Myocardial metabolism during graded intraportal verapamil infusion in awake dogs

Jeffrey Kline, Elena Leonova, Thomas C. Williams, James D. Schroeder, John A. Watts

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Verapamil produces comparatively greater in vivo left ventricular (LV) depression than other calcium channel antagonists produce, possibly because of myocardial metabolic derangements in addition to L-channel antagonism. Therefore, we studied myocardial lipid and carbohydrate usage and the effect of insulin treatment during progressive verapamil toxicity. Verapamil was infused through the portal vein to simulate oral overdose. Eighteen mongrel dogs were instrumented to measure multiple hemodynamic and metabolic parameters. After 1-week recovery, dogs underwent control euglycemic insulin dose-response studies (n = 6) in the conscious state: at 1,000 mU/min insulin infusion rate, myocardial glucose and lactate extraction increased seven- and threefold, respectively with no change in coronary artery blood flow or ventricular elasticity and end-systole (Ees). In 12 separate dogs, intraportal graded verapamil toxicity was induced in 3 h by increasing the infusion rate hourly: 0.04 → 0.08 → 0.1 mg/kg/min. At the end of hour 3, myocardial extraction of free fatty acids decreased from 33 ± 4 to 9 ± 3% (mean ± SEM, p <0.05), without significant change in myocardial blood flow or arterial free fatty acid concentration. Verapamil toxicity increased arterial glucose from 3.5 ± 0.16 to 6.1 ± 1.1 mM; simultaneously, myocardial glucose extraction doubled, although endogenous insulin concentrations did not increase. Arterial lactate concentrations and net myocardial lactate uptake both increased (p <0.05 vs basal blue). Ees decreased from 28 ± 1 mm Hg/mm (basal) to 20 ± 2 mm Hg/mm (end of hour 3, p <0.05). Animals were randomized into two treatment groups; either (a) insulin-glucose (1,000 mU/min, n = 6; arterial glucose was clamped ±10% with 50% dextrose), or (b) saline controls (n = 6) that received equivalent volume of saline. After 1-h insulin treatment, Ees increased to 34 ± 3 mm Hg; in controls, Ees was 15 ± 3 mm Hg/mm (p <0.05). With insulin-glucose treatment, neither myocardial glucose nor lactate extraction increased significantly (p = 0.06 for lactate). Verapamil therefore inhibits myocardial fatty acid uptake and impedes insulin-stimulated myocardial glucose uptake; under these conditions, insulin-glucose treatment increases myocardial contractile function independent of increased sugar transport. These findings indicate that verapamil toxicity produces myocardial insulin resistance and, potentially, nutrient deprivation that may contribute to clinically relevant negative inotropy.

Original languageEnglish (US)
Pages (from-to)719-726
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Volume27
Issue number5
DOIs
StatePublished - 1996
Externally publishedYes

Fingerprint

Verapamil
Dogs
Glucose
Insulin
Systole
Elasticity
Lactic Acid
Nonesterified Fatty Acids
Calcium Channel Blockers
Portal Vein
Insulin Resistance
Coronary Vessels
Fatty Acids
Hemodynamics
Carbohydrates
Lipids
Food

Keywords

  • Dogs
  • Insulin resistance
  • Intraportal infusion
  • Metabolism
  • Negative inotropy
  • Toxicity
  • Verapamil

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Myocardial metabolism during graded intraportal verapamil infusion in awake dogs. / Kline, Jeffrey; Leonova, Elena; Williams, Thomas C.; Schroeder, James D.; Watts, John A.

In: Journal of Cardiovascular Pharmacology, Vol. 27, No. 5, 1996, p. 719-726.

Research output: Contribution to journalArticle

Kline, Jeffrey ; Leonova, Elena ; Williams, Thomas C. ; Schroeder, James D. ; Watts, John A. / Myocardial metabolism during graded intraportal verapamil infusion in awake dogs. In: Journal of Cardiovascular Pharmacology. 1996 ; Vol. 27, No. 5. pp. 719-726.
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N2 - Verapamil produces comparatively greater in vivo left ventricular (LV) depression than other calcium channel antagonists produce, possibly because of myocardial metabolic derangements in addition to L-channel antagonism. Therefore, we studied myocardial lipid and carbohydrate usage and the effect of insulin treatment during progressive verapamil toxicity. Verapamil was infused through the portal vein to simulate oral overdose. Eighteen mongrel dogs were instrumented to measure multiple hemodynamic and metabolic parameters. After 1-week recovery, dogs underwent control euglycemic insulin dose-response studies (n = 6) in the conscious state: at 1,000 mU/min insulin infusion rate, myocardial glucose and lactate extraction increased seven- and threefold, respectively with no change in coronary artery blood flow or ventricular elasticity and end-systole (Ees). In 12 separate dogs, intraportal graded verapamil toxicity was induced in 3 h by increasing the infusion rate hourly: 0.04 → 0.08 → 0.1 mg/kg/min. At the end of hour 3, myocardial extraction of free fatty acids decreased from 33 ± 4 to 9 ± 3% (mean ± SEM, p <0.05), without significant change in myocardial blood flow or arterial free fatty acid concentration. Verapamil toxicity increased arterial glucose from 3.5 ± 0.16 to 6.1 ± 1.1 mM; simultaneously, myocardial glucose extraction doubled, although endogenous insulin concentrations did not increase. Arterial lactate concentrations and net myocardial lactate uptake both increased (p <0.05 vs basal blue). Ees decreased from 28 ± 1 mm Hg/mm (basal) to 20 ± 2 mm Hg/mm (end of hour 3, p <0.05). Animals were randomized into two treatment groups; either (a) insulin-glucose (1,000 mU/min, n = 6; arterial glucose was clamped ±10% with 50% dextrose), or (b) saline controls (n = 6) that received equivalent volume of saline. After 1-h insulin treatment, Ees increased to 34 ± 3 mm Hg; in controls, Ees was 15 ± 3 mm Hg/mm (p <0.05). With insulin-glucose treatment, neither myocardial glucose nor lactate extraction increased significantly (p = 0.06 for lactate). Verapamil therefore inhibits myocardial fatty acid uptake and impedes insulin-stimulated myocardial glucose uptake; under these conditions, insulin-glucose treatment increases myocardial contractile function independent of increased sugar transport. These findings indicate that verapamil toxicity produces myocardial insulin resistance and, potentially, nutrient deprivation that may contribute to clinically relevant negative inotropy.

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