Norepinephrine-induced Hypertension Research Articles

Abstract 3133: Selective Vulnerability Of Coronary Arteries To Hypercholesterolemia And Angiotensin II-induced Hypertension

Hypercholesterolemia and hypertension are major risk factors for cardiovascular disease. We aimed to determine their concomitant effects on coronary atherogenesis. An SR-BI (an HDL receptor) suppression and doxycycline-inducible angiotensin II (AngII) cassette was inserted downstream of the ApoE promoter to ablate ApoE expression and overproduce AngII. The resulting mutants (ApoE SA/SA ) exhibited mild coronary atherosclerosis after Western diet feeding. Doxycycline induced AngII-induced hypertension and drastically accelerated coronary atherosclerosis, with lesions exhibiting endothelial erosion, myeloid cell infiltration, and plaque rupture, resulting in myocardial infarction, heart failure, and male-propensity of sudden death. AngII, but not norepinephrine-induced hypertension, led to severe coronary atherogenesis under hypercholesterolemia, which was abolished by losartan. Notably, norepinephrine constricted femoral arteries, but it dilated coronary arteries. In contrast to coronary arteries, femoral arteries did not develop atherosclerosis. Proteomic analyses revealed distinctive differences between the two vascular beds. Coronary vasodilation to acetylcholine was highly susceptible to the risk factors, compared to femoral artery, and was markedly attenuated by AngII exposure and prostaglandin inhibition. Interestingly, coronary prostaglandin synthesis was suppressed in atherogenesis, and elevated coronary capacity to produce prostaglandins following methotrexate administration was associated with ameliorated early coronary endothelial dysfunction and improved cardiovascular survival, featuring markedly reduced lesional myeloid cells. Coronary arteries from patients with hypertension and hypercholesterolemia showed substantially impaired endothelium-dependent vasodilation, compared to internal mammary arteries of similar risk exposure, whereas their endothelium-independent vasodilation was intact. Thus, the combination of hypercholesterolemia and AngII-induced hypertension drastically promoted coronary atherosclerosis with spontaneous lesion rupture, which confers a selective vulnerability of coronary vasodilation to prostaglandin inhibition and AngII exposure.

Milrinone effects on cardiac mitochondria, hemodynamics, and death in catecholamine-infused rats.

BackgroundCatecholamine-storm is considered the major cause of enterovirus 71-associated cardiopulmonary death. To elucidate the effect of milrinone on cardiac mitochondria and death, a rat model of catecholamine-induced heart failure was investigated.MethodsYoung male Spray-Dawley rats received a continuous intravenous infusion of norepinephrine then followed by co-treatment with and without milrinone or esmolol. Vital signs were monitored and echocardiography was performed at indicated time points. At the end of experiments, hearts were extracted to study mitochondrial function, biogenesis, and DNA copy numbers.ResultsHypernorepinephrinemia induced persistent tachycardia, hypertension, and high mortality and significantly impaired the activities of the electron transport chain and suppressed mitochondrial DNA copy number, mitochondrial transcription factor A and peroxisome proliferator-activated receptor-gamma coactivator 1-α. Norepinephrine-induced hypertension could be significantly suppressed by milrinone and esmolol. Milrinone improved but esmolol deteriorated the survival rate. The left ventricle was significantly enlarged shortly after norepinephrine infusion but later gradually reduced in size by milrinone. The impairment and suppression of mitochondrial function could be significantly reversed by milrinone but not by esmolol.ConclusionsMilrinone may protect the heart via maintaining mitochondrial function from hypernorepinephrinemia. This study warrants the importance of milrinone and the preservation of mitochondrial function in the treatment of catecholamine-induced death.Impact Milrinone may protect the heart from hypernorepinephrinemia-induced death via maintaining myocardial mitochondrial activity, function, and copy number.Maintenance of cardiac mitochondrial function may be a potential therapeutic strategy in such catecholamine-induced heart failure.

