In rabbits, landiolol, a new ultra-short-acting beta-blocker, exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol.

PURPOSE: To compare the cardiovascular and sympathetic effects of a new ultra-short-acting, highly cardioselective beta- blocker, landiolol, with esmolol, using an in vivo rabbit model. METHODS: Different bolus doses of landiolol (0.3, 1.0, 3.0 and 10.0 mg*kg(-1)) or esmolol (0.5, 1.5 and 5.0 mg*kg(-1)) were given intravenously, and the effects on heart rate (HR) mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were compared. RESULTS: Both landiolol and esmolol produced a dose-dependent decrease in HR. The maximum percent reductions of HR were similar with landiolol 3 mg*kg(-1) and esmolol 5 mg*kg(-1) (-14.0 +/- 0.9% and -13.9 +/- 1.4%, mean +/- SE, respectively). HR decreased more rapidly with landiolol than with esmolol. Esmolol produced a dose-dependent decrease in MAP that was not observed with landiolol. The percent maximum reduction of MAP was -38.2 +/- 3.2% with esmolol 5 mg*kg(-1). RSNA increased in a dose-dependent fashion with esmolol, but no changes were noted with landiolol. CONCLUSION: These results suggest that, in rabbits, landiolol has slightly more potent negative chronotropic action than esmolol with significantly less effects on blood pressure.

Surgical stress attenuates reflex heart rate response to hypotension.

PURPOSE: The baroreflex-mediated increase in heart rate (HR) in response to acute reduction of systolic blood pressure (SBP) was studied in order to assess whether the changes in arterial baroreflex sensitivity depend on the intensity of surgical stress, and location of visceral and somatic stimulation during surgery. METHODS: Patients were divided into visceral stimulation groups [upper (n = 30) and lower (n = 30) abdominal surgery] and somatic stimulation groups [upper (n = 25) and lower (n = 25) limbs, and chest wall (n = 25) surgery]. Acute hypotension as a baroreflex depressor test was induced by prostaglandin E1 (PGE1) 10 min before surgical incision (control) and during surgical manipulation under isoflurane-N2O anaesthesia or isoflurane-N2O-fentanyl anaesthesia. Plasma level of ACTH was measured in an additional 40 patients who underwent upper abdominal surgery. RESULTS: During upper abdominal surgery, the heart rate baroreflex sensitivity (delta HR/delta SBP) was depressed from -0.47 +/- 0.05 (control) to -0.01 +/- 0.04 (P < 0.05). The reflex heart rate baroreflex sensitivity remained unchanged and was similar among the remaining groups of patients. The concentration of ACTH increased from 12.5 +/- 1.0 (control) to 343 +/- 78.6 pg.ml-1 (P < 0.05) with isoflurane-N2O anaesthesia but did not change with isoflurane-N2O-fentanyl anaesthesia during upper abdominal surgery. CONCLUSION: Upper abdominal surgery is associated with the most stressful stimulation to attenuate heart rate baroreflex sensitivity. Integrity of the baroreflex can be preserved by adding opioids to supplement inhalation anaesthesia.

Adenosine triphosphate attenuates renal sympathetic nerve activity through left ventricular chemosensitive receptors.

We previously reported that ATP, but not adenosine, administered i.v. attenuates the baroreflex-mediated increase in sympathetic nerve activity in response to arterial hypotension by a vagal afferent mechanism. It was not elucidated in that study which vagal afferent endings are involved. Mongrel dogs were anesthetized with alpha-chloralose, thoracotomy was performed and a 27-gauge hypodermic needle was inserted into the left circumflex coronary artery. The left renal sympathetic nerves were isolated and placed on a bipolar silver electrode for measurement of renal sympathetic nerve activity (RSNA). Dose-response effects of intracoronary or i.v. infusion of ATP (100, 200 or 400 microg/kg/min) on RSNA and mean arterial pressure were studied in neuraxis-intact and cervically vagotomized dogs. RSNA was increased dose-dependently with decreasing mean arterial pressure during the i.v. ATP infusion. Elevation of RSNA was attenuated by higher intracoronary ATP infusion rates, despite the fact that mean arterial pressure was decreased dose-dependently. Left ventricular end-diastolic pressure, however, remained unchanged. This suppression of RSNA by the intracoronary ATP infusion was completely abolished by bilateral cervical vagotomy. Our data suggest that ATP attenuates reflex increases in sympathetic nerve activity by possibly stimulating ventricular chemoreceptors with cardiac vagal afferents.

The effects of ketamine on renal sympathetic nerve activity and phrenic nerve activity in rabbits (with vagotomy) with and without afferent inputs from peripheral receptors.

