Elevated Systemic Arterial Pressure Research Articles

Development and Characterization of Liposomal Tumor Necrosis Factor (Tnf)

Free and liposomal formulations of caprylated TNF-SAM2, a TNF mutant, were evaluated in both a canine model for TNF-induced hypotension and in the murine Meth A sarcoma model for efficacy. The liposomal formulations consisted of caprylated TNF-SAM2 either bound to the outer leaflet of small unilamellar vesicles (SUVs) or encapsulated in multilamellar vesicles (MLVs). Whereas systemic administration of parental TNF-a to anesthesized mongrel dogs resulted in acute shock with a precipitous fall in systemic arterial pressure (SAP), the SUV-TNF-SAM2 resulted in no net hypotension. Both the free and liposomal-TNF-SAM2 elicited a hyperdynamic response with tachycardia and elevated cardiac output and SAP, which was not observed with parental TNF-a. Two tail-vein injections of these formulations were administered 4–5 days apart to BALB/c mice in which Meth A sarcoma cells were previously implanted subcutaneously or intradermally. Free TNF-SAM2 at 4 × 10 U/mouse caused highly significani tumor control compared to PBS on days 5 and 12; however, substantial toxicity (-24% lethality; was observed at this level. The liposomal formulations of caprylated TNF-SAM2 demonstratec significant tumor control at all dose levels (up to 8 × 10 U/mouse) on day 12 (p<0.025) wit! either no or reduced lethality (0–15%); the tumor responses were comparable to those with fret TNF-SAM2. We conclude that the liposomal caprylated-TNF-SAM2 formulations exhibit; therapeutic index superior to that of free parental TNF-a or free TNF-SAM2.

Hypertension in Diabetic Patients: An Update of Interventional Studies to Preserve Renal Function

Hypertension and diabetes mellitus are a malignant combination of diseases for the kidney. They markedly increase the risk for progressive renal injury and are the largest single cause of renal failure. Strategies to reduce the risk for renal injury in hypertensive diabetics are very important. Although Type I and Type II diabetes are different diseases, they may be associated with similar mechanisms of renal injury in hypertensive patients. Reduction of elevated systemic arterial pressure is of proven benefit in limiting progressive renal injury in diabetic hypertensives. However, converting enzyme inhibitors and possibly the nondihydropyridine calcium antagonists may possess antiproteinuric abilities independent of blood pressure reduction which, in addition to their antihypertensive effects, may be important in limiting the progression of human diabetic renal disease. Long-term clinical trials have evaluated the impact of these and other agents on progression of diabetic renal disease. This paper reviews these trials and focuses on renal effects of antihypertensive agents independent of blood pressure reduction.

Modulation by angiotensin III of nociception-related and arterial pressure-related neuronal responsiveness in the nucleus reticularis gigantocellularis of the rat.

We evaluated possible modulation by angiotensin III (AIII) of the interactive effect of noxious stimuli and elevation in systemic arterial pressure on the responsiveness of neurons in the nucleus reticularis gigantocellularis (NRGC) of the medulla oblongata. Combined extracellular single-neuron recording and microiontophoresis were carried out on male, adult Sprague-Dawley rats anesthetized with pentobarbital sodium. The responsiveness of NRGC neurons to nociception (tail clamp) and/or transient hypertension elicited by phenylephrine (5 micrograms/kg, i.v.), in the absence or presence of AIII, was used as the experimental index. Microiontophoretic application of the heptapeptide suppressed the responses of spontaneously active NRGC neurons to individually delivered nociception or hypertension. Interestingly, the preferential reduction in responsiveness to tail clamp upon simultaneous elevation in arterial pressure was reversed to one that favored nociception in the presence of AIII. These actions of the heptapeptide appeared to be receptor-specific, since they were discernibly blocked by its selective antagonist, Ile7-angiotensin III. Our results reveal that neuropeptides such as AIII may differentially modulate neuronal responsiveness according to the prevailing physiologic input(s) to the central nervous system of the animal.

Interaction between neuronal responses to nociception and hypertension in the nucleus reticularis gigantocellularis of the rat

We evaluated the interactive effects of noxious stimuli and elevation in systemic arterial pressure on the responsiveness of spontaneously active neurons in the nucleus reticularis gigantocellularis (NRGC) of male, adult Sprague-Dawley rats anesthetized with pentobarbital sodium. In NRGC neurons that responded to both nociception (tail clamp) and transient hypertension elicited by phenylephrine (5 μg/kg, i.v.), the responsiveness to tail clamp was reduced upon simultaneous elevation in arterial pressure. This preferential response pattern did not appear to be affected by the level of anesthesia, since it was demonstrated in animals that were maintained by hourly bolus supplements or continuous infusion of pentobarbital sodium. These data offer a feasible cellular explanation for the documented correlation between elevated nociceptive threshold and hypertension. They also showed that NRGC may be a central integrator for the processing of nociceptive and cardiovascular information.

