Cardiovascular effects of levosimendan during rewarming from hypothermia in rat

BackgroundPrevious research aimed at ameliorating hypothermia-induced cardiac dysfunction has shown that inotropic drugs, that stimulate the cAMP, – PKA pathway via the sarcolemmal β-receptor, have a decreased inotropic effect during hypothermia. We therefore wanted to test whether levosimendan, a calcium sensitizer and dose-dependent phosphodiesterase 3 (PDE3) inhibitor, is able to elevate stroke volume during rewarming from experimental hypothermia.MethodsA rat model designed for circulatory studies during experimental hypothermia (4 h at 15 °C) and rewarming was used. The following three groups were included: (1) A normothermic group receiving levosimendan, (2) a hypothermic group receiving levosimendan the last hour of stable hypothermia and during rewarming, and (3) a hypothermic placebo control group. Hemodynamic variables were monitored using a Millar conductance catheter in the left ventricle (LV), and a pressure transducer connected to the left femoral artery. In order to investigate the level of PKA stimulation by PDE3 inhibition, myocardial Ser23/24-cTnI phosphorylation was measured using Western-blot.ResultsAfter rewarming, stroke volume (SV), cardiac output (CO) and preload recruitable stroke work (PRSW) were restored to within pre-hypothermic values in the levosimendan-treated animals. Compared to the placebo group after rewarming, SV, CO, PRSW, as well as levels of Ser23/24-cTnI phosphorylation, were significantly higher in the levosimendan-treated animals.ConclusionThe present data shows that levosimendan ameliorates hypothermia-induced systolic dysfunction by elevating SV during rewarming from 15 °C. Inotropic treatment during rewarming from hypothermia in the present rat model is therefore better achieved through calcium sensitizing and PDE3 inhibition, than β-receptor stimulation.     

降钙素基因相关肽对不同程度冠脉狭窄时的心脏功能的影响

本实验观察了冠脉内注射降钙素基因相关肽（ＣＧＲＰ０．３μｇ／ｋｇ）对正常及不同程度冠脉狭窄犬的心功能的影响。结果表明正常犬冠脉内注射ＣＧＲＰ后,平均动脉压（ＭＡＰ）下降１．２ｋＰａ（Ｐ＜０．０５）,同时,心率（ＨＲ）、心输出量（ＣＯ）、左室收缩压峰值（ＬＶＳＰ）均不同程度增加;左室舒张末压（ＬＶＥＤＰ）轻度降低。在中度狭窄３０ｍｉｎ后,冠脉内注射ＣＧＲＰ对ＨＲ、ＭＡＰ无明显影响;而重度狭窄后注射ＣＧＲＰ,ＭＡＰ由狭窄时降低逐渐增高,ＨＲ由增快而变慢。ＣＯ、ＬＶＳＰ均显著增高,ＬＶＥＤＰ降低,此作用较冠脉狭窄前更为明显。提示ＣＧＲＰ扩张冠脉动脉,增加冠脉血流量和心排血量,增强心肌收缩力,对缺血心脏功能有保护作用。     

Divergent changes in the rate of development of pressure in the left ventricle and in the performance of the heart as a pump.

Dog hearts were prepared in situ so that heart rate (HR), left ventricular end diastolic pressure (LVEDP) and mean aortic pressure (MAP) could be controlled separately during computation of left ventricular dP/dt max and external stroke work (SW). Progressive increases in HR consistently raised dP/dt max over a wide range, and consistently lowered SW except at low rates. Progressive increases in LVEDP or MAP consistently raised both dP/dt max and SW. Infusion of noradrenaline consistently raided both dP/dt max and SW, except at very high HR when only dP/dt max was consistently raised. Our results lead us to question the validity of equating changes in pre-ejection measurements with changes in performance of the heart as a pump under abnormal conditions and in the assessment of inotropic agents.     

Cardiovascular effects of epinephrine during rewarming from hypothermia in an intact animal model.

