Abstract
Objective—To study underlying vascular responses in chronic heart failure in patients without ACE inhibitor treatment, and to compare them with age matched controls. Design—Forearm blood flow was studied using venous occlusion plethysmography in patients with chronic heart failure (n = 12) and matched controls (n = 13), after infusion of L-NMMA (a nitric oxide synthase inhibitor), glyceryl trinitrate (an endothelium independent vasodilator), and serotonin (an endothelium dependent vasodilator). Results—L-NMMA produced significant vasoconstriction in normal subjects (forearm blood flow reduced by 24%), but not in patients (6%; difference between groups p < 0.03). The vasodilator responses to glyceryl trinitrate were impaired in patients (p < 0.02). In normal controls, serotonin produced initial dilatation, followed by vasoconstriction at high doses. In patients, no vasodilator responses were observed, only late vasoconstriction (p < 0.03). Conclusions—The vascular responses of patients are confirmed as being abnormal. The lack of response to L-NMMA suggests that nitric oxide does not contribute to basal vascular tone in patients with chronic heart failure. The responses to glyceryl trinitrate and to serotonin suggest that there is both smooth muscle and endothelial dysfunction in patients with chronic heart failure. Keywords: heart failure; endothelium; nitrates; serotonin
Full Text
The Full Text of this article is available as a PDF (122.1 KB).
Figure 1 .
Change in forearm blood flow (FBF) in response to intra-arterial infusion of glyceryl trinitrate. Values are means, error bars = SEM. *p < 0.05, patients v controls in response to 9 and 12 nmol/min glyceryl trinitrate.
Figure 2 .
Change in forearm blood flow (FBF) in response to intra-arterial infusion of serotonin. Values are means, error bars = SEM. *p < 0.05, patients v controls at 0.017-1.7 µmol/min serotonin.
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Berkenboom G., Unger P., Fang Z. Y., Degre S., Fontaine J. Comparison of responses to acetylcholine and serotonin on isolated canine and human coronary arteries. Cardiovasc Res. 1989 Sep;23(9):780–787. doi: 10.1093/cvr/23.9.780. [DOI] [PubMed] [Google Scholar]
- Blauw G. J., van Brummelen P., Chang P. C., Vermeij P., van Zwieten P. A. Regional vascular effects of serotonin and ketanserin in young, healthy subjects. Hypertension. 1988 Mar;11(3):256–263. doi: 10.1161/01.hyp.11.3.256. [DOI] [PubMed] [Google Scholar]
- Bruning T. A., Chang P. C., Blauw G. J., Vermeij P., van Zwieten P. A. Serotonin-induced vasodilatation in the human forearm is mediated by the "nitric oxide-pathway": no evidence for involvement of the 5-HT3-receptor. J Cardiovasc Pharmacol. 1993 Jul;22(1):44–51. doi: 10.1097/00005344-199307000-00008. [DOI] [PubMed] [Google Scholar]
- Bruning T. A., van Zwieten P. A., Blauw G. J., Chang P. C. No functional involvement of 5-hydroxytryptamine1A receptors in nitric oxide-dependent dilatation caused by serotonin in the human forearm vascular bed. J Cardiovasc Pharmacol. 1994 Sep;24(3):454–461. doi: 10.1097/00005344-199409000-00014. [DOI] [PubMed] [Google Scholar]
- Busse R., Hecker M., Fleming I. Control of nitric oxide and prostacyclin synthesis in endothelial cells. Arzneimittelforschung. 1994 Mar;44(3A):392–396. [PubMed] [Google Scholar]
- Böger R. H., Bode-Böger S. M., Frölich J. C. The L-arginine-nitric oxide pathway: role in atherosclerosis and therapeutic implications. Atherosclerosis. 1996 Nov 15;127(1):1–11. doi: 10.1016/s0021-9150(96)05953-9. [DOI] [PubMed] [Google Scholar]
- Cohen R. A., Shepherd J. T., Vanhoutte P. M. 5-Hydroxytryptamine can mediate endothelium-dependent relaxation of coronary arteries. Am J Physiol. 1983 Dec;245(6):H1077–H1080. doi: 10.1152/ajpheart.1983.245.6.H1077. [DOI] [PubMed] [Google Scholar]
- Drexler H., Hayoz D., Münzel T., Hornig B., Just H., Brunner H. R., Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol. 1992 Jun 15;69(19):1596–1601. doi: 10.1016/0002-9149(92)90710-g. [DOI] [PubMed] [Google Scholar]
