John S. Althaus

Hormonal and hemodynamic responses to halothane and enflurane in spontaneously hypertensive rats

Forty-two spontaneously hypertensive rats (SHR) and 42 normotensive Wistar–Kyoto rats (WKY) were anesthetized with either halothane or enflurane. Blood pressure, heart rate, cardiac output, distribution of blood flow, plasma rennin activity, and plasma catecholamines were measured to determine in what manner the hypertensive animal responded to these two anesthetics. Major findings of the study were that plasma rennin activity did not increase in the SHR despite a 25% reduction in MAP. The infusion of saralasin, an angiotensin II antagonist, resulted in a further decrease in blood pressure in SHR anesthetized with halothane but not with enflurane. Plasma catecholamine concentrations were elevated in the awake SHR and were decreased in SHR anesthetized with enflurane. Both halothane and enflurane anesthesia resulted in similar alterations in blood flow in the SHR. The normotensive WKY responded to halothane and enflurane in a different manner than the SHR. Plasma rennin activity increased with the decrease in blood pressure with both agents. A further decrease in blood pressure with both agents. A further decrease in blood pressure occurred with saralasin infusion in WKY anesthetized with halothane or enflurane. Significant blood flow alternations occurred in the WKY anesthetized with both agents, but enflurane caused the greatest changes. The SHR may prove useful in examining the effects of anesthetic agents and other drugs so that we may have a better understanding of the perioperative management of the patient with essential hypertension.

Renovascular hypertension: effect of halothane and enflurane.

Male Wistar rats were anesthetized at 6 weeks of age and a silver clip placed around the renal artery to produce renovascular hypertension. The rats were allowed to grow on a normal sodium diet for the next 6–9 weeks. Using diethyl ether anesthesia, arterial and venous cannulae were placed and the animals allowed to awaken in restraining cages. The group of rats was divided into three groups: awake (n = 7), halothane 1.3 vol% (n = 9), and enflurane 2.2 vol% (n = 8). The protocol consisted of a 1-h control awake period, 1 h of stable anesthesia (one group received no anesthesia), and 30-min iv infusion of saralasin, a competitive inhibitor of angiotensin II. Plasma renin activity (PRA) and plasma catecholamines were measured after 1 h of stable anesthesia and after the saralasin infusion. In additional rats treated identically, radiolabelled microspheres were used to measure cardiac output and regional blood flows during halothane (n = 7) or enflurane (n = 6) anesthesia. Principal responses were as follows: mean arterial pressure (MAP) was 193 · 4 mmHg awake and decreased to 114 · 3 mmHg and 135 · 3 mmHg with halothane and enflurane, respectively. Saralasin decreased MAP in the awake group to 176 · 3 mmHg and to 69 · 3 mmHg and 96 · 5 mmHg with halothane and enflurane, respectively. PRA in the awake rats was 7.24 · 1.3 ng · ml−1 · h−1. PRA increased with halothane but decreased with enflurane. Plasma catecholamines were decreased markedly by saralasin and by both anesthetic agents. Cardiac output was normal in awake rats and blood pressure elevation was due to increased peripheral resistance. Both anesthetic agents decreased cardiac output and myocardial blood flow and increased brain blood flow. The authors conclude that the cardiovascular and hormonal responses to halothane and enflurane anesthesia in renovascular hypertensive rats are different than the responses seen in normotensive rats. Such alterations may explain the differences seen in regional blood flow to various organs.

Central serotonin depletion: effect on blood pressure during anesthesia.

Serotonin (5-HT) in the central nervous system has been implicated in blood pressure control in both normotensive and hypertensive states. Parachlorophenylalanine (PCPA) depletes 5-HT in the central nervous system. Normotensive Wistar rats, Wistar rats made hypertensive by renal artery clipping (RHR), and spontaneously hypertensive rats (SHR) were depleted of central serotonin by the administration of PCPA. Mean arterial blood pressure (MAP), heart rate (HR), and plasma norepinephrine (NE) levels were measured in rats both before and after they were administered anesthesia with enflurane. Blood pressure was further decreased by the administration of saralasin, a competitive inhibitor of angiotensin II. Principal results are as follows. Central 5-HT was depleted by 70% or more with PCPA. In general, brain catecholamines were not altered by this treatment. No consistent patteRN of change in MAP, HR, or plasma NE was observed for Wistar rats, RHR, or SHR during an awake control period in rats treated with PCPA compared with rats treated with vehicle. However, during enflurane anesthesia or enflurane anesthesia with saralasin, MAP, HR, and plasma NE were significantly greater in Wistar rats and RHR treated with PCPA compared to similar groups treated with vehicle. This was not observed in SHR: MAP, HR, and plasma NE were similar to vehicle-treated SHR. Nonsignificant changes in plasma epinephrine, plasma renin activity, or arterial blood gas tensions could not explain the differences seen in Wistar rats, RHR, or SHR. Central serotonin plays an important role in cardiovascular control during anesthesia with enflurane in Wistar rats but does not appear to play a dominant role in SHR.

Analgetic contribution of sufentanil during halothane anesthesia: a mechanism involving serotonin.

Catecholamine and serotonin concentrations in the cord, medulla, and hypothalamus were measured in rats after saline, after sufentanil sufficient to reduce the minimum alveolar concentration (MAC) of halothane by 30% or less, or after sufentanil sufficient to reduce the MAC of halothane by 80% or more. In the cord, high doses of sufentanil resulted in a 13.4% reduction (P < 0.05) in serotonin concentration compared to saline control and a 17.4% reduction (P < 0.05) in serotonin concentration compared to low dosages of sufentanil. A 12.8% reduction (P < 0.05) in medullary serotonin also was observed with high sufentanil compared to low sufentanil. Epinephrine decreased significantly in the hypothalamus at the high sufentanil dose. No other significant differences were found in catecholamine content. The experimental results support the hypothesis that sufentanit may contribute to an analgetic component of general anesthesia by modulating nociception via the release of 5-HT.