Rewarming from accidental hypothermia is often complicated by "rewarming shock," characterized by low cardiac output (CO) and a sudden fall in peripheral arterial pressure. In this study, we tested whether epinephrine (Epi) is able to prevent rewarming shock when given intravenously during rewarming from experimental hypothermia in doses tested to elevate CO and induce vasodilation, or lack of vasodilation, during normothermia. A rat model designed for circulatory studies during experimental hypothermia and rewarming was used. A total of six groups of animals were used: normothermic groups 1, 2, and 3 for dose-finding studies, and hypothermic groups 4, 5, and 6. At 20 and 24 degrees C during rewarming, group 4 (low-dose Epi) and group 5 (high-dose Epi) received bolus injections of 0.1 and 1.0 microg Epi, respectively. At 28 degrees C, Epi infusion was started in groups 4 and 5 with 0.125 and 1.25 microg/min, respectively. Group 6 served as saline control. After rewarming, both CO and stroke volume were restored in group 4, in contrast to groups 5 and 6, in which both CO and stroke volume remained significantly reduced (30%). Total peripheral resistance was significantly higher in group 5 during rewarming from 24 to 34 degrees C, compared with groups 4 and 6. This study shows that, in contrast to normothermic conditions, Epi infused during hypothermia induces vasoconstriction rather than vasodilation combined with lack of CO elevation. The apparent dissociation between myocardial and vascular responses to Epi at low temperatures may be related to hypothermia-induced myocardial failure and changes in temperature-dependent adrenoreceptor affinity.     

Different tolerance to hypothermia and rewarming of isolated rat and guinea pig hearts.

We examined the effect of hypothermia and rewarming on myocardial function and calcium control in Langendorff-perfused hearts from rat and guinea pig. Both rat and guinea pig hearts demonstrated a rise in myocardial calcium ([Ca]total) in response to hypothermic perfusion (40 min, 10 degrees C), which was accompanied by an increase in left ventricular end diastolic pressure (LVEDP). The elevation in [Ca]total was severalfold higher in guinea pig than in rat hearts, reaching 12.9 +/- 0.8 and 3.1 +/- 0.6 micromol.g dry wt-1, respectively. The rise in LVEDP, however, was comparable in the two species: 62.5 +/- 2.5 (guinea pig) and 52.5 +/- 5.1 mm Hg (rat). Following rewarming, [Ca]total remained elevated in guinea pig, whereas a moderate decline in [Ca]total was observed in the rat (13.6 +/- 1.9 and 2.2 +/- 0.3 micromol.g dry wt-1, respectively). Posthypothermic values of LVEDP were also significantly higher in guinea pig compared to rat hearts (42.5 +/- 6.8 vs 20.5 +/- 5.1 mm Hg, P < 0.027). Furthermore, whereas rat hearts demonstrated a 78 +/- 7% recovery of left ventricular developed pressure, there was only a 15 +/- 7% recovery in guinea pig hearts. Measurements of tissue levels of high energy phosphates and glycogen utilization indicated a higher metabolic requirement in guinea pig than in rat hearts in order to oppose the hypothermia-induced calcium load. Thus, we conclude that isolated guinea pig hearts are more sensitive to a hypothermic insult than rat hearts.     

Participation of the autonomic nervous system in the cardiovascular effects of milrinone

The cardiodynamic activity of intravenously administered milrinone was examined in alpha-chloralose anesthetized dogs. Two groups of dogs were used, one pretreated with hexamethonium to block autonomic reflexes, and a second group which received no pretreatment. In the untreated group milrinone produced dose-dependent increases in +dP/dt and heart rate while decreasing both systolic and diastolic blood pressure and left ventricular end diastolic pressure (LVEDP). After treatment with hexamethonium basal heart rate was significantly increased, whereas reflex changes in heart rate in response to i.v. norepinephrine or nitroglycerin were ablated. Systolic, but not diastolic blood pressure was also markedly reduced by hexamethonium. In the presence of hexamethonium responses to milrinone were qualitatively similar to milrinone responses in the absence of hexamethonium. However, the dose-response curves for milrinone were shifted dextrally for changes in +dP/dt and LVEDP, whereas the dose-response curve for blood pressure was shifted sinistrally. Thus, it appears that the autonomic nervous system enhances the effect of milrinone on +dP/dt and LVEDP, but attenuates its effect on blood pressure.     

Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death

The hemodynamic response to submaximal exercise was investigated in 38 mongrel dogs with healed anterior wall myocardial infarctions. The dogs were chronically instrumented to measure heart rate (HR), left ventricular pressure (LVP), LVP rate of change, and coronary blood flow. A 2 min coronary occlusion was initiated during the last minute of an exercise stress test and continued for 1 min after cessation of exercise. Nineteen dogs had ventricular fibrillation (susceptible) while 19 animals did not (resistant) during this test. The cardiac response to submaximal exercise was markedly different between the two groups. The susceptible dogs exhibited a significantly higher HR and left ventricular end-diastolic pressure (LVEDP) but a significantly lower left ventricular systolic pressure (LVSP) in response to exercise than did the resistant animals. (For example, response to 6.4 kph at 8% grade; HR, susceptible 201.4 +/- 5.1 beats/min vs. resistant 176.2 +/- 5.6 beats/min; LVEDP, susceptible 19.4 +/- 1.1 mmHg vs. resistant 12.3 +/- 1.7 mmHg; LVSP, susceptible 136.9 +/- 7.9 mmHg vs. resistant 154.6 +/- 9.8 mmHg.) beta-Adrenergic receptor blockade with propranolol reduced the difference noted in the HR response but exacerbated the LVP differences (response to 6.4 kph at 8% grade; HR, susceptible 163.4 +/- 4.7 mmHg vs. resistant 150.3 +/- 6.4 mmHg; LVEDP susceptible 28.4 +/- 2.1 mmHg vs. resistant 19.6 +/- 3.0 mmHg; LVSP, susceptible 122.2 +/- 8.1 mmHg vs. resistant 142.8 +/- 10.7 mmHg). These data indicate that the animals particularly vulnerable to ventricular fibrillation also exhibit a greater degree of left ventricular dysfunction and an increased sympathetic efferent activity.     

Glucose, glycogen, and insulin responses in the hypothermic rat

The rat appears to be unable to utilize glucose during hypothermia. The objective of this study was to examine carbohydrate homeostasis during induction, hypothermia, and rewarming phases. Groups of normothermic animals were euthanized to serve as time controls for comparison. Hypothermia (15 degrees C) was produced by exposure to helox (80% helium:20% oxygen) at 0 +/- 1 degree C. Hyperglycemia was noted during the induction process (169 +/- 8 in control vs 326 +/- 49 mg/dl). Serum glucose increased further during 4 hr of hypothermia, but following rewarming (Tre of 33 +/- 1 degrees C) was reduced (153 +/- 16 mg/dl) significantly (P less than 0.05). Serum insulin was depressed during hypothermic induction (from 48 +/- 4 in controls to 19 +/- 3 microU/ml in hypothermic rats) and increased only slightly during the arousal process, remaining significantly lower than in normothermic subjects. Initial hepatic, skeletal muscle, and cardiac glycogen concentrations were reduced 34, 68, and 75%, respectively, during hypothermic induction. While liver glycogen decreased further during 4 hr of hypothermia, skeletal and cardiac stores increased markedly. During rewarming, hepatic glycogen was markedly decreased, while skeletal and cardiac stores were maintained. These data suggest that hyperglycemia in the hypothermic rat can be accounted for by glycogenolysis and hypoinsulinemia. In addition, this study indicates repletion of skeletal and cardiac muscle glycogen during maintained hypothermia and sparing of muscle glycogen during rewarming.     

Nitrotyrosine and nitrate/nitrite levels in cardiac arrest survivors treated with endovascular hypothermia

The protective effect of therapeutic hypothermia in cardiac arrest survivors (CAS) has been previously well documented. Animal studies have indicated that attenuation of tissue oxidative stress (OS) may be involved in the mechanisms that lead to the beneficial effect of hypothermia. The extent of OS and nitric oxide (NO) production in adult CAS treated with endovascular hypothermia is, however, unknown. A total of 11 adult patients who experienced cardiac arrest out of hospital were included in the present study, and all were treated with mild hypothermia using the Thermogard XP (Alsius, USA) endovascular system. A target core temperature of 33 °C was maintained for 24 hours, with a subsequent rewarming rate of 0.15 °C per hour, followed by normothermia at 36.8 °C. Blood samples for the measurement of nitrotyrosine and nitrate/nitrite levels were drawn at admission and every 6 hours thereafter for two days. During the hypothermic period, the levels of nitrotyrosine and nitrates/nitrites were comparable with baseline values. During the rewarming period, serum levels of both parameters gradually increased and, during the normothermic period, the levels were significantly higher compared with hypothermic levels (nitrotyrosine, P<0.001; nitrates/nitrites, P<0.05). In our study, significantly lower levels of nitrotyrosine and nitrates/nitrites were demonstrated during hypothermia compared with levels during the normothermic period in adult CAS. These data suggest that attenuation of OS and NO production may be involved in the protective effect of hypothermia in adult CAS.     