- Elsner D., Müntze A., Kromer E. P., Riegger G. A. Systemic vasoconstriction induced by inhibition of nitric oxide synthesis is attenuated in conscious dogs with heart failure. Cardiovasc Res. 1991 May;25(5):438–440. doi: 10.1093/cvr/25.5.438. [DOI] [PubMed] [Google Scholar]
- Endo T., Imaizumi T., Tagawa T., Shiramoto M., Ando S., Takeshita A. Role of nitric oxide in exercise-induced vasodilation of the forearm. Circulation. 1994 Dec;90(6):2886–2890. doi: 10.1161/01.cir.90.6.2886. [DOI] [PubMed] [Google Scholar]
- Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
- Golino P., Piscione F., Willerson J. T., Cappelli-Bigazzi M., Focaccio A., Villari B., Indolfi C., Russolillo E., Condorelli M., Chiariello M. Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients. N Engl J Med. 1991 Mar 7;324(10):641–648. doi: 10.1056/NEJM199103073241001. [DOI] [PubMed] [Google Scholar]
- Habib F., Dutka D., Crossman D., Oakley C. M., Cleland J. G. Enhanced basal nitric oxide production in heart failure: another failed counter-regulatory vasodilator mechanism? Lancet. 1994 Aug 6;344(8919):371–373. doi: 10.1016/s0140-6736(94)91402-8. [DOI] [PubMed] [Google Scholar]
- Harris P. Congestive cardiac failure: central role of the arterial blood pressure. Br Heart J. 1987 Sep;58(3):190–203. doi: 10.1136/hrt.58.3.190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Johnston G. D., Nicholls D. P., Kondowe G. B., Finch M. B. Comparison of the acute vascular effects of frusemide and bumetanide. Br J Clin Pharmacol. 1986 Apr;21(4):359–364. doi: 10.1111/j.1365-2125.1986.tb05207.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katz S. D., Biasucci L., Sabba C., Strom J. A., Jondeau G., Galvao M., Solomon S., Nikolic S. D., Forman R., LeJemtel T. H. Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol. 1992 Apr;19(5):918–925. doi: 10.1016/0735-1097(92)90271-n. [DOI] [PubMed] [Google Scholar]
- Katz S. D., Schwarz M., Yuen J., LeJemtel T. H. Impaired acetylcholine-mediated vasodilation in patients with congestive heart failure. Role of endothelium-derived vasodilating and vasoconstricting factors. Circulation. 1993 Jul;88(1):55–61. doi: 10.1161/01.cir.88.1.55. [DOI] [PubMed] [Google Scholar]
- Kishi Y., Numano F. In vitro study of vascular endothelial injury by activated platelets and its prevention. Atherosclerosis. 1989 Apr;76(2-3):95–101. doi: 10.1016/0021-9150(89)90092-0. [DOI] [PubMed] [Google Scholar]
- Kiuchi K., Sato N., Shannon R. P., Vatner D. E., Morgan K., Vatner S. F. Depressed beta-adrenergic receptor- and endothelium-mediated vasodilation in conscious dogs with heart failure. Circ Res. 1993 Dec;73(6):1013–1023. doi: 10.1161/01.res.73.6.1013. [DOI] [PubMed] [Google Scholar]
- Kubo S. H., Rector T. S., Bank A. J., Raij L., Kraemer M. D., Tadros P., Beardslee M., Garr M. D. Lack of contribution of nitric oxide to basal vasomotor tone in heart failure. Am J Cardiol. 1994 Dec 1;74(11):1133–1136. doi: 10.1016/0002-9149(94)90466-9. [DOI] [PubMed] [Google Scholar]
- Lindsay D. C., Holdright D. R., Clarke D., Anand I. S., Poole-Wilson P. A., Collins P. Endothelial control of lower limb blood flow in chronic heart failure. Heart. 1996 May;75(5):469–476. doi: 10.1136/hrt.75.5.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Longhurst J., Capone R. J., Zelis R. Evaluation of skeletal muscle capillary basement membrane thickness in congestive heart failure. Chest. 1975 Feb;67(2):195–198. doi: 10.1378/chest.67.2.195. [DOI] [PubMed] [Google Scholar]
- Mancini G. B., Henry G. C., Macaya C., O'Neill B. J., Pucillo A. L., Carere R. G., Wargovich T. J., Mudra H., Lüscher T. F., Klibaner M. I. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996 Aug 1;94(3):258–265. doi: 10.1161/01.cir.94.3.258. [DOI] [PubMed] [Google Scholar]
- McMurray J. J., Ray S. G., Abdullah I., Dargie H. J., Morton J. J. Plasma endothelin in chronic heart failure. Circulation. 1992 Apr;85(4):1374–1379. doi: 10.1161/01.cir.85.4.1374. [DOI] [PubMed] [Google Scholar]
