Summary
Vascular endothelial cells play a key role in cardiovascular regulation by producing a number of potent vasoactive agents, including the vasodilator molecule nitric oxide (NO) and the vasoconstrictor peptide endothelin (ET)-l. A dysfunction of the vascular endothelium has been implicated in the pathophysiology of a number of cardiovascular diseases, important among which is essential hypertension. Impairment of NO synthesis, or increased inactivation of NO by superoxide radicals, may account for the increased peripheral vascular tone associated with hypertension, as well as contribute to the clinical consequences of this condition, which include vascular hypertrophy, increased platelet and monocyte adhesion to the endothelium, atherosclerosis, myocardial infarction and stroke. Similarly, increased ET-1 synthesis, or increased smooth muscle sensitivity to ET-1, could account for many of the features of hypertension, including increased peripheral vascular tone and vascular hypertrophy. Modulation of endothelial function is, therefore, an attractive therapeutic option in the treatment of hypertension.
Calcium antagonists have been shown to enhance the effects of NO, and inhibit those of ET-1, on vascular smooth muscle cells. In addition, calcium antagonists have antiatherogenic and antioxidant properties and could, therefore, prove to be useful therapeutic agents in preventing some of the important complications of hypertension. The long term effects on cardiovascular morbidity and mortality of the long-acting nifedipine gastrointestinal therapeutic system (nifedipine GITS) used in the treatment of essential hypertension are currently being investigated in the first multinational outcome study (INSIGHT) of an antihypertensive agent since the major studies of β-adrenoceptor blockers or thiazide diuretics. The results of this study are awaited with considerable interest.
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References
Vanhoutte PM. Endothelium and control of cardiovascular function. Hypertension 1989; 13: 658–67
Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev 1979; 30: 293–331
Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesise nitric oxide from L-arginine. Nature 1988; 333: 664–6
Komatsu Y, Itoh H, Suga S, et al. Regulation of endothelial production of C-type natriuretic peptide in coculture with vascular smooth muscle cells: role of the vascular natriuretic peptide system in vascular growth inhibition. Circ Res 1996; 78: 606–14
Vanhoutte PM. Vascular physiology: the end of the quest? Nature 1987: 327: 459–60
Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411–5
Peart WS. Concepts in hypertension: the Croonian Lecture. J Coll Physicians Lond 1980; 14: 141–52
Vallance P, Collier J. Biology and clinical relevance of nitric oxide. BMJ 1994: 309: 453–7
Ferro CJ, Webb DJ. The clinical potential of endothelin receptor antagonists in cardiovascular medicine. Drugs 1996; 51: 12–27
Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 1989; 2: 998–1000
Haynes WG, Noon JP, Walker BR, et al. Inhibition of nitric oxide synthesis increases blood pressure in healthy humans. J Hypertens 1993; 11: 1375–80
Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994; 344: 852–4
Haynes WG, Ferro CJ, O’Kane KPJ, et al. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in man. Circulation 1996; 93: 1860–70
Lamas L, Marsden PA, Li GK, et al. Endothelial nitric oxide synthase: molecular cloning and characterisation of a distinct constitutive enzyme isoform. Proc Natl Acad Sci USA 1992: 89: 6348–52
Buga GM, Gold ME, Fukuto JM, et al. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension 1991; 17: 187–93
Weiner CP, Lizasoain I, Baylis SA, et al. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA 1994; 91: 5212–6
Schmidt HHHW, Zernikow B, Baeblich S, et al. Basal and stimulated formation and release of L-arginine-derived nitrogen oxides from cultured endothelial cells. J Pharmacol Exp Ther 1990; 254: 591–7
Cooke J, Tsao P. Is nitric oxide an endogenous antiatherogenic molecule? Arterioscler Thromb 1994; 14: 653–5
Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1774–7
Rees DD, Palmer RMJ, Moncada S. Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989; 86: 3375–8
Radomski MW, Palmer RMJ, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990; 87: 5193–7
Winquist RJ, Bunting PB, Baskin EP, et al. Decreased endothelium-dependent relaxation in New Zealand genetic hypertensive rats. J Hypertens 1984; 2: 541–5