Pathophysiological Study on Thoracic Ascending Aorta of Mice with Myh11 R247C Heterozygous Mutation in Norepinephrine-induced Hypertension Model

To explore the thoracic ascending aortic （TAA） pathophysiological characteristics of heterozygous mutant Myh11 R247C/+ mice under the norepinephrine-induced hypertension mode. Female heterozygous mutant Myh11 R247C/+ and wild type Myh11 +/+ mice were selected as experimental group (HET group) and control group (WT group)，respectively. The hypertensive model was induced by intraperitoneal injection of norepinephrine (NE)，and TAA diameter and invasive blood pressure (Bp) data were collected dynamically in real time using high-frequency ultrasound imaging and invasive arterial blood pressure monitoring technique，so as to indirectly analyze TAA compliance of two groups of mice. At the same time，the incidences of hemothorax and TAA rupture were further analyzed by autopsy and histology. After injection of NE，heterozygous mice did not show a higher Bp increase percentage in systole or diastole comparing with wildtype mice. However，heterozygous mice exhibited 17% and 32% higher TAA diameter dilation percentage than wildtype ones in systole and diastole respectively. Two heterozygous mice had TAA dissection and rupture，and the incidence of hemothorax in heterozygous mice (3/5) was higher than that in wildtype (0/5). It was very likely that the altered TAA wall compliance of mutant Myh11 R247C/+ mice had led to a higher TAA dilation degree than that in wildtype，and even could be the potential reason of TAA dissection and rupture.

Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter

Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of MICU2, a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if MICU2 expression was cardioprotective, we produced and characterized Micu2-/- mice. Mutant mice had left atrial enlargement and Micu2-/- cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of Micu2-/- ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor (Micu2-/- vs. wild type, P = 7.8 × 10-40), which suppresses angiotensin II receptor signaling via allosteric transinhibition. We found that Micu2-/- and wild-type mice had comparable basal blood pressures and elevated responses to angiotensin II infusion, but that Micu2-/- mice exhibited systolic dysfunction and 30% lethality from abdominal aortic rupture. Aneurysms and rupture did not occur with norepinephrine-induced hypertension. Aortic tissue from Micu2-/- mice had increased expression of extracellular matrix remodeling genes, while single-cell RNA-seq analyses showed increased expression of genes related to reactive oxygen species, inflammation, and proliferation in fibroblast and smooth muscle cells. We concluded that Micu2-/- mice recapitulate features of diastolic heart disease and define previously unappreciated roles for Micu2 in regulating angiotensin II-mediated hypertensive responses that are critical in protecting the abdominal aorta from injury.

Vascular effects of a tripeptide fragment of novokinine in hypertensive rats: Mechanism of the hypotensive action

BackgroundActivation of angiotensin AT2 receptors (AT2R) counteracts vasoconstrictor effects of AT1R stimulation and contributes to blood pressure control. We examined effects on mean arterial pressure (MAP) and renal hemodynamics of LKP, a tripeptide fragment of novokinine, an established AT2R agonist. MethodsEffects of intravenous LKP infusion and then superimposed losartan (AT1R antagonist) on MAP, total renal (RBF, Transonic probe) and renal medullary blood flows (laser-Doppler), and on renal excretion, were examined in anesthetized (1) Wistar rats with acute norepinephrine-induced hypertension, untreated or pretreated with AT2R antagonist (PD 123319) and (2) spontaneously hypertensive rats (SHR) maintained on standard or high-sodium (HS) diet. ResultsIn Wistar rats LKP decreased MAP (−4%, p<0.01) and increased renal medullary perfusion, these effects were abolished in rats pretreated with PD 123319 in which a post-LKP increase in MAP (+6%, p<0.02) occurred. LKP did not alter MAP in SHR; in those on HS diet RBF decreased (−14%, p<0.02), the response that was reverted by losartan. Addition of losartan always decreased or tended to decrease MAP. ConclusionsLKP lowered MAP in norepinephrine-induced hypertension, probably via activation of AT2R. At reduced availability of AT2R, as in SHR, LKP appeared to bind to different receptors, possibly AT1, and induced systemic or renal vasoconstriction. Compared to the parent novokinine, a smaller LKP molecule might be easier absorbed after oral application and more useful in therapy.