犬心右室,左室大面积梗塞时的容量负荷评价

在１２只犬,结扎四支冠脉,造成犬心右室、左室大面积梗塞和心源性休克时,左室收缩压（ＬＶＳＰ）及最大正负压力阶差（±ｄｐ／ｄｔｍａｘ．）分别下降５４％、５１％和４７％,而右室收缩压（ＲＶＳＰ）及±ｄｐ／ｄｔｍａｘ．仅降低９％、２５％和２７％。组Ⅰ（６只犬）快速扩容（低分子右旋糖酐３０ｍｌ／ｋｇ,２０ｍｉｎ内静脉输入）,结果右室反向搏动增强,双心室±ｄｐ／ｄｔｍａｘ．进一步降低,右房压（ＲＡＰ）及左室舒张末压（ＬＶＥＤＰ）极度升高达２．９±０．２ｋＰａ和５．０±０．３ｋＰａ（Ｐ均＜０．０１）,甚至诱发室颤。组Ⅱ缓慢静点多巴胺（１０μｇ／ｋｇ·ｍｉｎ）和硝酸甘油（１μｇ／ｋｇ·ｍｉｎ）３０ｍｉｎ,有效提高了动脉压（ＡＰ）,心输出量（ＣＯ）,ＬＶＳＰ及左室±ｄｐ／ｄｔｍａｘ．使休克逆转。结果表明,大面积左、右室梗塞伴休克时,右室残余心肌的代偿性收缩仍能造成ＲＶＳＰ与右室泵功能呈分离状态;此时快速扩容将进一步损害左、右室功能,而联合使用硝酸甘油和多巴胺能有效纠正休克同时不造成ＲＡＰ和ＬＶＥＤＰ的升高。     

Effects of sympathetic stimulation during cooling on hypothermic as well as posthypothermic hemodynamic function

This experimental study was performed to explore hemodynamic effects of a moderate dose epinephrine (Epi) during hypothermia and to test the hypothesis whether sympathetic stimulation during cooling affects myocardial function following rewarming. Two groups of male Wistar rats (each, n=7) were cooled to 15 degrees C, maintained at this temperature for 1 h, and then rewarmed. Group 1 received 1 microg/min Epi, i.v., for 1 h during cooling to 28 degrees C, a dose known to elevate cardiac output (CO) by approximately 25% at 37 degrees C. Group 2 served a saline solution control. At 37 degrees C, Epi infusion elevated CO, left ventricular systolic pressure, maximum rate of left ventricle pressure rise, and mean arterial pressure. During cooling to 28 degrees C, these variables, with the exception of mean arterial pressure, decreased in parallel to those in the saline solution group. In contrast, in the Epi group, mean arterial pressure remained increased and total peripheral resistance was significantly elevated at 28 degrees C. Compared with corresponding prehypothermic values, most hemodynamic variables were lowered after 1 h at 15 degrees C in both groups (except for stroke volume). After rewarming, alterations in hemodynamic variables in the Epi-treated group were more prominent than in saline solution controls. Thus, before cooling, continuous Epi infusion predominantly stimulates myocardial mechanical function, materialized as elevation of CO, left ventricular systolic pressure, and maximum rate of left ventricle pressure rise. Cooling, on the other hand, apparently eradicates central hemodynamic effects of Epi and during stable hypothermia, elevation of peripheral vascular vasopressor effects seem to take over. In contrast to temperature-matched, non-Epi stimulated control rats, a significant depression of myocardial mechanical function occurs during rewarming following a moderate sympathetic stimulus during initial cooling.     