Wu X, Mäkynen H, Kähönen M, et al. Mesenteric arterial function in vitro in three models of experimental hypertension. J Hypertens 1996; 14: 365–72
Lyons D, Webster J, Benjamin N. The effect of antihypertensive therapy on responsiveness to local intra-arterial NG-monomethyl-L-arginine in patients with essential hypertension. J Hypertens 1994; 12: 1047–53
Panza JA, Quyyumi AA, Callahan TS, et al. Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol 1993; 21: 1145–51
Panza JA, Casino PR, Kilcoyne CM, et al. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993; 87: 1468–74
Taddei S, Virdis A, Mattei P, et al. Vasodilatation to acetylcholine in primary and secondary forms of human hypertension. Hypertension 1993; 21 (6 Pt 2): 929–33
Treasure CB, Klein JL, Vita JA, et al. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-dependent relaxation in human coronary resistance vessels. Circulation 1993; 7: 86–93
Egashira K, Suzuki S, Hirooka Y, et al. Impaired endothelium-dependent vasodilatation of large epicardial and resistance coronary arteries in patients with essential hypertension: different responses to acetylcholine and substance P. Hypertension 1995; 25: 201–6
Taddei S, Mattei P, Virdis A, et al. Forearm vasodilatation in response to acetylcholine is increased by potassium in essential hypertensive patients. J Hypertens 1993; 11Suppl. 5: S144–5
Tschudi MR, Criscione L, Lüscher TF. Effect of aging and hypertension on endothelial function of rat coronary arteries. J Hypertens 1991; 9Suppl. 6: S164–5
Angus JA, Lew MJ. Interpretation of the acetylcholine test of endothelial dysfunction in hypertension. J Hypertens 1992; 10Suppl. 7: S179–86
Cockcroft JR, Chowienczyk PJ, Benjamin N, et al. Preserved endothelium-dependent vasodilatation in patients with essential hypertension. New Engl J Med 1994; 330: 1036–40
Ferro CJ, Haynes WG, Hand MF, et al. Are the vascular endothelin and nitric oxide systems involved in the pathophysiology of essential hypertension. Eur J Clin Invest 1996; 26Suppl. 1: A51
Huang A, Koller A. Both nitric oxide and prostaglandin-mediated responses are impaired in skeletal muscle arterioles of hypertensive rats. J Hypertens 1996; 14: 887–95
Panza JA, Casino PR, Kilcoyne CM, et al. Impaired endothelium-dependent vasodilatation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level. J Am Coll Cardiol 1994; 23: 1610–6
Nava E, Noll G, Lüscher TF. Increased activity of constitutive nitric oxide synthase in cardiac endothelium in spontaneous hypertension. Circulation 1995; 91: 2310–3
Nava E, Lüscher TF. Endothelium-derived vasoactive factors in hypertension: nitric oxide and endothelin. J Hypertens 1995; 13Suppl. 2: S39–48
Diedrich D, Yang Z, Bühler FR, et al. Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve the cyclooxygenase pathway. Am J Physiol 1990; 258: H445–51
Nakazono K, Watanabe N, Matsuno K, et al. Does Superoxide underlie the pathogenesis of hypertension? Proc Natl Acad Sci USA 1991; 88: 10045–8
Grunfeld S, Hamilton CA, Mesaros S, et al. Role of Superoxide in the depressed nitric oxide production by the endothelium of genetically hypertensive rats. Hypertension 1995; 26: 854–7
Tschudi M, Mesaros S, Lüscher TF, et al. Direct in situ measurement of nitric oxide in mesenteric resistance arteries; increased decomposition by Superoxide in hypertension. Hypertension 1995; 27: 32–5
Anderson TJ, Meredith IT, Yeung AC, et al. Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans. Circulation 1996; 93: 1647–50
Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347: 781–6
Inoue A, Yanagisawa M, Kimura S, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three different genes. Proc Natl Acad Sci USA 1989; 86: 2863–7
Bloch KD, Eddy RL, Shows TB, et al. cDNA cloning and chromosomal assigment of the gene encoding endothelin-3. J Biol Chem 1989; 264: 18156–61
Arai H, Hori H, Aramori I, et al. Cloning and expression of a cDNA encoding an endothelin receptor. Nature 1990; 348: 730–2
Sakurai T, Yanagisawa M, Inoue I, et al. Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 1990; 348: 732–5
Spokes RA, Ghatei MA, Bloom SR. Studies with endothelin-3 and endothelin-1 on rat blood pressure and isolated tissues: evidence for multiple endothelin receptor subtypes. J Cardiovasc Pharmacol 1989; 13Suppl. 5: S191–2
Davenport AP, O’Reilly G, Kuc RE. Endothelin ETA and ETB mRNA and receptors expressed by smooth muscle in the human vasculature: majority of the ETA subtype. Br J Pharmacol 1995; 114: 1110–6
