1992,70, Suppl. 11, s32-s39

Age, Hypertension and Hypercholesterolaemia Alter Endothelium-Dependent Vascular Regulation Thomas F. Luscher’*’, Felix C. Tanner’ and Yasuaki Dohi’ ‘Department of Medicine, Divisions of Clinical Pharmacology and Cardiology, and *Department of Research, Laboratory of Vascular Research, University Hospital, CH-4031 Basel, Switzerland Abstract: As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium-derived vasoactive substances are nitric oxide, prostacyclin, endothelin-l and contracting factors requiring the activity of cyclooxygenase.The endothelium is an obvious target organ of cardiovascular risk factors. Accordingly, functional alterations do occur with aging, hypertension and hypercholesterolaemia. All three conditions are associated with a decreased basal and stimulated release of endothelium-derived nitric oxide. On the other hand, the release of endothelin-1 appears to increase with age, while the sensitivity to the peptide markedly decreases under the same conditions. In the spontaneously hypertensive rat, acetylcholine and stretch evoke the release of a cyclooxygenasedependent endothelium-derived contracting factor, most likely prostaglandin H,. The circulating levels of endothelin-1 on the other hand are not increased in experimental and human hypertension. In the porcine coronary circulation, oxidized low-density lipoproteins selectively reduce endothelium-dependent relaxations to aggregating platelets, serotonin and thrombin which are mediated by nitric oxide. The alterations of endothelial function occurring with aging, hypertension and hypercholesterolaemia may have important clinical implications for the pathogenesis of cardiovascular disease.

Age, hypertension and hypercholesterolaemia are major risk factors for the development of cardiovascular disease. Due to its anatomical location, the endothelium is an obvious target organ of hypertension and hypercholesterolaemia. As the endothelium plays an important protective role in the circulation by the release of substances which inhibit platelet aggregation and evoke vasodilatation such as endotheliumderived relaxing factor (EDRF), changes in endothelial function occurring with aging, hypertension and hypercholesterolaemia could contribute to the increase in peripheral vascular resistance and the development of vasospasm, thrombus formation and myocardial infarction. This manuscript focusses on alterations in endothelium-dependent responses in aging, hypertensive and hypercholesterolaemic blood vessels and updates previous reviews (Liischer 1988b & c, 1989a & b; Liischer & Vanhoutte 1991).

Endothelium-derived substances and blood pressure control. Infusion of haemoglobin - an inactivator of endotheliumderived nitric oxide - increases arterial blood pressure in normal subjects (Savitsky et al. 1978). Intravenous infusion of L-NG-monomethyl arginine (L-NMMA), an inhibitor of the formation of nitric oxide from L-arginine (Palmer et al. 1988; Rees et al. 1989a), augments arterial blood pressure in rats and rabbits (Rees et al. 1989b; Tolins et al. 1990). Similarly, intraarterial application of L-NMMA in the human forearm decreases local blood flow (Vallance et al. 1989). Thus, the continuous release of endothelium-derived nitric oxide (EDNO) contributes to the regulation of peripheral vascular resistance. On the other hand, alterations in the basal release of EDNO as well as other endotheliumderived vasoactive factors could contribute to the increase in peripheral vascular resistance in hypertension. Systemic infusion of endothelium-dependent vasodilators

such as acetylcholine, adenosine diphosphate (ADP) and substance P markedly decreases blood pressure in the rabbit (Dude1 & Forstermann 1988). In the forearm of healthy human subjects, intraarterial administration of acetylcholine causes profound increases in forearm blood flow (fig. 1, Linder et al. 1990). The vasodilator effects of acetylcholine are unaffected by acetylsalicylic acid and phentolamine indicating that neither prostacyclin nor inhibition of adrenergic neurotransmission do contribute to the relaxation (Linder et al. 1990). As infusion of L-NMMA blunts the vasodilator effects of acetylcholine in the human forearm circulation (Vallance et al. 1989), EDNO must in large parts mediate the response. Similarly, in perfused and pressurized mesenteric arteries of rats, endothelium-dependent relaxations to acetylcholine are inhibited by L-NMMA suggesting an important role of nitric oxide in the microcirculation (Dohi et al. 1990). In the rat and rabbit, intravenous infusion of endothelin1 causes a profound and long-lasting increase in blood pressure as well as marked contractions of isolated mesenteric resistance arteries (fig. 2, Dohi & Liischer 1991; Yanagisawa et al. 1988). In the human forearm circulation, the peptide increases peripheral vascular resistance and decreases local blood flow (Brain et al. 1989; Kiowski et al. 1991). In the porcine aorta, endothelin is continuously released in an endothelium-dependent manner as it is in endothelial cells in culture (Boulanger & Liischer 1990; Schini et al. 1989). The release of the peptide can be further stimulated with thrombin and the calcium ionophore A23 187 (Yanagisawa et al. 1988; Boulanger & Liischer 1990; Schini et al. 1989). The production of endothelin is influenced by EDNO which is concomitantly formed during stimulation with thrombin (Liischer & Vanhoutte 1990). Hence, L-NMMA augments the thrombin-induced stimula-