Fetal cardiac function after labetalol or pindolol for maternal hypertension in a sheep model of increased placental vascular resistance

We hypothesized that labetalol and pindolol have no detrimental effects on fetal cardiac function and pulmonary hemodynamics when administered for norepinephrine-induced maternal hypertension in a chronic sheep model of increased placental vascular resistance. Specifically, we investigated the effects of labetalol and pindolol on fetal cardiopulmonary responses to acute hypoxemia. Twenty chronically instrumented near-term ewes with increased placental vascular resistance after placental embolization were anesthetized and randomized to receive labetalol or pindolol for norepinephrine-induced hypertension. Thereafter, maternal inspiratory oxygen fraction was decreased to induce fetal hypoxemia. At the end of each phase, fetal hemodynamics were assessed by Doppler ultrasonography. The data were analyzed using repeated measures ANOVA. Maternal administration of norepinephrine had no effect on fetal hemodynamics. Pindolol decreased fetal heart rate and weight-indexed left ventricular cardiac output and increased pulmonary vascular impedances, while labetalol had no effect on these parameters. During hypoxemia, fetal heart rate increased to baseline in the pindolol group and pulmonary vascular impedances increased in the labetalol group, with no changes in fetal cardiac outputs. Pindolol decreased fetal left ventricular cardiac output and induced vasoconstriction in the pulmonary vasculature, but neither pindolol nor labetalol significantly modified fetal cardiopulmonary responses to acute hypoxemia.

Dobutamine-Induced High Cardiac Index did not Prevent Vasospasm in Subarachnoid Hemorrhage Patients: A Randomized Controlled Pilot Study

Prevention of vasospasm is a challenging issue in subarachnoid hemorrhage (SAH) patients and the objective is to compare high dobutamine-induced cardiac index (CI) and high norepinephrine-induced hypertension for the prevention of vasospasm in SAH patients. Single center, single blind, controlled randomized study. Patients hospitalized in intensive care unit (ICU) for a moderate to severe SAH (WFNS grade ≥2) were randomized to receive dobutamine to reach a 25 % increase in cardiac index or norepinephrine to reach a mean arterial pressure ≥100 mmHg. Norepinephrine could be used in the dobutamine group to maintain a cerebral pressure perfusion ≥60 mmHg. Primary endpoint was the incidence of angiographic vasospasm in the first 14 days in the ICU setting, which was upheld by a cerebral arteriography. Secondary endpoints were the incidence of delayed ischemic deficits, duration of mechanical ventilation, and ICU length of stay (LOS). During the 3-year study, 41 patients were randomized. Six patients were excluded--3 because of consent withdrawal and 3 who did not receive the assigned treatment. Respectively, 17 and 18 patients in the dobutamine and the norepinephrine group were kept in analysis. Five (28 %) patients in the dobutamine group and 5 (27 %) patients in the norepinephrine group developed vasospasm in ICU (p = 1). Seven (41 %) patients presented a delayed ischemic deficit in the dobutamine group and 9 (50 %) in the norepinephrine group (p = 0.24). Duration of mechanical ventilation was 8 [0.5-11.5] days in the dobutamine group and 19 [2.7-23] days in the norepinephrine group (p = 0.01). ICU LOS was 11 [6-15] days in the dobutamine group and 21 [9-28] days in the norepinephrine group (p = 0.01). As compared to norepinephrine-induced hypertension, dobutamine-induced high CI did not reduce the rate of vasospasm in SAH patients. Dobutamine may reduce durations of mechanical ventilation and ICU LOS.