One reason for the reported conflicting results of the effect of ketamine on hemodynamics and respiration may be variations in afferent inputs from peripheral receptors to the central nervous system. In order to evaluate unmasked direct effects of ketamine on sympathetic nerve and phrenic nerve outflow, totally deafferented (involving vagus, sinus nerve, aortic depressor nerve) rabbits (n = 18), rabbits with vagotomy (n = 21), and neuraxis-intact rabbits (n = 6) were used in this study. The animals were anesthetized with urethane and mechanically ventilated. Ketamine 0.5, 1, or 2 mg/kg was injected intravenously and mean arterial pressure (MAP), heart rate (HR), and integrated renal sympathetic nerve and phrenic nerve activity (IRSNA, IPNA) were recorded before, and 1, 2, 3, 5, and 10 min after injection. MAP and IRSNA were significantly decreased, even by the smallest dose of ketamine, in the totally deafferented group. IPNA was decreased by the largest dose of ketamine only in the totally deafferented group. On the other hand, spontaneous respiratory frequency was decreased in the totally deafferented and vagotomy groups, but more so in the totally deafferented group. In the neuraxis-intact group, the only significant change with the largest dose of ketamine, 2 mg/kg was a slight increase in HR. We conclude that ketamine can suppress vasomotor and respiratory centers directly, and that the suppression is counterbalanced by afferent inputs from peripheral receptors.

[Is the baroreflex heart response to prostaglandin E1 less than that to nitroglycerin?].

The purpose of this study is to investigate and compare the reflex heart rate response to bolus injections of prostaglandin E1 (PGE1) and to nitroglycerin (NTG). One hundred and fifty seven patients under isoflurane nitrous oxide in oxygen anesthesia were studied prior to elective surgery. They were divided into following two groups: NTG group; n = 101 (male 54, female 47), 49.8 +/- 19.1 years of age, and PGE1 group; n = 56 (male 31, female 25), 54.7 +/- 15.3 years of age. The bolus injections of NTG and PGE1 produced a significant increase in heart rate as an indicator of arterial baroreflex response. However, there was no statistical difference between the two groups. Negative linear relationship between age and magnitude of reflex heart rate response to reduction of blood pressure (delta HR/delta SBP) was present in NTG group (r = -0.57, P < 0.01) and PGE1 group (r = -0.50, P < 0.01). These results suggest that the degree of the reflex heart rate response to bolus injection of NTG and PGE1 is almost identical in patients under isoflurane anesthesia.

Effects of fentanyl, diazepam, and the combination of both on arterial baroreflex and sympathetic nerve activity in intact and baro-denervated dogs.

The combination of fentanyl and diazepam significantly decreases systemic vascular resistance and blood pressure. We attempted to elucidate the reason the combination of these drugs can reduce blood pressure. In alpha-chloralose-anesthetized dogs, we investigated the effects of fentanyl and diazepam on mean arterial pressure (MAP) and arterial baroreflex control of renal sympathetic nerve activity (RSNA) in both intact (Study 1) and baroreflex-denervated dogs (Study 2). Study 1 included five dogs that received fentanyl 10 micrograms/kg followed by diazepam 0.4 mg/kg after a 10-min interval. Five more received both drugs in reversed sequence. The arterial baroreflex depressor test was performed with sodium nitroprusside before and after administration of each drug. Sensitivity of arterial baroreflex was examined by using the ratio of maximum increase of RSNA to maximum decrease of MAP (delta RSNA/delta MAP). RSNA and MAP significantly decreased only after both drugs had been administered (P < 0.05). Fentanyl alone did not attenuate arterial baroreflex sensitivity. Diazepam after fentanyl and diazepam alone attenuated baroreflex sensitivity to the same extent (P < 0.05). Study 2 comprised 14 dogs that underwent further surgical preparation of bilateral carotid sinus, aortic, and vagal nerve denervations. Seven received fentanyl, 5 and 10 micrograms/kg, and the other seven received diazepam, a total of 0.4 mg/kg. Fentanyl decreased both RSNA and MAP. Diazepam decreased only MAP significantly. The results indicate that fentanyl decreases mainly sympathetic outflow, whereas diazepam attenuates arterial baroreflex. We conclude that these combined effects of fentanyl and diazepam significantly decrease arterial blood pressure.

Mixtures of sodium nitroprusside and trimethaphan for induction of hypotension.