ENDOTHELIUM-DERIVED VASOACTIVE SUBSTANCES

Acetylcholine (pglmid100ml tissue)

Fig. 1. Changes in blood flow in the forearm of healthy volunteers. Acetylcholine was infused intraarterially at a rate ranging from 0.08 to 16.0 pg/min./100 ml tissue and induced a concentrationdependent increase in blood flow. (from Linder el al. 1990, by permission of the American Heart Association)

tion of endothelin production to a similar degree as the inhibitor of soluble guanylate cyclase methylene blue (Boulanger & Liischer 1990). On the other hand, superoxide dismutase which prevents the inactivation of nitric oxide by superoxide radicals and the stable analogue of cyclic G M P 8-bromo-cyclic GMP inhibit the thrombin-induced formation of the peptide (Boulanger & Liischer 1990). Thus, EDNO inhibits the thrombin-induced formation of endothelin from intact blood vessels via a cGMP-dependent mechanism. The same effect is observed with exogenous nitric oxide representing a new mechanism of action of nitrovasodilators in the blood vessel wall (Boulanger & Liischer 1991). Aging. In perfused and pressurized mesenteric resistance arteries of Wistar-Kyoto rats (WKY), the presence of the endothelium reduces the sensitivity and the maximal response to nore-

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Fig. 2. Effect of different contractile agonists on the diameter of perfused and pressurized rat mesenteric resistance arteries. Endothelin-l induces much more potent contractions than serotonin and norepinephrine. The endothelium antagonizes the contractions to all agonists to a similar degree.

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pinephrine. Since this effect can in large parts be prevented by L-NMMA and since the endothelium reduces the contraction induced by phenylephrine to a similar extent as that induced by norepinephrine, basally released nitric oxide must reduce the response of the microcirculation to vasoconstrictor stimuli (Dohi et al. 1990). The basal release of nitric oxide decreases slightly with advancing age (Dohi et al. 1990). In large conduit arteries of the rat, endothelium-dependent relaxation to calcium ionophore A23 187, histamine and adenosine triphosphate decreases with age (Soltis 1987; Moritoki et al. 1986; Hongo et al. 1988). However, decreased (Soltis 1987; Hongo et al. 1988) as well as increased (Hynes & Duckles 1987) endothelium-dependent relaxation to muscarinic agonists was reported in the aged rat. In resistance arteries of rats, endothelium-dependent relaxation to acetylcholine decreases with increasing age (Dohi & Liischer 1990). Since the relaxation induced by the nitric oxide donor SIN-1 does not change with age, the decreased response to the muscarinic agonist must be due to a decreased production and/or release of EDNO after stimulation with acetylcholine (Dohi & Liischer 1990). In mesenteric resistance arteries of Fischer 344 rats, the sensitivity, but not the maximal response, to endothelin-1 markedly decreases with age (Dohi & Liischer 1990). Since contractions induced by norepinephrine in the same preparation are not affected by aging, the alteration is specific for endothelin-1 (Dohi & Liischer 1990). The decreased sensitivity to the peptide may be explained by down-regulation of endothelin-1 receptors on smooth muscle cells. In line with that interpretation, the circulating levels of endothelin increase with advancing age in humans (Miyauchi et al. 1989a). Hyper tension. Basal release of EDRE In spontaneously hypertensive rats (SHR), the inhibitory effect of the endothelium against contractions induced by norepinephrine is reduced indicating a diminished basal formation of endothelium-derived nitric oxide in hypertensive mesenteric resistance arteries (fig. 3, Dohi et al. 1990). Removal of the endothelium enhances the response to sodium nitroprusside in mesenteric resistance arteries, most likely due to an inhibitory effect of basally released endothelium-derived relaxing factor (Diederich et al. 1990). This augmentation of the response to sodium nitroprusside is reduced in stroke-prone SHR as compared to WKY again suggesting that the basal release of nitric oxide is impaired in hypertensive resistance arteries (Diederich et al. 1990). Endothelium-dependent relaxations. The endothelium-dependent relaxations to acetylcholine are attenuated in the aorta of rats with spontaneous hypertension (Konishi & Su 1983; Winquist et al. 1984; Liischer & Vanhoutte 1986a), renal hypertension, salt-induced hypertension, coarctation and DOCA-salt induced hypertension (Liischer et al. 1987; Lockette et al. 1986; Miller et al. 1987; Sim & Singh 1987;