Norepinephrine-induced hypertension dilates vasospastic basilar artery after subarachnoid haemorrhage in rabbits

Vasopressor-induced hypertension is routinely indicated for prevention and treatment of cerebral vasospasm (CVS) after subarachnoid haemorrhage (SAH). Mechanisms underlying patients' clinical improvement during vasopressor-induced hypertension remain incompletely understood. The aim of this study was to evaluate angiographic effects of normovolaemic Norepinephrine (NE)-induced hypertension therapy on the rabbit basilar artery (BA) after SAH. Cerebral vasospasm was induced using the one-haemorrhage rabbit model; sham-operated animals served as controls. Five days later the animals underwent follow-up angiography prior to and during NE-induced hypertension. Changes in diameter of the BA were digitally calculated in mean microm +/- SEM (standard error of mean). Significant CVS of 14.2% was documented in the BA of the SAH animals on day 5 compared to the baseline angiogram on day 0 (n = 12, p < 0.01), whereas the BA of the control animals remained statistically unchanged (n = 12, p > 0.05). During systemic administration of NE, mean arterial pressure increased from 70.0 +/- 1.9 mmHg to 136.0 +/- 2.1 mmHg in the SAH group (n = 12, p < 0.001) and from 72.0 +/- 3.1 to 137.8 +/- 1.3 in the control group (n = 12, p < 0.001). On day 5 after SAH, a significant dilatation of the BA in response to norepinephrine could be demonstrated in both groups. The diameter of the BA in the SAH group increased from 640.5 +/- 17.5 microm to 722.5 +/- 23.7 microm (n = 12, p < 0.05; ). In the control group the diameter increased from 716.8 +/- 15.5 microm to 779.9 +/- 24.1 microm (n = 12, p < 0.05). This study demonstrated that NE-induced hypertension causes angiographic dilatation of the BA in the SAH rabbit model. Based on these observations, it can be hypothesised that clinical improvement during vasopressor-induced hypertension therapy after SAH might be explained with cerebral vasodilatation mechanisms that lead to improvement of cerebral blood flow.

Role of Menkes ATPase in Angiotensin II-Induced Hypertension

The extracellular superoxide dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)-induced hypertension by modulating levels of extracellular superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II-induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular superoxide anion production in MNK mutant (MNK mut ) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNK mut mice. These effects in MNK mut mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular superoxide anion production, is not affected in MNK mut mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNK mut mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II-induced hypertension and endothelial function by regulating SOD3 activity and vascular superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases.

Adrenomedullin modulates hemodynamic and cardiac effects of angiotensin II in conscious rats.

We examined whether adrenomedullin, a vasoactive peptide expressed in the heart, modulates the increase in blood pressure, changes in systolic and diastolic function, and left ventricular hypertrophy produced by long-term administration of ANG II or norepinephrine in rats. Subcutaneous administration of adrenomedullin (1.5 microg.kg(-1).h(-1)) for 1 wk inhibited the ANG II-induced (33.3 microg.kg(-1).h(-1) sc) increase in mean arterial pressure by 67% (P < 0.001) but had no effect of norepinephrine-induced (300 microg.kg(-1).h(-1) sc) hypertension. Adrenomedullin enhanced the ANG II-induced improvement in systolic function, resulting in a further 9% increase (P < 0.01) in the left ventricular ejection fraction and 19% increase (P < 0.05) in the left ventricular fractional shortening measured by echocardiography, meanwhile norepinephrine-induced changes in systolic function were remained unaffected. Adrenomedullin had no effect on ANG II- or norepinephrine-induced left ventricular hypertrophy or expression of hypertrophy-associated genes, including contractile protein and natriuretic peptide genes. The present study shows that adrenomedullin selectively suppressed the increase in blood pressure and augmented the improvement of systolic function induced by ANG II. Because adrenomedullin had no effects on ANG II- and norepinephrine-induced left ventricular hypertrophy, circulating adrenomedullin appears to act mainly as a regulator of vascular tone and cardiac function.

