Determinants of drug response in severe chronic heart failure. 1. Activation of vasoconstrictor forces during vasodilator therapy.

Packer, Milton; Meller, Jose; Medina, Norma; Yushak, Madeline; Gorlin, Richard

doi:10.1161/01.cir.64.3.506

Cited by 95 publications

(16 citation statements)

References 53 publications

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“…It is important to point out that the SBP when the initial oral ISDN was administered on day 1 In addition, vasodilator therapy has been shown to activate the sympathetic nervous and renin-angiotensin systems. 29 30 The activation of these systems limits the hypotensive response, induces tachycardia, and may produce rebound changes after sudden withdrawal of vasodilator therapy. Therefore …”

Section: Methodsmentioning

confidence: 99%

Tolerance to isosorbide dinitrate: rate of development and reversal.

Parker¹,

Fung²,

Ruggirello³

et al. 1983

Circulation

145

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The present investigation was designed to determine the rate of development of tolerance during initiation of therapy with oral ISDN and the rate of tolerance reversal after withdrawal of this drug. MethodsStudy population. Ten patients, nine men and one woman, ranging in age from 37 to 77 years (mean 56), with stable, exercise-induced angina pectoris were studied. Patients who had had previous exposure to ISDN or other oral or cutaneous nitrate preparations were not included. These patients had been taking nitroglycerin, but this was not used in the 24 hr before study and was not required in any patient during this period of investigation. Other exclusion characteristics included the presence of cardiomegaly, cardiac failure, cerebral vascular disease, hepatic disease, renal dysfunction, or the administration of fl-blocking agents or vasodilators. Patients were also excluded if they had a history of severe headaches or symptoms of postural hypotension after nitroglycerin administration.Study design Day 1. After an overnight fast, control measurements were made of heart rate and blood pressure with patients in the supine and standing positions, and a 5 ml sample of venous CIRCULATION Downloaded from http://ahajournals.org by on

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Section: Methodsmentioning

confidence: 99%

Tolerance to isosorbide dinitrate: rate of development and reversal.

Parker¹,

Fung²,

Ruggirello³

et al. 1983

Circulation

145

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“…Together with the difference in the maximum absolute change in the mean right atrial pressure between both treatment days (Figure 4), this may suggest early attenuation of venodilator efficacy in our patient population. Early attenuation of vasodilator efficacy is an important issue with a number of vasodilators [3], such as prazosin, nitroglycerin, and nitrates [9][10][11][12][13][14][15][16] and may relate to reflex vasoconstrictory forces with or without neurohumoral activation [17][18][19][20], enhanced salt and water reabsorption [21], or a drug-specific effect [22]. Late hemodynamic tolerance and lack of a clinical benefit of fiosequinan may occur in patients with an activated renin-angiotensin system [23].…”

Section: Reproducibility and Accumulation Of Hemodynamic Effects Aftementioning

confidence: 99%

Duration and reproducibility of initial hemodynamic effects of flosequinan in patients with congestive heart failure

Bartels

Remme

Wiesfeld

et al. 1990

Cardiovasc Drug Ther

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The duration and reproducibility of hemodynamic effects of flosequian, a direct-acting, balanced-type vasodilator, were studied in 19 heart failure patients (NYHA class 3.0 +/- 0.7) receiving 100 mg orally (day 1), placebo (day 2), and again 100 mg (day 3). Flosequinan immediately reduced systemic and pulmonary resistance (23% and 35%, respectively, at 60-90 minutes postdrug) and decreased pulmonary wedge, right atrial, mean pulmonary artery, and mean arterial pressure by 38%, 50%, 25%, and 7%, respectively. Concomitantly, cardiac output, and stroke volume and work increased by 26%, 20%, and 22%, respectively. Most hemodynamic effects persisted for 48 hours. In contrast, changes in pulmonary wedge and arterial pressures, stroke volume, and stroke work only lasted for 2-12 hours. Maximum absolute changes on day 3 were generally comparable with first-dose effects with, again, long-lasting effects on systemic resistance and cardiac output. However, changes in pulmonary artery, wedge, and resistance were significantly shorter than after first dose administration. These data indicate sustained and reproducible arterial dilating effects of flosequinan, but less pronounced and shorter lasting pulmonary arterial and venodilator properties.

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“…[1][2][3][4][5] Proposed mechanisms of this phenomenon of tolerance include alterations in intracellular nitrate metabolism6,7 or the activation of neurohumoral systems counteracting the vasodilator potency of nitrates. [8][9][10][11] In vitro findings stressed the critical role of intracellular sulfhydryl groups in activation of guanylate cyclase6.12,'3 and nitrate tolerance development.…”

mentioning

confidence: 99%

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.

et al. 1989

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N-acetylcysteine is assumed to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, but data on interactions of N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of Nacetylcysteine on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n=12) during long-term nitroglycerin treatment (1.5 ,g/kg/min i.v. for 5-6 days). In dogs with nitroglycerin-specific tolerance (shift of venous or epicardial artery dilation to 15-17-fold higher dosages), N-acetylcysteine (100 mg/ kg i.v.) had no dilator effect and did not alter the dose-response relations of nitroglycerin. Yet, in nontolerant dogs (n=17), N-acetylcysteine augmented (1.5-2.0-fold) the dilation of epicardial arteries and the reduction of peripheral vascular resistance induced by 0.5-1.5 ,ug/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 ,M) was potentiated by N-acetylcysteine (0.01-1.0 mM) in saline or in canine plasma, but N-acetylcysteine alone was ineffective. We conclude that 1) N-acetylcysteine does not restore nitroglycerin responsiveness in tolerant epicardial arteries or veins in vivo, 2) a small, tolerance-independent augmentation of nitroglycerin-induced dilation may result from Nacetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin. (Circulation 1989;79:188-197) D uring continued administration of organic nitrates, their anti-ischemic effects are severely blunted. 1-5 Proposed mechanisms of this phenomenon of tolerance include alterations in intracellular nitrate metabolism6,7 or the activation of neurohumoral systems counteracting the vasodilator potency of nitrates.8-11 In vitro findings stressed the critical role of intracellular sulfhydryl groups in activation of guanylate cyclase6.12,'3 and nitrate tolerance development.These observations led to the study of the interactions between nitroglycerin and the sulfhydryl donor N-acetylcysteine (NAC) in nontolerant and tolerant

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Determinants of drug response in severe chronic heart failure. 1. Activation of vasoconstrictor forces during vasodilator therapy.

Cited by 95 publications

References 53 publications

Tolerance to isosorbide dinitrate: rate of development and reversal.

Tolerance to isosorbide dinitrate: rate of development and reversal.

Duration and reproducibility of initial hemodynamic effects of flosequinan in patients with congestive heart failure

Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.

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