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THOMAS F. LUSCHER ET AL. WKY

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Norepinephrine (-log M) Fig. 3. Contractions induced by extraluminal norepinephrine in pressurized mesenteric resistance arteries with and without endothelium obtained from 16-20 week old WKY (left) and SHR (right). In both animals, removal of the endothelium significantly augmented the contractions induced by norepinephrine (P < 0.05-0.005). The shift caused by removal'of the endothelium was smaller in SHR (1.4-fold) then in WKY (2.9-fold). (from Dohi ef al. 1990, by permission of the American Heart Association)

Van de Voorde et al. 1984 & 1986; Van de Voorde et al. 1984). In the aorta of the Dahl rat, the reduction of endothelium-dependent relaxations to acetylcholine is directly related to the level of arterial blood pressure (Liischer et al. 1987). Normalization of blood pressure with antihypertensive drugs (reserpine, hydrochlorothiazide plus hydralazine) restores endothelium-dependent relaxations in hypertensive Dahl rats (Liischer et al. 1987). This suggests that in this form of hypertension the impaired endothelium-dependent relaxations are a consequence rather than a cause of the high blood pressure. The endothelium-dependent relaxations to thrombin are reduced in Dahl hypertensive, but not in spontaneously hypertensive rats (Liischer 1988; Liischer et al. 1987; Webb et al. 1987). By contrast, those to ADP are impaired in both hypertensive strains (Hongo et al. 1988; Liischer et al. 1987; Liischer & Vanhoutte 1986b). Serotonin and aggregating platelets do not evoke endothelium-dependent relaxations either in the aorta nor in the carotid artery of the rat (Liischer et al. 1988). However, in the aorta of normotensive rats, the contractions evoked by aggregating platelets are inhibited in the presence of the endothelium (Liischer & Vanhoutte 1986b), while the endothelium loses its inhibitory capacity against platelet-induced contractions in SHR (Liischer & Vanhoutte 1986b). In mesenteric resistance arteries of SHR studied in a myograph system, the endothelium-dependent relaxations to acetylcholine are reduced (Diederich et al. 1990; De Mey & Gray 1985; Liischer et al. 1990). As in large arteries, the relaxations are impaired predominantly at higher concentrations of the muscarinic agonist. Similarly, in pressurized perfused mesenteric resistance arteries (Dohi et al. 1990; Tesfamariam & Halpern 1988) as well as in mesenteric microvessels of SHR studied in vivo (Carvalho et al. 1987), the endothelium-dependent relaxations to acetylcholine are

reduced. The defect primarily involves the intraluminal activation of endothelial cells by acetylcholine suggesting that part of the cells most exposed to high blood pressure and shear stress becomes progressively dysfunctional in hypertension (Dohi et al. 1990). Both in perfused mesenteric resistance arteries (Dohi et al. 1990) and in those studied in the myograph system (De Mey & Gray 1985; Gray & De Mey 1985), endothelium-dependent relaxations become impaired as blood pressure rises. In the forearm of hypertensive patients, the dilatation evoked by intraarterial acetylcholine is attenuated (Fig. 4; Linder et al. 1990; Panza et al. 1988). Since the response to sodium nitroprusside - which as endothelium-derived relaxing factor activates cyclic GMP in vascular smooth muscle - is not significantly reduced, the impaired response to acetylcholine most likely involves an endothelial defect. Endothelium-dependent contractions. Acetylcholine causes endothelium-dependent contractions in the aorta of adult SHR, while the responses are weak or absent in WKY of the same age (fig. 5, Liischer & Vanhoutte 1986b). In old rats (12 months of age), endothelium-dependent contractions to acetylcholine occur also in normotensive rats, but are more pronounced in spontaneously hypertensive animals (Koga et af. 1989). Thus, the occurrence of endothelium-dependent contractions to acetylcholine may reflect the premature aging of the arterial wall under hypertensive conditions. The endothelium-dependent contractions to acetylcholine are abolished by inhibitors of phospholipase A2 or of cyclooxygenase demonstrating that the metabolism of endogenous arachidonic acid is involved (Liischer & Vanhoutte 1986a); it most likely represents prostaglandin H, (Kato et al. 1990). Indeed, the contractions to exogenous prostaglandin H2are prevented by thromboxane receptor antagon-