Effect of Intensified Red Blood Cell Aggregability on Arterial Pressure and Mesenteric Microcirculation

Intensified aggregability of red blood cells (RBC) was produced in adult white rats by the step-by-step intravascular administration of a high-molecular-weight dextran, with a molecular weight approximating that of blood fibrinogen. As a result, the systemic arterial pressure was elevated by more than one-third of the initial level, whereas the diameter of arterioles in the intestinal mesentery remained practically unchanged. This provided sufficient grounds for the conclusion that the increase in the total peripheral resistance was due to disturbances in blood rheological properties. Despite the elevated arterial pressure, the blood flow velocity in mesenteric arterioles displayed a clear-cut tendency to slow down. Simultaneously, a large number of RBC aggregates appeared in the mesenteric microvessels. In patients with a stable form of arterial hypertension the RBC aggregability index was found to be significantly increased as compared with that of the healthy control group. Following treatment with Ca 2+- and β-adrenergic blockers the index decreased significantly in parallel with the lowering of arterial pressure. The obtained results suggest that the intensified RBC aggregation in microvessels causing a disturbance of normal blood flow structure, and hence of blood rheological properties, might be an important factor responsible for the elevation of systemic arterial pressure in humans with arterial hypertension.

Calcium and platelets in normotensive and hypertensive human pregnancy

The primary objective of this study was to determine the baseline platelet intracellular free Ca2+ concentration in normotensive and hypertensive primigravid women and to note any correlation between variables (ie. platelet intracellular free Ca2+ concentration and arterial blood pressure). A cross-sectional study of 24 normotensive and 36 primiparous women whose pregnancies were complicated by gestational hypertension, in the third trimester. Platelet intracellular free Ca2+, serum Ca2+, and renal clearance of Ca2+ were recorded. Mean platelet intracellular free Ca2+ concentration was significantly increased in those subjects whose pregnancies were complicated by proteinuric gestational hypertension (pre-eclampsia) compared with the normotensive primiparous control sample. Those subjects with non-proteinuric pregnancy-induced hypertension did not show this significant increase in baseline platelet intracellular free Ca2+ concentration despite having a persistent and statistically significantly elevated systemic arterial blood pressure. On pooling these data for both normotensive and hypertensive primigravidae a significant positive correlation was noted between the variables of platelet intracellular free Ca2+ concentration and arterial blood pressure. The renal clearance of free Ca2+ was progressively reduced with increasing severity of the disease but had returned to normal 6 weeks postpartum. Serum Ca2+ concentrations corrected for albumin were however higher in the hypertensive patients. Transmembrane Ca2+ fluxes are altered in hypertensive pregnancy by a specific mechanism, probably of placental origin.

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.

Neurophysiologic Monitoring of Patients with Head Injuries

Despite new technologic developments designed to analyze the brain's electrical activity, monitoring the electroencephalogram or evoked potentials has not yet provided important information with regard to acute management of patients with head injury. Measurement of cerebral blood flow as well as jugular oxygen saturation is of more practical importance. Particularly when monitored continuously, these measures can provide useful information about the use of hyperventilation and control of elevated systemic arterial pressure.

The Effect of an Increase in Systemic Arterial Pressure in the Newborn with Right Ventricular Hypertension