A mixture of sodium nitroprusside (SNP) and trimethaphan, empirical 1:10 weight ratio, has been advocated to decrease untoward side effects of SNP when used to induce hypotension during anesthesia and operation. The purpose of this study was to investigate the effects of various ratios of mixtures of SNP and trimethaphan on heart rate (HR), renal sympathetic nerve activity (RSNA), and renal artery blood flow to find the best ratio of SNP and trimethaphan for producing induced hypotension. Five mixtures with different ratios of SNP and trimethaphan, as well as each drug alone, were given intravenously to mongrel dogs in amounts adequate to achieve a stable mean arterial blood pressure of 75 +/- 5 mm Hg. Sodium nitroprusside alone significantly increased HR (163% +/- 14.5%) and RSNA (222% +/- 24%). Trimethaphan alone significantly decreased RSNA (11.6% +/- 4.5%). There were significant positive correlations between SNP-to-trimethaphan ratios and percent changes in HR (r2 = 0.301, P less than 0.01) and in RSNA (r2 = 0.648, P less than 0.01). Renal artery blood flow was well maintained with all ratios. Sodium nitroprusside and trimethaphan interacted synergistically to produce hypotension. However, they antagonize each other in their effects on arterial baroreflex-mediated changes in HR and RSNA. According to linear regression lines, HR changed least with a SNP-to-trimethaphan ratio of 1:5, and RSNA changed least with SNP-to-trimethaphan ratios of 1:2.5 and 1:5. Our results indicate that mixtures of SNP and trimethaphan in ratios of approximately 1:2.5 to 1:5 may produce induced hypotension with stable reflex sympathetic nerve activity.

Vagal involvement in the action of exogenous adenosine triphosphate on reflex renal sympathetic nerve activity.

The reason why adenine compounds when used as hypotensive agents are devoid of significant reflex sympathetic activity, such as rebound hypertension and tachycardia, is not clearly understood. This study, performed on alpha-chloralose-anesthetized dogs, examined, first, the effects of adenosine triphosphate (ATP) and adenosine as compared with those of sodium nitroprusside on efferent renal sympathetic nerve activity (RSNA), as an indicator of general reflex sympathetic activity, and second, whether vagal involvement could be demonstrated in the action of ATP and adenosine on RSNA. Renal sympathetic nerve activity increased progressively with increasing doses of sodium nitroprusside (5, 10, and 20 micrograms/kg) and adenosine (0.5, 2.0, and 4.0 mg/kg), whereas ATP suppressed RSNA at 2.0 and 4.0 mg/kg. High doses of ATP and adenosine (4.0 mg/kg) were injected into intact (n = 7) and vagotomized dogs (n = 7). Both ATP and adenosine induced rapid onset of hypotension without rebound hypertension and tachycardia. After vagotomy, the attenuation of RSNA by ATP was completely abolished and rebound hypertension and tachycardia were observed. Vagotomy did not alter the effect of adenosine on RSNA. It is concluded that ATP-induced hypotension is associated with attenuation of sympathetic efferent nerve activity mediated through vagal afferent pathways. Vagal afferent impulses are thought to be one of the mechanisms that inhibit reflex sympathetic activities, such as rebound hypertension after ATP-induced hypotension. The mechanisms by which adenosine inhibits reflex sympathetic activity are not, however, secondary to vagal afferent involvement and must be multifactorial.

Attenuation of arterial baroreceptor reflex response to acute hypovolemia during induced hypotension.

Preservation of the arterial baroreflex response is important to restore cardiac output and blood pressure by reflex sympathetic nerve activation in the event of sudden hypotension caused by acute blood loss during surgery. However, the arterial baroreflex may be significantly attenuated by both anesthetics and hypotensive agents. In isoflurane-anesthetized dogs, the authors investigated the arterial baroreflex response 1) to bolus injections of sodium nitroprusside (SNP), prostaglandin E1 (PGE1) and trimethaphan (TM); and 2) to rapid blood loss (5 ml/kg) before and during induced hypotension with SNP, PGE1, and TM by measuring mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). Hypotension produced by both SNP and PGE1 was accompanied by an increase in RSNA and HR. The increase in RSNA and HR following the SNP bolus injection was significantly greater than that following injection of PGE1 (P less than 0.05). Trimethaphan was associated with a decrease in RSNA and HR. Rapid blood loss resulted in the same degree of MAP reduction (20 +/- 2 mmHg) before and during induced hypotension. Sensitivities of baroreflex, as evaluated by ratios of maximum changes in RSNA or HR to MAP (delta RSNA/delta MAP, delta HR/delta MAP), in response to rapid blood loss, were significantly suppressed during continuously induced hypotension, as compared with responses before induced hypotension. Despite the same degree of induced hypotension (70 +/- 5 mmHg of MAP), delta RSNA/delta MAP and delta HR/delta MAP in response to rapid blood loss were significantly greater with PGE1 than those with SNP (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Baroreceptor reflex response to acute blood loss during induced hypotension--a comparison of sodium nitroprusside, prostaglandin E1 and trimethaphan].

