Left ventricular mechanical consequences of dihydropyridine calcium channel modulation in conscious and anesthetized chronically instrumented dogs.
BACKGROUND
Volatile anesthetics depress left ventricular contractile function by altering voltage-dependent slow calcium (Ca2+) channel activity in the sarcolemmal membrane. This investigation examined the left ventricular systolic and diastolic mechanical effects of the dihydropyridine Ca2+ channel antagonist nifedipine and agonist Bay k 8644 (Bay k) in dogs in the conscious state and during anesthesia.


METHODS
Forty-eight experiments were conducted using 16 chronically instrumented dogs during autonomic nervous system blockade. Myocardial contractility was evaluated with the slope (Mw) of the regional preload recruitable stroke work relationship. Diastolic function was assessed using a time constant of isovolumic relaxation (tau), a regional chamber stiffness constant (Kp), and maximum segment lengthening velocity during rapid ventricular filling (dL/dtmax). On 3 separate days (24 experiments), a nifedipine infusion at 0.5, 1.0, 2.0, or 4.0 micrograms.kg-1.min-1 was administered. Hemodynamics and left ventricular pressure-segment length diagrams were recorded after a 10-min equilibration at each dose in the conscious state or during isoflurane or halothane anesthesia (0.8 MAC). In 24 parallel experiments, a Bay k infusion at 0.5, 1.0, 2.0, or 4.0 micrograms.kg-1.min-1 was administered, and hemodynamics and left ventricular function parameters were assessed after a 10-min equilibration in the conscious state or during isoflurane or halothane administration (1.2 MAC).


RESULTS
In conscious dogs, nifedipine significantly (P < 0.05) decreased Mw (71 +/- 5 to 42 +/- 4 mmHg during the high dose) and increased tau (35 +/- 1 to 48 +/- 3 ms during the high dose) without changes in dL/dtmax or Kp. In anesthetized dogs, nifedipine decreased Mw and dL/dtmax) (31 +/- 4 during isoflurane to 27 +/- 3 mm/s during the high dose) and increased tau and Kp (0.43 +/- 0.05 during isoflurane to 0.53 +/- 0.04 mm-1 during the high dose). Administration of Bay k increased Mw, decreased tau, and increased dL/dtmax in conscious dogs. In contrast, no changes in tau were observed in dogs anesthetized with isoflurane or halothane during infusions of Bay k despite concomitant increases in Mw. Bay k also enhanced dL/dtmax and decreased Kp during isoflurane but not halothane anesthesia.


CONCLUSIONS
Nifedipine caused direct negative inotropic actions in conscious and anesthetized dogs and worsened volatile anesthetic-induced negative lusitropic effects. Bay k improved left ventricular systolic and diastolic function in the conscious state. Bay k also improved contractility during anesthesia; however, Bay k only partially reversed volatile anesthetic-induced abnormalities in indexes of left ventricular diastolic function in dogs during autonomic nervous system blockade.
Pagel
P S
PS
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226.
Hettrick
D A
DA
Warltier
D C
DC
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000758:Anesthesia; D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D001340:Autonomic Nerve Block; D001341:Autonomic Nervous System / Q000502:physiology; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology*; D003243:Consciousness; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D004347:Drug Interactions; D006221:Halothane / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology*; D013599:Systole / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects*
D000777:Anesthetics; D015220:Calcium Channels; D004095:Dihydropyridines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C038806:1,4-dihydropyridine; D007530:Isoflurane; D009543:Nifedipine; D006221:Halothane