Tschudi MR, Lüscher TF. Characterisation of contractile endothelin and angiotensin receptors in human resistance arteries: evidence for two endothelin and one angiotensin receptor. Biochem Biophys Res Commun 1994; 204: 685–90
Haynes WG, Strachan FE, Webb DJ. Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 1995; 92: 357–63
Takayanagi R, Kitazumi K, Takashi C, et al. Presence of a non-selective type of endothelin receptor on vascular endothelium and its linkage to vasodilatation. FEBS Lett 1991; 282: 103–6
Davenport AP, Maguire JJ. Is endothelin-induced vasoconstriction mediated only by ETA receptors in humans? Trends Pharmacol Sci 1994; 15: 9–11
Douglas S, Gellai M, Ezekiel M, et al. BQ-123, a selective endothelin subtype A-receptor antagonist, lowers blood pressure in different rat models of hypertension. J Hypertens 1994; 12: 561–7
Li JS, Larivière R, Schiffrin EL. Effect of a nonselective endothelin antagonist on vascular remodelling in deoxycorticosterone acetate-salt hypertensive rats; evidence for a role of endothelin in vascular hypertrophy. Hypertension 1994; 24: 183–8
Yang Z, Richard V, von Segresser L, et al. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries: a new mechanism for vasospasm? Circulation 1990; 82: 188–95
Kohno M, Murakawa K, Horio T, et al. Plasma immunoreactive endothelin-1 in experimental malignant hypertension. Hypertension 1991; 18: 93–100
Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 1992; 267: 16066–8
Larivière R, Thibault G, Schriffin E. Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not spontaneously hypertensive rats. Hypertension 1993; 21: 294–300
Clozel M. Endothelin sensitivity and receptor binding in the aorta of spontaneously hypertensive rats. J Hypertens 1989; 7: 913–7
Dohi Y, Lüscher TF. Endothelin-1 in hypertensive resistance arteries: intraluminal and extraluminal dysfunction. Hypertension 1991; 18: 543–9
Roberts-Thomson P, McRitchie R, Chalmers R. Experimental hypertension produces diverse changes in the regional vascular responses to endothelin-1 in the rabbit and the rat. J Hypertens 1994; 12: 1225–34
Haynes WG, Hand MF, Johnstone H, et al. Direct and sympathetically mediated venoconstriction in essential hypertension. J Clin Invest 1994; 94: 1359–64
Yoshida M, Nonoguchi H, Owada A, et al. Three cases of malignant hypertension: the roles of endothelin-1 and the renin-angiotensin-aldosterone system. Clin Nephrol 1994; 42: 295–9
Florijin K, Derkx F, Visser W, et al. Plasma immunoreactive endothelin-1 in pregnant women with and without preeclampsia. J Cardiovasc Pharmacol 1991; 17Suppl. 7: S446–8
Yokokawa K, Tahara H, Kohno M, et al. Hypertension associated with endothelin secreting malignant haemangioendothelioma. Ann Int Med 1991; 114: 213–5
Schiffrin EL, Deng LY, Larochelle P. Blunted effects of endothelin upon small subcutaneous resistance arteries of mild essential hypertensive patients. J Hypertens 1992; 10: 437–44
Schiffrin EL, Deng LY, Sventek P, et al. Expression of endothelin-1 gene in small arteries in human essential hypertension. J Hypertens 1996; 14Suppl. 1: S290
Noll G, Wenzel RR, Schneider M, et al. Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents. Circulation 1996; 93: 866–9
Omlamd T, Lie R, Aakvaag A, et al. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 1994; 89: 1573–9
Lerman A, Edwards B, Hallett J, et al. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl Med J 1991; 325: 997–1001
Winkles J, Alberts G, Brogi E, et al. Endothelin-1 binding and endothelin immunoreactivity in normal and atherosclerotic human arteries. Biochem Biophys Res Commun 1993; 191: 1081–8
Zeiher MA, Goebel H, Schachinger V, et al. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque. Circulation 1995; 91: 941–7
Lüscher TF, Yang Z. Calcium antagonists and ACE inhibitors: effect on endothelium and vascular smooth muscle. Drugs 1993; 46Suppl. 2: 121–32
Johns A, Freay AD, Adams DJ, et al. The role of calcium in the activation of endothelial cells. J Cardiovasc Pharmacol 1988; 12Suppl. 5: 119–23
Erne P, Bolli P, Burgisser E, et al. Correlation of platelet calcium with blood pressure: effect of antihypertensive therapy [letter]. N Engl J Med 1984; 310: 1084
Folkow B, Hallback M, Jones JV, et al. Dependence on external calcium for the noradrenaline contractility of the resistance vessels in spontaneously hypertensive rats. Acta Physiol Scand 1977; 101: 84–97