To evaluate the effect of an elevation in systemic arterial pressure upon pulmonary blood flow and arterial oxygenation during right ventricular hypertension (RVH), we acutely studied 13 1-d-old piglets. Catheters were positioned in the pulmonary artery, both atria, and the aorta for hemodynamic measurements. An electromagnetic probe was positioned in the main pulmonary artery for pulmonary blood flow measurement. Systemic and regional blood flow were measured with the radiolabeled microsphere technique. A balloon-mounted catheter was advanced in the aorta and maintained at the lower thoracic level. After induction of RVH (pulmonary artery banding), a significant decrease in arterial O2 pressure from 54.4 +/- 1.6 to 10.6 +/- 0.4 kPa (p less than 0.01), a 30% reduction in systemic arterial pressure, and a 44% decrease in pulmonary blood flow were observed. During RVH, partial inflation of the aortic balloon to restore the systemic arterial pressure to its initial value led to an increase in arterial O2 pressure to 23.5 +/- 3.1 kPa (p less than 0.01). Full inflation of the balloon further increased the arterial O2 pressure to 32.6 +/- 2.9 kPa (p less than 0.01). Aortic balloon inflation increased pulmonary blood flow in 11 and systemic O2 delivery in nine of the 13 animals. RVH was associated with a significant increase in cerebral and right ventricular myocardial free-wall blood flow and a decrease in renal and bowel blood flow and O2 delivery (p less than 0.01). Aortic balloon inflation during RVH did not change either the cerebral or myocardial free-wall blood flow, but further significantly decreased renal and bowel blood flow and O2 delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension of renal origin

In the early nineteenth century Bright [4] brought attention to the association between renal disease and hypertension. Later in the century, Tigerstedt and Bergmann [39] injected a water-soluble extract derived from the renal cortex of a healthy rabbit, termed renin, into a vein of a second rabbit, producing a marked and sustained hypertension. No further studies on the association of renal disease and hypertension were carried out until Goldblatt et al's [13] classic experiments in the dog in 1934. Goldblatt demonstrated that reversible elevation in systemic arterial pressure could be produced by clamping the main renal artery of one of two healthy kidneys. The blood pressure returned to normal on removal of the kidney or clamp. Taking a cue from Goldblatt's observations, clinicians

Reduction in baroreceptor reflex response by angiotension III and its modification by Ile 7-angiotensin III and bestatin in the rat

We evaluated the participation of endogenous brain angiotensin III (AIII) in central cardiovascular regulation, using the intracerebroventricular injection technique in Sprague-Dawley rats anesthetized with pentobarbital sodium (50 mg/kg, i.p.). AIII (100 pmol) promoted an elevation in systemic arterial pressure and a reduction in the baroreceptor reflex (BRR) response. Its specific antagonist, Ile 7-AIII (100 nmol), and the aminopeptidase inhibitor, bestatin (200 nmol), on the other hand, augmented the response of the same reflex. The suppressive action of AIII (100 pmol) on the BRR was attenuated, and the enhancing effect of Ile 7-AIII (100 nmol) was potentiated, however, when these two peptides were administered simultaneously with bestatin (200 nmol). All these events were significantly different from their controls during the first 10–15 min following injection, parallel to the time course of a discernible action of AIII on systemic arterial pressure. We discussed that the endogenous AIII in the central nervous system may participate in cardiovascular control by tonically inhibiting the BRR, in concert with other brain neuropeptides.

Pressor response to small elevations of cerebroventricular pressure in conscious rats.

Acute relationships between cerebrospinal fluid hydrostatic pressure and arterial pressure were quantified in conscious rats. The rats were catheterized with a left femoral artery catheter, and a double set of catheters was implanted into the third cerebral ventricle. In three groups of rats, artificial cerebrospinal fluid with various sodium concentrations (142, 152, and 162 mM) was infused into the third ventricle for 3 hours at 1.0 microliter/min. Mean arterial pressure (MAP) and third ventricular pressure were monitored simultaneously, and both increased progressively over the 3-hour infusion period; the rate of rise was significantly greater with infusion of the hypertonic solution. There were no significant differences between the rat groups infused with low, normal, or high artificial cerebrospinal fluid sodium in either the slope or the intercept of the regression equation relating cerebrospinal fluid pressure and MAP: a 1 cm H2O rise of cerebrospinal fluid pressure was always associated with nearly a 1 mm Hg rise in MAP. In other rats, changes in both cerebrospinal fluid pressure and MAP were shown to be highly dependent on the rate of ventricular infusion. We conclude that elevations of systemic arterial pressure are associated with only small elevations of cerebrospinal fluid pressure and that physiological changes of cerebrospinal sodium (+/- 10 mM) influence arterial pressure by altering intravascular hydrostatic pressure rather than sodium or osmosensitive receptors in the cerebral ventricles.

Effects of renal receptor activation on neurosecretory vasopressin cells.