Enhancement of anesthetic effect of halothane by spiradoline, a selective kappa-agonist.

Reduction in the anesthetic requirement of halothane by narcotics has been studied extensively in humans and animals. Problems of respiratory depression, cardiovascular depression, muscle rigidity, and abuse potential make narcotics less than ideal as supplements to general anesthesia with inhalational agents. Spiradoline, a clinical candidate, is a highly potent and selective kappa-agonist. As such it was considered important to study the effects of spiradoline on the minimum anesthetic concentration (MAC) of halothane required to block responses to noxious stimulation. The results of these experiments in rats showed a dose and plasma concentration-dependent reduction in halothane MAC over a wide range of subcutaneous doses of spiradoline (0.03 to 300 mg/kg). A maximum MAC reduction of 70% was obtained. Plasma levels of spiradoline (6 to 1800 ng/ml) were linearly related to dose. Measurement of blood pressure, heart rate, and PCO2 determined over the course of each experiment showed minor variations which would be acceptable if observed in a clinical setting. It is concluded that spiradoline has promise as an anesthetic supplement.

Application of the median method to the determination of kinetic constants for competitive enzyme inhibition

A procedure was developed to determine kinetic constants for competitive inhibition (Km, Ki, Vmax) by the median method. Simulated experiments were used to compare the accuracy and precision of kinetic constants determined by the median method with unweighted and weighted least-squares analysis. The median method was superior to unweighted least-squares analysis. The weighted least-squares method was superior to the median method when the error was normally distributed but the median method was superior when two or more outliers were present. The dependence of the accuracy and precision of kinetic constants obtained by the median method on several experimentally important parameters, including the number of experimental points, the number and range of substrate concentrations, and the number and range of inhibitor concentrations, was determined.

Central depletion of catecholamines--importance of hypertension and anesthesia.

The importance of the brain noradrenergic sympathetic nervous system in blood pressure control during anesthesia with halothane and enflurane was investigated in normotensive and hypertensive rats. Central noradrenergic neurons were destroyed by instillation of 6-hydroxydopamine (6-OHDA) into the cerebral ventricle of both normotensive Wistar rats and spontaneously hypertensive rats (SHR). One week later, arterial and venous lines were placed in the rats under anesthesia; the rats were allowed to recover; and blood pressure and plasma renin activity were measured while the rats were awake. Anesthesia then was induced with 1.3 vol% halothane (Wistar n = 8, Wistar 6-OHDA n = 10, SHR n = 8, SHR 6-OHDA n = 6) or 2.2 vol% enflurane (Wistar n = 6, Wistar 6-OHDA n = 10, SHR n = 8, SHR 6-OHDA n = 6). A control group (Wistar n = 10, Wistar 6-OHDA n = 6, SHR n = 8, SHR 6-OHDA n = 6) was treated identically, but remained unanesthetized throughout the experiment. The untreated normotensive and hypertensive rats received no intraventricular injections. After 1 hr of stable anesthesia, plasma renin activity was measured again, and saralasin, a competitive inhibitor of angiotensin II, was infused to determine the importance of the renin-angiotensin system in blood pressure control. Treatment with 6-OHDA resulted in a 60–90% depletion of norepinephrine in the medulla and hypothalamus. Normotensive Wistar rats treated with 6-OHDA responded to halothane and enflurane anesthesia in a manner similar to untreated normotensive rats. In contrast, hypertensive animals treated with 6-OHDA and then anesthetized with halothane had a significantly greater decrease in blood pressure than untreated hypertensive rats (100 ± 4 mm Hg vs 125 ± 4 mm Hg, respectively). Both treated and untreated hypertensive rats responded similarly to enflurane anesthesia. Significant decreases in blood pressure were seen in all animals with saralasin infusion except untreated hypertensive rats during enflurane anesthesia. The data suggest that although both halothane and enflurane result in a major depressant effect on the circulation, the role of central noradrenergic mechanisms for regulation of blood pressure is more important in hypertensive rats anesthetized with halothane than in hypertensive rats anesthetized with enflurane.

1733 THEOPHYLLINE REDUCES HYPOXIC VENTILATORY DEPRESSION WITHOUT NCREASING CATECHOLAMINES

Theophylline (T) reduces hypoxic ventilatory depression in newborn pig lets and can enhance the release of catecholamines (CATs) which in turn may stimulate ventilation. To determine if the effect of T on ventilation was due to the release of CATs, we measured plasma CATs and ventilation in two groups of spontaneously breathing newborn piglets <4 days old treated with either T (n=7) or normal saline (NS) (n=6) both during normoxia and hypoxia. The piglets were anesthetized with ketamine and xylazine, intubated and the femoral artery catheterized o Epinephrine (EPI) and norepinephrine (NE) were measured before and 30 minutes after treatment with T (15 mg/kg) or NS. The animals were exposed to 10% oxygen and the CATs remeasured after 5 minutes of hypoxia. Respiratory rate (RR), expiratory flow integrated to minute ventilation (Ve), heart rate and blood pressure were continuously recorded. CATs were assayed by high pressure liquid chromatography with electrochemical detection.Treatment with T during normoxla was associated with an increase in tidal volume. During hypoxia treatment with T prevented the falI in Ve and RR seen in the NS group. EPI and NE increased during hypoxia but there was no difference between the groups at 5 minutes. In our model the increase in CATs observed during hypoxia was not enhanced by T. This is consistent with the hypothesis that some mechanism other than catecholamine release is responsible for the effect of T in reducing neonatal hypoxic respiratory depression.