The cardiovascular responses to an infusion of KRN2391, a potassium channel opener, was studied in halothane-anesthetized dogs. Intravenous administration of KRN2391 at 1.0 and 5.0 μg·kg·min for 60 min produced dose-dependent decreases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) associated with dose-dependent increases in the cardiac index (CI) and stroke volume index (SVI) but was not accompanied by an increase in heart rate (HR). The maximum decrease in MAP during the infusion of KRN2391 at 1.0 and 5.0 μg·kg·min was -13±7% (P<0.01) and -37±10% (P<0.01), respectively. The maximum reduction in SVR after 1.0 and 5.0 μg·kg·min was -20±11% (P<0.01) and -60±16% (P<0.01), respectively. A KRN2391 infusion of 1.0 and 5.0 μg·kg·min increased Cl a maximum of 11±13% (P<0.05) and 65±33% (P<0.01), respectively. KRN2391 1.0 μg·kg·min showed a tendency to increase SVI but this change was not significant, KRN2391 5.0 μg·kg·min, however, produced a significant increase in SVI. The present results demonstrate that the decrease in MAP and the increases in CI and SVI caused by KRN2391 are due to a reduction in the afterload. Therefore, we conclude that these cardiovascular profiles of KRN2391 may be benificial in perioperative uses including the control of systemic blood pressure and the treatment of hypertension during halothane anesthesia in clinical practice.
Purpose: The investigational agent, KRN239 I, is a potassium channel opener with a nitrate moiety which possesses potent vasodilatory action. We compared the haemodynamic effects of KRN239 l-induced hypotension with those of nicardipine, Methods: Sixteen dogs were anaesthetized with isoflurane 1.3% in oxygen (I MAC). After the baseline period, mean arterial pressure (MAP) was decreased to 60 mmHg for 60 min with an infusion of either KRN239 l(n =8) or nicardipine (n=8). Results: The KRN2391-and nicardipine-induced hypotension resulted in maximal decreased systemic vascular resistance of 35% and 25%, increases in cardiac index of 145% and 197%, and stroke volume index of 150% and 212%, respectively, (P < 0.01 ). There was no change in heart rate, Nicardipine was associated with increases (P < 0.01) in both right atrial and mean pulmonary artery pressures, whereas these variables remained unchanged with KRN239 I, Pulmonary capillary wedge pressure decreased with KRN2391 (P < 0.01 ), but not with nicardipine. Condusion: While both drugs were equally able of inducing hypotension, our results show that the haemodynamic profile of KRN2391-and nicardipine-induced hypotension was a hyperdynamic state expressed by the marked increase in cardiac index with va~/ing changes in right and left ventricular filling pressures, and suggest that KRN2391 may be a useful vasodilator for induced hypotension.Objectis Le KRN239 I, un compos~ pr(~sentement ~ I'~tude porteur d'une fraction mol~culaire nitrate, exerce une activit~ vasodilatatrice puissante par ouverture des canaux potassiques. Nous avons compar~ les effets h~mo-dynamiques de I'hypotension induite par le KRN2391 avec ceux de la nicardipine. M~thodes : Seize chiens ont EtE anesthEsiEs ~ I'isoflurane 1,3% (I MAC). AprEs la pEriode d'Equilibration, la pression artErielle moyenne (PAM) a Et~ rEduite ~ 60 mmHg avec une perfusion de KRN2391 (n=8) ou de nicardipine (n=8). ll~sultats : I'hypotension induite par le KRN2391 et la nicardipine a fair baisser la resistance vasculaire systEmique respectivement de 35% et 2.5%, augmenter I'index cardiaque de 14596 et 19796 et la fraction d'~jec-tion indexEe de 15096 et 21296 (P < 0,01 ). Par contre, la fr6quence cardiaque n'a pas change. La nicardipine 6tait associEe ,~ des augmentations (P < 0,01) des pressions auriculalres droites et artErielles pulmonaires moyennes, alors que ces variables ne changeaient pas avec le KRN2391. La pression capillaire bloquEe diminuair avec le KRN2391 (P < 0,01 ) mais pas avec la nicardipine. Conclusion : Alors que les deux m(~dicaments ont la mgme capacitE d'induction hypotensive, nos r6sultats montrent que le profil hEmodynamique de I'hypotension produite par le KRN2391 et la nicardipine indique un Etat hyperdynamique qui se manifeste par une augmentation importante de I'index cardiaque et des changements variables des pressions de remplissage des ventricules droit et gauche. Ces rEsultats suggErent aussi que le KRN2391 pourrait Ctre utilisE pour induire l'hypotension dElib~rEe.
Because a mixture of sodium nitroprusside (SNP) and trimetaphan (TMP) induces hypotension at a dose much lower than that of either agent, SNP and TMP are believed to act synergistically. However, the mechanism of this synergy remains to be elucidated. Sixteen dogs were anesthetized with halothane in oxygen. After a baseline period, mean arterial pressure (MAP) was reduced to 60 mmHg for 60 minutes by infusion of 0.02% SNP (n=8) or a SNP (0.02% ) -TMP (0.2%) mixture (n= 8). The MAP in both groups decreased to approximately 50% of baseline values (P<0.01).Hypotension induced by SNP and by the SNP-TMP mixture was associated with similar reductions (P<0.01) in systemic vascular resistance. The cardiac index (CI) increased during the hypotensive period (P<0.05) and 10 minutes (P<0.05) after infusion of SNP was stopped. In contrast, CI decreased at 30 minutes (P<0.01) and 60 minutes (P<0.05) of the hypotensive period in the SNP-TMP group. Furthermore, CI was significantly lower in the SNP-TMP group than in the SNP group. Stroke volume index (SVI) increased (P<0.01) during and after hypotension induced with SNP, whereas SVI remained unchanged during the hypotensive period in the SNP-TMP group. With the SNP-TMP mixture, decreases (P<0.01) in heart rate (HR) were observed throughout the observation period. In contrast, HR did not change during hypotension induced by SNP. This study shows that both SNP and a SNP-TMP mixture were equally effective in reducing afterload during induced hypotension but had different effects on CI. The differences in CI between SNP and the SNP-TMP mixture may be attributed to different effects on SVI and HR.
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