Himmel HM, Whorton AR, Strauss HC. Intracellular calcium, currents and stimulus-response coupling in endothelial cells. Hypertension 1993; 21: 112–27
Yang ZH, Von SL, Bauer E, et al. Different activation of the endothelial L-arginine and cyclooxygenase pathway in the human internal mammary artery and saphenous vein. Circ Res 1991; 68: 52–60
Goerre S, Wenk M, Bärtsch P, et al. Endothelin-1 in pulmonary hypertension associated with high altitude exposure. Circulation 1995; 91: 359–64
Goto K, Kasuya Z, Matsuki N, et al. Endothelin activates the dihydropyridine-sensitive, voltage-dependent calcium channel in vascular smooth muscle. Proc Natl Acad Sci USA 1989; 86: 3915–8
Clarke JG, Benjamin N, Larkin SW, et al. Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol 1989; 257: H2033–5
Clozel M, Kuhn H, Hefti F. Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats. Hypertension 1990; 16: 532–40
Boulanger CM, Desta B, Clozel J-P, et al. Chronic treatment with the CA2+ channel inhibitor RO 40-5967 potentiates the endothelium-dependent relaxations in the aorta of the hypertensive salt sensitive Dahl rat. Blood Pressure 1994; 3: 193–6
Hirooka Y, Imaizumi T, Masaki H, et al. Captopril improves impaired endothelium-dependent vasodilatation in hypertensive patients. Hypertension 1992; 20: 175–80
Ghiadoni L, Taddei S, Magagna A, et al. Effect of lacidipine on endothelial function in hypertensive patients. Am J Hypertens 1996; 9: 155A
Perticone F, Ceravolo R, Maio R, et al. Effects of long term isradipine treatment on endothelial vasodilation in hypertensives. Am J Hypertens 1996; 9: 165A
Schiffrin EL, Deng LY, Larochelle P. Effects of a β-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension. Hypertension 1994; 23: 83–91
Taddei S, Virdis MP, Arzilli F, et al. Endothelium-dependent forearm vasodilatation is reduced in normotensive subjects with familial history of hypertension. J Cardiovasc Pharmacol 1992; 20Suppl. 12: S193–5
Willis AL, Nagel B, Churchill V, et al. Antiatherosclerotic effects of nicardipine and nifedipine in cholesterol-fed rabbits. Arteriosclerosis 1985; 5: 250–5
Yamada Y, Furui H, Furumichi T, et al. Inhibitory effects of endothelial cells and calcium channel blockers on platelet aggregation. Jpn Heart J 1990; 31: 201–15
Mentley RK, Brezinski ME, Tse E, et al. Cardioprotective actions of nisoldipine in postperfusion myocardial ischaemia. Am Heart J 1988; 115: 948–54
Yang Z, Noll G, Lüscher TF. Calcium antagonists inhibit proliferation of human coronary artery smooth muscle cells in response to pulsatile stretch and platelet-derived growth factor. Circulation 1993; 88: 832–6
Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol; modification of low-density lipoproteins that increase its atherogenicity. N Engl J Med 1989; 320: 915–24
Mak IT, Boehme P, Weglicki WB. Antioxidant effects of calcium channel blockers against free radical injury in endothelial cells. Correlation of protection with preservation of glutathione levels. Circ Res 1992; 70: 1099–103
Lichtlen PR, Hugenholtz P, Rafflenbeul W, et al. Retardation of the angiographic progression of coronary artery disease in man by the calcium channel blocker nifedipine. Lancet 1990; 335: 1109–13
Waters D, Lesperance J, Francetich M, et al. A controlled trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis. Circulation 1990; 82: 1940–53
Brogden RN, Sarkin EM. Isradipine: an update of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of mild to moderate hypertension. Drugs 1995; 49: 618–49
Elliot HL. Endothelial dysfunction: clinical applicability of calcium antagonist drugs. In: Lüscher TF, editor. The endothelium in cardiovascular disease. Berlin: Springer-Verlag, 1995: 148–56
Zanchetti A, on behalf of the Italian Nifedipine GITS Study Group. The 24-hour efficacy of a new once-daily formulation of nifedipine. Drugs 1994; 48Suppl. 1: 23–31
Brown MJ, Castaigne A, Mancia G, et al. Hypertension intervention trial in high risk patients: a comparison of the effects of nifedipine GITS and hydrochlorothiazide/amiloride on cardiovascular and cerebrovascular morbidity and mortality (INSIGHT) [Abstract no. 112]. Seventh European Meeting on Hypertension; 1995 Jun 9: Milan: 28
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Ferro, C.J., Webb, D.J. Endothelial Dysfunction and Hypertension. Drugs 53 (Suppl 1), 30–41 (1997). https://doi.org/10.2165/00003495-199700531-00006
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DOI: https://doi.org/10.2165/00003495-199700531-00006