Combination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid

A new approach to improving left ventricular performance in heart failure

Gregory D. Pennock, Thomas E. Raya, Joseph J. Bahl, Steven Goldman, Eugene Morkin

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Background. An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. Methods and Results. To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 μg/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21±2 and 26±2 mm Hg, respectively, vs 34±3 mm Hg, P<.05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P<.05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in τ, the time constant of LV pressure decline (17.5±1.0 vs 22.2±1.7 milliseconds, P<.05) and a larger absolute value for -dP/dtmax (-4561±361 vs -3346±232 mm Hg/s, P<.05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P>.05). Conclusions. The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.

Original languageEnglish (US)
Pages (from-to)1289-1298
Number of pages10
JournalCirculation
Volume88
Issue number3
StatePublished - Sep 1993

Fingerprint

Captopril
Thyroid Hormones
Heart Failure
Cardiotonic Agents
Acids
Cytoplasmic and Nuclear Receptors
Treatment Failure
Cardiac Output
Ligation
Sprague Dawley Rats
3,5-diiodothyropropionic acid
Coronary Vessels
Heart Rate
Blood Pressure
Genes

Keywords

  • Cardiotonic agents
  • Heart failure
  • Thyroid

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Combination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid : A new approach to improving left ventricular performance in heart failure. / Pennock, Gregory D.; Raya, Thomas E.; Bahl, Joseph J.; Goldman, Steven; Morkin, Eugene.

In: Circulation, Vol. 88, No. 3, 09.1993, p. 1289-1298.

Research output: Contribution to journalArticle

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abstract = "Background. An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. Methods and Results. To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 μg/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21±2 and 26±2 mm Hg, respectively, vs 34±3 mm Hg, P<.05 for each). The addition of DITPA to captopril produced a 36{\%} increase in resting cardiac index (P<.05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in τ, the time constant of LV pressure decline (17.5±1.0 vs 22.2±1.7 milliseconds, P<.05) and a larger absolute value for -dP/dtmax (-4561±361 vs -3346±232 mm Hg/s, P<.05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P>.05). Conclusions. The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.",
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T2 - A new approach to improving left ventricular performance in heart failure

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AU - Raya, Thomas E.

AU - Bahl, Joseph J.

AU - Goldman, Steven

AU - Morkin, Eugene

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N2 - Background. An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. Methods and Results. To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 μg/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21±2 and 26±2 mm Hg, respectively, vs 34±3 mm Hg, P<.05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P<.05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in τ, the time constant of LV pressure decline (17.5±1.0 vs 22.2±1.7 milliseconds, P<.05) and a larger absolute value for -dP/dtmax (-4561±361 vs -3346±232 mm Hg/s, P<.05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P>.05). Conclusions. The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.

AB - Background. An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. Methods and Results. To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 μg/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21±2 and 26±2 mm Hg, respectively, vs 34±3 mm Hg, P<.05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P<.05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in τ, the time constant of LV pressure decline (17.5±1.0 vs 22.2±1.7 milliseconds, P<.05) and a larger absolute value for -dP/dtmax (-4561±361 vs -3346±232 mm Hg/s, P<.05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P>.05). Conclusions. The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.

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