Ischemic preconditioning is not additive to preservation with hypothermia or crystalloid cardioplegia in the globally ischemic rat heart

The aim of this study was to evaluate the additive protective efficiency of ischemic preconditioning when used in combination with conventional clinically relevant cardioprotective methods of hypothermia or hypothermic cardioplegia during sustained global ischemia.Isolated rat hearts were aorta-perfused with Krebs-Henseleit buffer and were divided into six groups (n = 10 each). Group I: Ischemia at 34°C for 60 min; Group PC+I: preconditioned (PC) ischemia at 34°C, 2 episodes of 5 min ischemia and 10 min reperfusion at 34°C followed by I; Group HI: hypothermic ischemia at 10°C for 60 min; Group PC+HI: preconditioned (PC) hypothermic ischemia, 2 episodes of 5 min ischemia and 10 min reperfusion at 34°C followed by HI; Group CPL+HI: single dose of 'Plegisol' cardioplegia followed by HI; Group PC+CPL+HI: preconditioned hypothermic cardioplegia, followed by CPL+HI. At the end of 60 min ischemia, all the hearts were reperfused at 34°C for 30 min when post-ischemic recovery in left ventricular contractile function and coronary vascular dynamics was computed and compared.There was a significant depression in the post-ischemic recovery of developed pressure (P_max), positive derivative of pressure (+dp/dt), negative derivative of pressure (-dp/dt) and heterometric autoregulation (HA) of contractile force in all the groups, with no major differences between the groups. Left ventricular end-diastolic pressure (LVEDP) was significantly elevated after I at 34°C. Preconditioning (PC+I) prevented the rise in the LVEDP and this was accompanied by a significant reduction in the release of purine metabolises in the coronary effluents, particularly adenosine, during the immediate reperfusion period. Hypothermia (HI) provided essentially the same level of metabolic and mechanical preservation as offered by PC+I. Combination of hypothermia with preconditioning (PC+HI) or cardioplegia (PC+CPL+HI), did not further enhance the preservation. Post-ischemic recovery in the regional contractile function (segment shortening, %SS) followed nearly identical pattern to global (P_max) recovery. Post-ischemic recovery in coronary flow (CF) was significantly reduced and coronary vascular resistance (CVR) was significantly increased in all the groups. Myogenic autoregulation (transient and sustained) was generally enhanced indicating increased vascular reactivity. Preconditioning did not alter the time-course of these changes.Preconditioned ischemia (34°C) preserved left ventricular diastolic functions and prevented the contracture development after sustained ischemia reperfusion at 34°C. This protective effect of preconditioning was possibly mediated by the reduction in the breakdown of purine metabolises. Hypothermia alone or in combination with crystalloid cardioplegia prevented the irreversibility of the ischemic injury but produced contractile and vascular stunning which was not improved by ischemic preconditioning. The results of this study indicate that preconditioning when combined with hypothermia or hypothermic cardioplegia offered no significant additional protection.     

Tissue-specific extravasation of albumin-bound Evans blue in hypothermic and rewarmed rats

The effects of hypothermia and rewarming on endothelial integrity were examined in intestines, kidney, heart, gastrocnemius muscle, liver, spleen, and brain by measuring albumin-bound Evans blue loss from the vasculature. Ten groups of twelve rats, normothermic with no pentobarbital, normothermic sampled at 2, 3, or 4 h after pentobarbital, hypothermic to 20, 25, or 30 degrees C, and rewarmed from 20, 25, or 30 degrees C, were cooled in copper coils through which water circulated. Hypothermic rats were cooled to the desired core temperature and maintained there for 1 h; rewarmed rats were cooled to the same core temperatures, maintained there for 1 h, and then rewarmed. Following Evans blue administration, animals were euthanized with methoxyflurane, tissues removed, and Evans blue extracted. Because hypothermia and rewarming significantly decrease blood flow, organ-specific flow rates for hypothermic and rewarmed tissues were used to predict extravasation. Hypothermia decreased extravasation in tissues with continuous endothelium (brain, muscle) and increased it in tissues with discontinuous endothelium (liver, lung, spleen). All tissues exhibited significant (p < 0.05) differences from normothermic controls. These differences are attributed to a combination of anesthesia, flow, and (or) change in endothelial permeability, suggesting that appropriate choice of organ and temperature would facilitate testing pharmacological means of promoting return to normal perfusion.     

Intensive albumin therapy and pressure modifications during acute coronary ischemia in the dog]

The influence, on left ventricular pressure, of an intensive human albumin administration, has been studied in eight open chest dogs, during a second myocardial ischemia produced by coronary occlusion. After elevation of plasmatic proteins, the systolic and telediastolic left ventricular pressure, the dP/dt and the cardiac rate are measured. Any hypotensive effect was not observed in the human albumin-perfused dogs, nor in another control groups of six animals.     