Mechanisms involved in norepinephrine-induced hypertension in rats

Chronic norepinephrine (NE) infusion in rats results in an increase in blood pressure, but the mechanisms responsible for this effect remain unclear. To investigate these mechanisms and determine whether angiotensin II (AII) and endothelin-1 (ET-1) are involved, we infused NE intravenously in adult male Sprague Dawley rats (1, 24 or 48μg/kg/hr or vehicle) for 14 days. Blood pressure was monitored by telemetry throughout and 24hr average mean arterial pressures (MAP) calculated. Anesthetized pressure-natriuresis relationships for the left kidney were determined at the end of the 14-day infusion. Mean arterial pressure increased in a biphasic manner in the 24 and 48μg/kg/hr NE groups, with an initial peak on days 2-3 (ΔMAP 10±1 and 14±2mmHg respectively; P<0.01 vs vehicle) followed by a fall (day 5 ΔMAP 6±1 and 6±2mmHg respectively; P<0.05 vs vehicle) and then a small but significant and sustained elevation (days 13-14 ΔMAP 3±1 and 10±1mmHg respectively; P<0.05 vs vehicle). Infusion of vehicle or 1μg/kg/hr NE had no effect on MAP. Pressure-natriuresis relationships were not altered by 14 days NE infusion. In separate groups of rats, 48μg/kg/hr NE was infused for 14 days during AT1 receptor blockade, ETA&B receptor blockade or vehicle treatment. The initial peak in MAP was not affected by ETA&B receptor blockade (ΔMAP 14±2mmHg for NE plus ETA&B receptor blockade and 13±3mmHg for 48μg/kg/hr NE only) but was blunted by AT1 receptor blockade (ΔMAP 4±2mmHg for NE plus AT1 receptor blockade and 14±1mmHg for 48μg/kg/hr NE only, P<0.001). The fall in MAP following the initial peak did not occur in the rats with ETA&B receptor blockade (day 5 ΔMAP 13±2mmHg for NE plus ETA&B receptor blockade and 4±1mmHg for 48μg/kg/hr NE only). The rise in MAP achieved at days 13-14 during ETA&B receptor blockade was not significantly different to that in the 48μg/kg/hr NE only group (12±2 and 9±1mmHg respectively). Following cessation of 48μg/kg/hr NE infusion, MAP dropped rapidly below pre-infusion levels and seven days after cessation MAP was not significantly different to pre-NE infusion levels. Thus intravenous infusions of 24 and 48μg/kg/hr NE significantly increased MAP, an effect apparently involving at least 2 phases. The initial rise in MAP does not appear to involve ET-1 but may be partly mediated by AII, while the subsequent fall in MAP appears to be due to ET-1. The sustained rise in MAP does not appear to be mediated by a shift in the pressure-natriuresis relationship.

Increase in renal medullary nitric oxide synthase activity protects from norepinephrine-induced hypertension.

Studies were performed in conscious Sprague-Dawley rats to determine the role of the alpha(2)-adrenergic receptor-mediated increase in the renal medullary nitric oxide synthase (NOS) activity as a counterregulatory mechanism of blood pressure control in response to increased renal adrenergic stimulation. A subpressor dose of norepinephrine (NE, 8 microg. kg(-1). h(-1)) was infused intravenously, and NOS activity was determined with arginine-citrulline conversion by high-performance liquid chromatography in renal cortical and outer and inner medullary tissues. It was found that after 7 days of intravenous NE infusion, NOS activity was significantly higher in both the outer and inner medullary tissues (158+/-45 versus 30+/-24 pmol. mg(-1). h(-1) [outer medulla] and 5.1+/-0.7 versus 2.0+/-0.5 nmol. mg(-1). h(-1) [inner medulla] for NE-treated versus control rats, respectively). To determine whether the increase of NOS activity was mediated through renal medullary alpha(2)-receptors, the receptor antagonist rauwolscine (RAU, 1 microg. kg(-1). min(-1)) was infused via an implanted renal medullary interstitial catheter, and the consequences of intravenous NE administration were evaluated. NOS activity was significantly lower in the RAU-infused animals and did not increase with infusion of NE. To determine the systemic effects of the renal medullary alpha(2)-receptors, studies were performed to determine the consequences of chronic intravenous infusion of subpressor amounts of NE in the presence and absence of renal medullary alpha(2)-receptor inhibition. Under conditions in which RAU was continuously infused into the renal medulla, the same subpressor dose of NE caused sustained and reversible hypertension (mean arterial pressure increased from 120+/-3 to 131+/-3 mm Hg). Chronic blunting of the renal medullary NOS activity with N(G)-nitro-L-arginine methyl ester (75 microg. kg(-1). h(-1)) also enabled NE to produce a significant rise in mean arterial pressure (from 117+/-2 to 134+/-4 mm Hg). We conclude that the hypertensive effects of moderate elevations of renal adrenergic activity were chronically buffered by the alpha(2)-receptor-mediated increase in NOS activity within the renal medulla.

Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension.

The major source of superoxide (.O2-) in vascular tissues is an NADH/NADPH-dependent, membrane-bound oxidase. We have previously shown that this oxidase is activated in angiotensin II-but not norepinephrine-induced hypertension. We hypothesized that hypertension associated with chronically elevated angiotensin II might be caused in part by vascular .O2- production. We produced hypertension in rats by a 5-day infusion of angiotensin II or norepinephrine. Rats were also treated with liposome-encapsulated superoxide dismutase (SOD) or empty liposomes. Arterial pressure was measured in conscious rats under baseline conditions and during bolus injections of either acetylcholine or nitroprusside. Vascular .O2- production was assessed by lucigenin chemiluminescence. In vitro vascular relaxations were examined in organ chambers. Norepinephrine infusion increased blood pressure to a similar extent as angiotensin II infusion (179 +/- 5 and 189 +/- 4 mm Hg, respectively). In contrast, angiotensin II-induced hypertension was associated with increased vascular .O2- production, whereas norepinephrine-induced hypertension was not. Treatment with liposome-encapsulated SOD reduced blood pressure by 50 mm Hg in angiotensin II-infused rats while having no effect on blood pressure in control rats or rats with norepinephrine-induced hypertension. Similarly, liposome-encapsulated SOD enhanced in vivo hypotensive responses to acetylcholine and in vitro responses to endothelium-dependent vasodilators in angiotensin II-treated rats. Hypertension caused by chronically elevated angiotensin II is mediated in part by .O2-, likely via degradation of endothelium-derived NO. Increased vascular .O2- may contribute to vascular disease in high renin/angiotensin II states.

NOREPINEPHRINE-INDUCED HYPERTENSION EFFECTS ON THE CONGENITAL CORONARY LESIONS OF PERINATAL PIGLETS. PERINATAL PREVENTION OF ATHEROGENESIS?1333

The congenital coronary lesions of piglets (Biology of the Neonate, in press) were perturbed by the primary perinatal catecholamine, norepinephrine. Newborn piglets had 45 minutes of sustained norepinephrine-induced hypertension before 4, 72, or 168 hours of baseline conditions. After euthanasia, the anterior descending coronary artery was serially sectioned for light and electron microscopy. Changes were limited to the endothelium and subendothelial intima of the most proximal segment of the anterior descending coronary artery. As similar changes are normally present in perinatal piglets, the experimental animals were compared with sham-operated controls to determine if there was a modification of the naturally-occurring congenital lesions. The increase of coronary lesions >50% circumference (15 of 33 piglets, 45%) was not statistically significant (11 of 32 control piglets, 34%); however, the experimental groups showed unique features. At 4 hours, there was marked intimal edema, disruption of the endothelium, and fragmentation and dissolution of the internal elastic lamina. There was selective invasion of the intima by monocyte-macrophages and platelets. After 72 and 168 hours there was an increase in preexisting modified smooth muscle cell plaques in which there developed prominent fibroplasia and collagenization. It is proposed that perinatal rheologic trauma to the coronary wall induced by acute hypertension may be responsible for these changes and may be an initiating factor in atherogenesis. Perinatal control of catecholamine-induced hypertension may play a role in the prevention of atherogenesis.