- Nakamura M., Funakoshi T., Arakawa N., Yoshida H., Makita S., Hiramori K. Effect of angiotensin-converting enzyme inhibitors on endothelium-dependent peripheral vasodilation in patients with chronic heart failure. J Am Coll Cardiol. 1994 Nov 1;24(5):1321–1327. doi: 10.1016/0735-1097(94)90115-5. [DOI] [PubMed] [Google Scholar]
- Nakamura M., Yoshida H., Arakawa N., Mizunuma Y., Makita S., Hiramori K. Endothelium-dependent vasodilatation is not selectively impaired in patients with chronic heart failure secondary to valvular heart disease and congenital heart disease. Eur Heart J. 1996 Dec;17(12):1875–1881. doi: 10.1093/oxfordjournals.eurheartj.a014806. [DOI] [PubMed] [Google Scholar]
- Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
- RODDIE I. C., SHEPHERD J. T., WHELAN R. F. The action of 5-hydroxytryptamine on the blood vessels of the human hand and forearm. Br J Pharmacol Chemother. 1955 Dec;10(4):445–450. doi: 10.1111/j.1476-5381.1955.tb00102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith C. J., Sun D., Hoegler C., Roth B. S., Zhang X., Zhao G., Xu X. B., Kobari Y., Pritchard K., Jr, Sessa W. C. Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. Circ Res. 1996 Jan;78(1):58–64. doi: 10.1161/01.res.78.1.58. [DOI] [PubMed] [Google Scholar]
- Steele I. C., Nugent A. M., Maguire S., Hoper M., Campbell G., Halliday M. I., Nicholls D. P. Cytokine profile in chronic cardiac failure. Eur J Clin Invest. 1996 Nov;26(11):1018–1022. doi: 10.1046/j.1365-2362.1996.2560587.x. [DOI] [PubMed] [Google Scholar]
- Stewart D. J., Pohl U., Bassenge E. Free radicals inhibit endothelium-dependent dilation in the coronary resistance bed. Am J Physiol. 1988 Oct;255(4 Pt 2):H765–H769. doi: 10.1152/ajpheart.1988.255.4.H765. [DOI] [PubMed] [Google Scholar]
- Treasure C. B., Klein J. L., Vita J. A., Manoukian S. V., Renwick G. H., Selwyn A. P., Ganz P., Alexander R. W. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation. 1993 Jan;87(1):86–93. doi: 10.1161/01.cir.87.1.86. [DOI] [PubMed] [Google Scholar]
- Tsutamoto T., Kanamori T., Morigami N., Sugimoto Y., Yamaoka O., Kinoshita M. Possibility of downregulation of atrial natriuretic peptide receptor coupled to guanylate cyclase in peripheral vascular beds of patients with chronic severe heart failure. Circulation. 1993 Jan;87(1):70–75. doi: 10.1161/01.cir.87.1.70. [DOI] [PubMed] [Google Scholar]
- Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989 Oct 28;2(8670):997–1000. doi: 10.1016/s0140-6736(89)91013-1. [DOI] [PubMed] [Google Scholar]
- Wei C. M., Lerman A., Rodeheffer R. J., McGregor C. G., Brandt R. R., Wright S., Heublein D. M., Kao P. C., Edwards W. D., Burnett J. C., Jr Endothelin in human congestive heart failure. Circulation. 1994 Apr;89(4):1580–1586. doi: 10.1161/01.cir.89.4.1580. [DOI] [PubMed] [Google Scholar]
- Winlaw D. S., Smythe G. A., Keogh A. M., Schyvens C. G., Spratt P. M., Macdonald P. S. Increased nitric oxide production in heart failure. Lancet. 1994 Aug 6;344(8919):373–374. doi: 10.1016/s0140-6736(94)91403-6. [DOI] [PubMed] [Google Scholar]
- Wroblewski H., Kastrup J., Nørgaard T., Mortensen S. A., Haunsø S. Evidence of increased microvascular resistance and arteriolar hyalinosis in skin in congestive heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol. 1992 Mar 15;69(8):769–774. doi: 10.1016/0002-9149(92)90503-q. [DOI] [PubMed] [Google Scholar]
- Yang Z. H., Richard V., von Segesser L., Bauer E., Stulz P., Turina M., Lüscher T. F. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. A new mechanism of vasospasm? Circulation. 1990 Jul;82(1):188–195. doi: 10.1161/01.cir.82.1.188. [DOI] [PubMed] [Google Scholar]
- Zeiher A. M., Drexler H., Wollschläger H., Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991 Feb;83(2):391–401. doi: 10.1161/01.cir.83.2.391. [DOI] [PubMed] [Google Scholar]
- Zelis R., Mason D. T., Braunwald E. Partition of blood flow to the cutaneous and muscular beds of the forearm at rest and during leg exercise in normal subjects and in patients with heart failure. Circ Res. 1969 Jun;24(6):799–806. doi: 10.1161/01.res.24.6.799. [DOI] [PubMed] [Google Scholar]