Hemodynamic changes before and after short and prolonged periods of hypothermia in dogs

Dogs were cooled to 30 °C and either rewarmed immediately or after being kept at 30 °C for 6 hr. The acid-base balance was determined and hemodynamic data were collected. At the beginning of the rewarming period the arterial blood pressure and the left ventricular work output were increased after short hypothermia, but not after prolonged hypothermia. The survivors of prolonged hypothermia had had a higher arterial blood pressure and left ventricular work output before cooling began than did nonsurvivors. An additional load on the cardiovascular system (A-V shunt) was incompatible with survival. The so-called rewarming shock, therefore, appears to be cardiogenic, and the treatment of the victims of accidents causing hypothermia due to exposure should be directed against cardiogenic shock.     

Beneficial effects of perfluorochemical artificial blood on cardiac function following coronary occlusion

This study compares the effects of perfluorochemical artificial blood versus whole blood on the systolic and diastolic function of regionally ischemic myocardial preparations. Regional ischemia was produced by ligation of the circumflex coronary artery in isolated, blood-perfused rabbit hearts. Three minutes after occlusion, half the hearts were switched from the blood perfusate to perfluorochemical artificial blood; the other half continued to be perfused with blood. Isovolumic left ventricular (LV) developed pressure, dP/dt and resting pressure were monitored before, and for 2 hours after coronary occlusion. After 90 minutes of regional ischemia, perfluorochemical-treated hearts exhibited significantly greater developed pressure than those perfused with blood (78 +/- 6% versus 61 +/- 5% of preligation values; P less than 0.05). At the end of the experiment, LV dP/dt was 21% greater in the perfluorochemical-perfused group than in the blood-perfused group (74 +/- 8% versus 53 +/- 10%; P less than 0.01). Perfluorochemical perfusion also preserved diastolic function by preventing the 58% increase in left ventricular chamber stiffness (i.e., resting pressure; P less than 0.01) associated with circumflex ligation. Thus, in the present model of regional ischemia, perfluorochemical artificial blood is significantly better than blood at maintaining both systolic and diastolic myocardial function after a major coronary artery has been occluded.     

Alteration in myocardial oxygen balance during exercise after beta-adrenergic blockade in dogs

The effects of beta-adrenergic blockade upon myocardial blood flow and oxygen balance during exercise were evaluated in eight conscious dogs, instrumented for chronic measurements of coronary blood flow, left ventricular pressure, aortic blood pressure, heart rate, and sampling of arterial and coronary sinus venous blood. The administration of propranolol (1.5 mg/kg iv) produced a decrease in heart rate, peak left ventricular (LV) dP/dt, LV (dP/dt/P, and an increase in LV end-diastolic pressure during exercise. Mean coronary blood flow and myocardial oxygen consumption were lower after propranolol than at the same exercise intensity in control conditions. The oxygen delivery-to-oxygen consumption ratio and the coronary sinus oxygen content were also significantly lower. It is concluded that the relationship between myocardial oxygen supply and demand is modified during exercise after propranolol, so that a given level of myocardial oxygen consumption is achieved with a proportionally lower myocardial blood flow and a higher oxygen extraction.     

Changes in cardiovascular β-adrenoceptor responses during hypothermia

The purpose of this study was to determine cardiovascular β-adrenergic responses during hypothermia. In the present study, we used isoproterenol (Iso), a nonselective, potent β-adrenoceptor agonist, well known for its positive chronotropic and inotropic pharmacologic actions at normothermia. Rats were instrumented to measure mean arterial pressure (MAP) and left ventricular (LV) pressure–volume changes using a Millar pressure–volume conductance catheter. Core temperature was manipulated from 37 (normothermia) to 24 °C (hypothermia) and back to 37 °C (rewarming) using both internal and external heat exchangers. During cooling at each temperature (33, 30, 27, and 24 °C), central hemodynamic variables and MAP were measured while intravenously infusing Iso (doses of 1.7, 5, 10, and 20 ng/min). Seven animals underwent all phases of the protocol. At normothermia Iso infusion resulted in a significant, dose-dependent increase in heart rate (HR), stroke volume (SV), cardiac output (CO), LV dP/dt_max (left ventricular maximum derivative of systolic pressure over time) but no change in MAP. During cooling Iso infusion caused no dose-dependent change in any of the hemodynamic variables. After rewarming, baseline HR and LV dP/dt_max were increased, whereas SV was significantly reduced when compared with their pre-hypothermic baseline values. This study shows that physiological cardiovascular responses mediated by the β-adrenoceptor are significantly diminished during core hypothermia.     