CONGENITAL CORONARY LESIONS OF NEWBORN PIGLETS SHOW NOREPINEPHRINE-INDUCED HYPERTENSION EFFECTS INDEPENDENT OF THROMBOSIS AND LIPIDS. † 175

Newborn piglets were subjected to 45 minutes of sustained norepinephrine-induced hypertension, and then monitored for 4, 72, or 168 hours at baseline conditions after which they were sacrificed and the anterior descending coronary artery was serially sectioned and studied by light and electron microscopy.

Norepinephrine-induced hypertension following cardiac arrest: Effects on myocardial oxygen use in a swine model: Ann. Emerg. Med. 1994; 24/5: 907–914

Study objective: Recent studies suggest that norepinephrine-induced hypertension early after cardiac arrest ameliorates cerebral hypoperfusion and improves neurologic outcome. The purpose of this study was to evaluate the effects of early norepinephrine-induced hypertension on postresuscitation myocardial blood flow and oxygen use. Design: Prospective, controlled laboratory study. Participants: Ten swine. Interventions: All animals underwent 10 minutes of ventricular fibrillation cardiac arrest followed by 5 minutes of low-flow cardiopulmonary bypass (10 mL/kg•min), norepinephrine (0.12 mg/kg), and defibrillation. Animals then were assigned to a hypertension group (mean aortic pressure, 95 mm Hg) or a control group (mean aortic pressure, 75 mm Hg) by titrating a norepinephrine infusion to attain the prescribed aortic pressure. Results: Myocardial blood flow, perfusion pressure, and oxygen metabolism were compared between groups at different times using analysis of variance with a post-hoc Tukey test. Groups had similar myocardial blood flow during ventricular fibrillation, total defibrillation energy, and time to restoration of spontaneous circulation. Fifteen minutes after restoration of spontaneous circulation, the hypertension group had significantly elevated myocardial blood flow, 965±314 mL/min•100g versus 325±67 mL/min•100g in the control group ( P 2 /min•100g versus 6.4±3.4 mL O 2 /min•100g ( P P Conclusion: In the early resuscitation period, increasing the norepinephrine dose to induced mild hypertension significantly increases oxygen use in the postischemic myocardium.

The Effects of Acute Norepinephrine-Induced Hypertension on the Coronary Arteries of Newborn Piglets

Newborn piglets were subjected to 45 min of sustained norepinephrine-induced hypertension and then monitored for 4 hr at baseline conditions. They were then sacrificed and the anterior descending coronary artery was serially sectioned for study by light and electron microscopy. Other groups were sacrificed after 72 and 168 hr of baseline conditions. Changes were limited to the endothelium and subendothelial intima of the most proximal segment of the anterior descending coronary artery. As similar changes are normally present in perinatal piglets, the experimental animals were compared with sham-operated controls to determine if there was a modification of the naturally occurring congenital lesions. Although the prevalence of coronary lesions in control and experimental animals was not significantly different, the experimental groups showed unique features. At 4 hr, there was marked intimal edema and disruption of the endothelium with fragmentation and dissolution of the internal elastic lamina. There was selective invasion of the intima by platelets and monocytemacrophages. After 72 and 168 hr, there was an increase and progression in preexisting modified smooth muscle cell plaques in which there developed prominent fibroplasia and collagenization. It is proposed that acute hypertension may be responsible for these changes. Such perinatal surges in blood pressure may be involved in the initiation of atherogenesis.

