Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin.

Abstract

BACKGROUND Vasodilator therapy may be associated with reflex counter-regulatory responses, and these responses may play a role in the development of tolerance to nitroglycerin (GTN). METHODS AND RESULTS Standing systolic blood pressure, body weight, urinary sodium, and hormonal responses to continuous (n = 10) and intermittent (n = 10) transdermal GTN administration were studied in normal volunteers. There was rapid attenuation of the hypotensive response to transdermal GTN therapy in the continuous but not in the intermittent therapy group. Significant weight gain and sodium retention occurred during continuous but not during intermittent GTN therapy. This was accompanied by a greater decrease in hematocrit in the continuous group, a finding that suggests that plasma volume expansion occurred during continuous GTN therapy. Continuous GTN therapy was associated with increases in plasma norepinephrine, atrial natriuretic peptide, arginine, vasopressin, and plasma renin activity. A different pattern of neurohormonal response was seen during intermittent therapy, with values tending to return to baseline levels after the nitrate-free interval. CONCLUSIONS Continuous transdermal GTN therapy leads to counter-regulatory responses associated with sodium retention and probable plasma volume expansion. By contrast, intermittent transdermal GTN therapy is associated with a different pattern of hormonal response, the lack of sodium retention and no evidence of plasma volume expansion. It is likely that these counter-regulatory responses play an important role in the attenuation of nitrate effects.

Nitroglycerin Tolerance in Human Vessels

“…The Krebs and Krebs-HEPES solutions were gassed with carbogen (95% O 2 and 5% CO 2 ) and were of the following compositions (in mmol/L): NaCl 118, KCl 3.89, KH 2 PO 4 1.18, NaHCO 3 …”

“…However, the relevance of in vitro studies has been questioned because they exclude some factors that may be of importance to tolerance induction in vivo. 3 The data from in vivo animal studies are conflicting. Some studies using isolated vessels 21,23 or hemodynamic indices 24,25 have demonstrated that tolerance induction is associated with no cross-tolerance to non-nitrate sources of NO.…”

“…1,2 This imposes the major limitation of efficacy on nitrate therapy for stable angina pectoris, congestive heart failure, and acute myocardial infarction. This attenuation of hemodynamic effects may be due in part to neurohumoral mechanisms opposing nitric oxide (NO)-mediated vascular relaxation 3 (pseudotolerance) and in part to a diminished NO effect 4,5 (true tolerance). The mechanism(s) responsible for true tolerance remain controversial.…”

Angiotensin II Dose-Dependently Stimulates Human Renal Proximal Tubule Transport by the Nitric Oxide/Guanosine 3′,5′-Cyclic Monophosphate Pathway

“…35 In human subjects, by contrast, SNP fails to induce significant natriuresis, 37 and another SNP donor nitroglycerin even induces sodium retention and plasma volume expansion. 38 Thus, the role of NO/cGMP in adaptive natriuretic response to salt loading has been consistently confirmed in experimental animals but not human subjects. It is tempting to speculate that the contrasting effects of NO/cGMP on PT transport revealed in the present study may be at least partially responsible for these conflicting results.…”

Update on nitrate tolerance.

“…In a recent study in normal subjects, the effect of continuous nitroglycerin patch application was studied to assess neurohormonal activation and reflex counterregulatory effects during nitrate therapy (Parker et al, 1991). The subjects were hospitalised in a clinical investigations unit and maintained on a diet with constant caloric, fluid, sodium, chloride and potassium intake.…”