This experiment was designed to evaluate the reflexive heart rate (HR) response to acute blood loss during sodium nitroprusside (SNP), prostaglandin E1 (PGE1) and trimethaphan (TM) induced-hypotension in isoflurane anesthetized dogs. Reflexive increase in HR to acute blood loss was significantly greater during PGE1 induced-hypotension than during that with SNP. TM inhibited the reflexive HR response to acute blood loss. These results suggest that PGE1 induced-hypotension provides a safer margin than that with SNP and TM when rapid bleeding occurs during anesthesia and surgery.

[The effects of ONO 3708, a new thromboxane receptor antagonist, on cardiovascular response during the early phases of endotoxin shock in anesthetized dogs].

The effects of ONO 3708, a new thromboxane A2 receptor antagonist, on cardiovascular and airway responses, at an early phase during endotoxin shock were investigated in anesthetized dogs. The i.v. infusion (1mg.kg-1) of E.coli endotoxin caused an increase in mean pulmonary artery pressure (MPAP) from 9.9 +/- 1.0 to 19.1 +/- 2.3 mmHg at 5 min, and at 15 min after infusion, elevated MPAP returned toward the control level. Pretreatment with ONO 3708 abolished these effects of endotoxin on pulmonary artery pressure at an early phase. The change in airway pressure reached a maximum of 14.4 +/- 1.7 cmH2O from 10.0 +/- 1.9 at 5 min, followed by a gradual decline toward a baseline value at 30 min in the control group. ONO 3708 significantly attenuated increase in airway pressure induced by E. coli endotoxin. But pretreatment with ONO 3708 could not prevent decrease in systemic arterial pressure and cardiac output induced by endotoxin. These results suggest that role of thromboxane A2 on the cardiovascular response during endotoxin shock is played only on pulmonary vascular changes, and ONO 3708 has a beneficial effect at least during the early phase of endotoxin shock.

Effects of dibutyryl cyclic AMP on hemodynamics and plasma catecholamine concentrations during ammonium chloride-induced metabolic acidosis in anesthetized dogs.

We investigated, using anesthetized dogs, the effect of dibutyryl cyclic AMP (db-cAMP), a derivative of cyclic AMP (cAMP), on cardiovascular variants and plasma catecholamines during metabolic acidosis. These effects were also compared with those of dopamine. The db-cAMP and dopamine were infused at 200 and 20 micrograms/kg.min, respectively. Metabolic acidosis (pH 7.00, PaCO2 40 torr) was induced by the iv infusion of 1-M ammonium chloride solution (NH4Cl). In the normal acid-base state, both db-cAMP and dopamine significantly increased cardiac output and decreased systemic vascular resistance (SVR). During metabolic acidosis, db-cAMP increased cardiac output by 69 +/- 14% and decreased SVR by 36 +/- 2%, while dopamine did not produce changes in cardiac output and increased SVR. Dopamine caused an elevation of epinephrine and norepinephrine in the normal acid-base state, but db-cAMP did not. During metabolic acidosis, dopamine significantly increased the plasma concentration of epinephrine and norepinephrine, while db-cAMP significantly decreased epinephrine concentration. These results suggest that db-cAMP may have a more beneficial effect on hemodynamics compared with dopamine when therapeutic support is needed during circulatory insufficiency with severe metabolic acidosis.

Protective effects of ONO 3708, a new thromboxane A2 receptor antagonist, during experimental endotoxin shock.

The effects of ONO 3708, a new thromboxane A2 (TXA2) receptor antagonist, on platelet aggregation in human plasma, the survival rate of rats subjected to lethal endotoxin shock, and the pathophysiological consequences of endotoxin shock in anesthetized dogs were investigated. ONO 3708 inhibited dose dependently human platelet aggregation induced by 2.5 microM of STA2, analogue of TXA2. Treatment with ONO 3708, 1 mg/100 g i.v., significantly improved the survival rate of rats in endotoxin shock from 38 to 72% at 24 hr and from 27 to 61% at 48 hr. ONO 3708 significantly attenuated endotoxin-induced thrombocytopenia, but not leukopenia. In anesthetized dogs, endotoxin-induced pulmonary hypertension was completely prevented, and increased airway pressure was significantly attenuated by ONO 3708. These results suggest that ONO 3708, the antagonist of TXA2 receptor, has beneficial effects during endotoxin shock, at least in part by inhibiting platelet aggregation.