Regulation of cardiac sarcolemmal Ca2+ channels and Ca2+ transporters by thyroid hormone

In order to examine the regulatory role of thyroid hormone on sarcolemmal Ca²⁺-channels, Na⁺–Ca²⁺ exchange and Ca²⁺-pump as well as heart function, the effects of hypothyroidism and hyperthyroidism on rat heart performance and sarcolemmal Ca²⁺-handling were studied. Hyperthyroid rats showed higher values for heart rate (HR), maximal rates of ventricular pressure development+(dP/dt)max and pressure fall–(dP/dt)max, but shorter time to peak ventricular pressure (TPVP) and contraction time (CT) when compared with euthyroid rats. The left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP), as well as aortic systolic and diastolic pressures (ASP and ADP, respectively) were not significantly altered. Hypothyroid rats exhibited decreased values of LVSP, HR, ASP, ADP, +(dP/dt)max and –(dP/dt)max but higher CT when compared with euthyroid rats; the values of LVEDP and TPVP were not changed. Studies with isolated-perfused hearts showed that while hypothyroidism did not modulate the inotropic response to extracellular Ca²⁺ and Ca²⁺ channel blocker verapamil, hyperthyroidism increased sensitivity to Ca²⁺ and decreased sensitivity to verapamil in comparison to euthyroid hearts. Studies of [³H]-nitrendipine binding with purified cardiac sarcolemmal membrane revealed decreased number of high affinity binding sites (B_max) without any change in the dissociation constant for receptor-ligand complex (K_d) in the hyperthyroid group when compared with euthyroid sarcolemma; hypothyroidism had no effect on these parameters. The activities of sarcolemmal Ca²⁺-stimulated ATPase, ATP-dependent Ca²⁺ uptake and ouabain-sensitive Na⁺–K⁺ ATPase were decreased whereas the Mg²⁺-ATPase activity was increased in hypothyroid hearts. On the other hand, sarcolemmal membranes from hyperthyroid samples exhibited increased ouabain-sensitive Na⁺–K⁺ ATPase activity, whereas Ca²⁺-stimulated ATPase, ATP-dependent Ca²⁺ uptake, and Mg²⁺-ATPase activities were unchanged. The V_max and K_a for Ca²⁺ of cardiac sarcolemmal Na⁺–Ca²⁺ exchange were not altered in both hyperthyroid and hypothyroid states. These results indicate that the status of sarcolemmal Ca²⁺-transport processes is regulated by thyroid hormones and the modification of Ca²⁺-fluxes across the sarcolemmal membrane may play a crucial role in the development of thyroid state-dependent contractile changes in the heart.     

Oxygen delivery and utilization in hypothermic dogs

Hypothermia produces a decrease in metabolic rate that may be beneficial under conditions of reduced O2 delivery (Do2). Another effect of hypothermia is to increase the affinity of hemoglobin for O2, which can adversely affect the release of O2 to the tissues. To determine the overall effect of hypothermia on the ability of the peripheral tissues to extract O2 from blood, we compared the response to hypoxemia of hypothermic dogs (n = 8) and of normothermic controls (n = 8). The animals were anesthetized, mechanically ventilated, and paralyzed to prevent shivering. The inspired concentration of O2 was progressively reduced until the dogs died. The core temperatures of the control and hypothermic dogs were 37.7 +/- 0.3 and 30.5 +/- 0.1 degree C, respectively (P less than 0.01). The O2 consumption (VO2) of the control dogs was significantly greater than that of the hypothermic dogs (P less than 0.05), being 4.7 +/- 0.4 and 3.2 +/- 0.3 ml X min-1 X kg-1, respectively. Hypothermia produced a left shift of the oxyhemoglobin dissociation curve (ODC) to a PO2 at which hemoglobin is half-saturated with O2 of 19.8 +/- 0.7 Torr (control = 32.4 +/- 0.7 Torr, P less than 0.01). The O2 delivery at which the VO2 becomes supply dependent (DO2crit) was 8.5 ml X min-1 X kg-1 for control and 6.2 ml X min-1 X kg-1 for hypothermia. The hypothermic dogs maintained their base-line VO2's at lower arterial PO2's than control.(ABSTRACT TRUNCATED AT 250 WORDS)