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Fig. 5 . Original recordings of isometric tension in rings with endothelium of aortas from adult SHR and WKY. Quiescent rings of both groups were exposed to increasing concentrations of acetylcholine (10-8-10-5 M). Aortic rings of hypertensive rats contract to acetylcholine, while those of normotensive animals do not show any change in tension at this age. (from Liischer & Vanhoutte 1986, by permission of the American Heart Association)

ists, but unaffected by inhibitors of the synthesis of the prostanoid (Kato et a/. 1990). Isolated aortae obtained from normotensive rats are contracting when stretched, a response which is larger in arteries from DOCA-hypertensive rats (Rinaldi & Bohr 1989). Removal of the endothelium reduces the stretch-induced increase in tension without affecting contractions to norepinephrine (Rinaldi & Bohr 1989). These observations indicate that hypertension also promotes stretch-induced endothelium-dependent contractions. Platelet-derived products. The altered endothelial function, together with the greater aggregability of platelets from hypertensive subjects (Amstein et al. 1988; De Clerk 1986; Baudouin-Legros et al. 1986; Fetkovska et al. 1990; Guicheney et a/. 1985; Valtier et a/. 1986; Nara et al. 1984), may favour the occurrence of vasoconstriction and thrombusformation in hypertensive blood vessels. Various abnormalities of platelet function as well as alterations in the vascular responses to platelet-derived products occur in hypertension (Valtier et a/. 1986; Nara et al. 1984). In the aorta of SHR contracted with prostaglandin Fz,, serotonin causes larger contractions in rings with, than in those without endothelium (Liischer & Vanhoutte 1986b). These differences are particularly apparent in the presence of ketanserin, which blocks 5-HT2-serotonergic receptors on vascular smooth muscle. Under these conditions, an inhibitory effect of the endothelium against contractions induced by serotonin is apparent in aortas obtained from normotensive rats, while the endothelium facilitates contractions induced by serotonin in hypertensive aortas (Liischer & Vanhoutte 1986b). In isolated perfused hearts from WKY, the monoamine induces moderate increases in flow, while marked decreases

in flow occur in hearts from SHR (Liischer et al. 1986). The constrictor effect of serotonin in the coronary circulation of hypertensive hearts can be blocked by indomethacin. These results are consistent with the concept that under hypertensive conditions a cyclooxygenase-dependent endothelium-derived contracting factor (EDCF,) is liberated in response to platelet products (Liischer & Vanhoutte 1988). Endothelin. The plasma levels of endothelin-1 in spontaneously hypertensive, but not DOCA-salt hypertensive rats are lower than those in age-matched normotensive controls (Suzuki et al. 1990). There is little or no endothelin-3 in rat plasma (Saito et al. 1989). The circulating levels of endothelin-1 in patients with essential hypertension have been reported to be normal (Miyauchi et a/. 1989; Davenport et al. 1990) or increased (Shichini et a/. 1989 & 1990). On the other hand, plasma levels of endothelin are increased in patients with renal insufficiency, cardiogenic shock and in the coronary sinus of patients with coronary artery disease (Shichini et a/. 1989 & 1990; Stewart & Cernacek 1989; Emori et al. 1989). The first reports on the responsiveness of isolated blood vessels from hypertensive rats to endothelin yielded conflicting results (Tomobe et al. 1988; Diederich et a/. 1989; Criscione et al. 1989; Miyauchi et al. 1989; Auch-Schwelk & Vanhoutte, personal communication). Indeed, while some authors reported a reduced sensitivity to endothelin in the aorta and renal artery and in perfused mesenteric resistance arteries of SHR (Auch-Schwelk & Vanhoutte, personal communication; Dohi & Liischer 1991), others reported normal (Diederich et al. 1989) or augmented responses (Tomobe et a/. 1988; Miyauchi et a/. 1989).

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Fig. 6. Effect of oxidized low density lipoproteins (Ox LDL) on endothelium-dependent relaxations to platelets in porcine coronary arteries. Relaxations were inhibited in arteries exposed to lipoproteins (P

Age, hypertension and hypercholesterolaemia alter endothelium-dependent vascular regulation.

As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium-derived vasoa...
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