Norepinephrine-induced hypertension following cardiac arrest: Effects on myocardial oxygen use in a swine model

Recent studies suggest that norepinephrine-induced hypertension early after cardiac arrest ameliorates cerebral hypoperfusion and improves neurologic outcome. The purpose of this study was to evaluate the effects of early norepinephrine-induced hypertension on postresuscitation myocardial blood flow and oxygen use. Prospective, controlled laboratory study. Ten swine. All animals underwent 10 minutes of ventricular fibrillation cardiac arrest followed by 5 minutes of low-flow cardiopulmonary bypass (10 mL/kg.min), norepinephrine (0.12 mg/kg), and defibrillation. Animals then were assigned to a hypertension group (mean aortic pressure, 95 mm Hg) or a control group (mean aortic pressure, 75 mm Hg) by titrating a norepinephrine infusion to attain the prescribed aortic pressure. Myocardial blood flow, perfusion pressure, and oxygen metabolism were compared between groups at different times using analysis of variance with a post-hoc Tukey test. Groups had similar myocardial blood flow during ventricular fibrillation, total defibrillation energy, and time to restoration of spontaneous circulation. Fifteen minutes after restoration of spontaneous circulation, the hypertension group had significantly elevated myocardial blood flow, 965 +/- 314 mL/min.100 g versus 325 +/- 67 mL/min.100 g in the control group (P < .001), myocardial oxygen consumption of 51.2 +/- 26.9 mL O2/min.100 g versus 6.4 +/- 3.4 mL O2/min.100 g (P < .001), and myocardial oxygen extraction of 46% +/- 20% versus 14% +/- 4% (P < .01). In the early resuscitation period, increasing the norepinephrine dose to induce mild hypertension significantly increases oxygen use in the postischemic myocardium.

Molecular and cellular mechanisms of induction and regression of cardiac fibrosis in various models of myocardial hypertrophy

This review is the summary of our findings on collagen gene expression and regulation in ventricular myocardium in experimental animal models of cardiac hypertrophy and in cardiac fibroblasts in response to hormonal stimuli. Cardiac fibrosis, or accumulation of collagen in the myocardium, is seen in several models of cardiac hypertrophy, such as those induced by aging, pressure overload, and norepinephrine-induced hypertension. Results on collagen gene expression have indicated that initial up-regulation of collagen gene expression usually precedes collagen accumulation in hypertrophied heart in those models. Thyroid hormone-induced cardiac hypertrophy, however, is distinguished from those types of hypertrophy by the absence of fibrosis and by down-regulation of collagen gene expression in ventricular tissue. Our in vitro studies on cardiac fibroblasts indicate that absence of fibrosis in thyroid hormone-induced hypertrophy could be the result of an inhibitory effect of thyroid hormone on collagen gene expression at transcriptional levels. Thyroid hormone was also shown to cause regression of cardiac fibrosis in the heart of a genetic model of collagen overproduction, the tight skin (TSK) mouse. These findings indicate that cardiac fibrosis and cardiac hypertrophy are induced via different mechanisms and that presence of cardiac hypertrophy does not imply cardiac fibrosis. The findings on inhibitory effects of thyroid hormone on collagen gene expression further suggest that biological inhibitory pathways, such as hormonal regulation, could be activated to compensate for excessive collagen production or for diminished collagen degradation by cardiac fibroblasts in cases of predisposition to cardiac fibrosis.

Comparative cardiovascular effects of SNP, ATP and phentolamine during norepinephrine-induced hypertension in dogs.

There has been no study comparing the advantage and disadvantage of various antihypertensive agents during surgery for pheochromocytomas because the study is difficult in clinical setting. In the present experiments using dogs, after increasing the arterial blood pressure with norepinephrine, we decreased it to the baseline with sodium nitroprusside (SNP), adenosine triphosphate (ATP), or phentolamine (PE) and compared the hemodynamic changes. A hyperdynamic state was found with ATP and with PE, but not with SNP. The norepinephrine-induced pulmonary hypertension could be successfully treated with SNP, but not with ATP or PE. The reason for these differences are thought to be the different vasodilative properties on peripheral arteries and veins. We conclude that agents that dilates the arteries and veins should be used to regulate the arterial pressure during surgical removal of a pheochromocytoma.