Electrical stimulation of afferent renal nerves (ARN) has been shown to excite neurosecretory vasopressin (AVP) cells of the supraoptic nucleus (SON). To investigate the sensory modality of the ARN involved, the present study examined in pentobarbital-anesthetized rats the responses of putative AVP cells to procedures intended to differentially activate renal receptor populations. Neurosecretory SON cells were identified by antidromic invasion from the neurohypophysis and classified as AVP secreting on the basis of spontaneous activity patterns and responses to arterial baroreceptor activation. Neither elevation of systemic arterial pressure (50-100 mmHg, 9 cells) following sinoaortic and cardiopulmonary afferent nerve transection nor renal venous occlusion (15 cells) altered AVP cell discharge. Renal ischemia, produced by renal arterial occlusion (50-120 s, 14 cells), and renal arterial infusion of adenosine (1-50 micrograms, 8 cells) were also without effect. However, infusions into the renal artery of bradykinin (1-3 micrograms) excited 9/15, of capsaicin (1-3 micrograms) excited 13/15, and of sodium cyanide (5-40 micrograms) excited 1/11 AVP cells examined. These data demonstrate that, in the anesthetized rat, putative neurosecretory AVP cells in the SON are responsive to activation of bradykinin- and capsaicin-sensitive renal receptors and suggest that activation of these receptors contributes to the hormonal regulation of the circulation.

Absence of hypertension despite chronic marked elevations in plasma norepinephrine in conscious dogs.

To better define the mechanisms of blood pressure control in states of catecholamine excess, we infused norepinephrine for 28 days using subcutaneously implanted osmotic pumps in dogs previously instrumented for monitoring left ventricular dynamics and cardiac output. Plasma norepinephrine rose from 238 +/- 27 to 4346 +/- 952 pg/ml at 21 days, while epinephrine and dopamine levels did not change. Heart rate fell from 85 +/- 4 to 63 +/- 6 beats/min, while arterial pressure was unchanged from baseline. Total peripheral resistance rose 0.011 +/- 0.003 mm Hg/ml/min from a control value of 0.029 +/- 0.002 mm Hg/ml/min, and cardiac output decreased 1093 +/- 292 ml/min from a baseline level of 3575 +/- 156 ml/min. Since stroke volume did not change, the maintenance of arterial pressure is related to decreases in cardiac output secondary to bradycardia. Buffering mechanisms are responsible for maintenance of systemic arterial pressure because hexamethonium and atropine caused hypertension. Although left ventricular end-diastolic pressure, end-diastolic diameter, shortening, rate of change of pressure, velocity of myocardial shortening, cardiac work, stroke work, and the double product did not change significantly during the study, postmortem examination demonstrated biventricular hypertrophy. Thus, despite markedly elevated catecholamine levels and no elevation of systemic arterial pressure, myocardial hypertrophy developed. These studies lend support to the hypothesis that norepinephrine may be a direct myocardial tropic hormone and suggest that intense activation of reflex buffering mechanisms maintains blood pressure in the normal range during chronic catecholamine infusion.

Coronary artery disease risk factor management in the hypertensive patient

Recent advances in understanding the relation of risk factors to coronary artery disease (CAD) have initiated a change in the approach to managing the hypertensive patient. Reduction of elevated blood pressure still remains a major therapeutic priority. However, the risk of cardiovascular morbidity is also related to hypercholesterolemia, hyperuricemia, hyperglycemia, hyperfibrinogenemia and obesity; all aggravate the risk of CAD in the patient with high blood pressure. Life-style is also important: cigarette smoking, high alcohol consumption and lack of physical exercise all predispose to precocious atheromatous CAD. Thus, the most favorable prognosis in terms of reducing CAD risk is accomplished by reducing elevated systemic arterial pressure while simultaneously improving all other risk factors. The method by which blood pressure is lowered is an important consideration. The ancillary metabolic activities of antihypertensive drugs now available differ widely. Diuretics and β blockers, for example, have potentially adverse metabolic effects, whereas agents such as selective α 1-adrenoceptor inhibitors appear to beneficially affect several metabolic cofactors influencing the CAD risk profile. The impact of such drug-induced metabolic changes on overall prognosis of the hypertensive patient remains to be clarified. In the absence of other contraindications, however, it is sensible to use drugs that do not increase the metabolic predilection to precocious CAD.

Pulmonary edema as a cause for fulminant death following microinjection of kainic acid into the rat medulla oblongata

The present study confirmed histopathologically the suggestion that pulmonary edema may underlie the fulminant death following microinjection of kainic acid into many medullary sites in rats anesthetized with pentobarbital sodium. We also observed a sustained elevation in systemic arterial pressure, cardiac contractility and heart rate before the animal succumbed to kainate neurotoxicity. It is suggested that the increased systemic hydrostatic pressure may retrogradely promote pulmonary hypertension that precipitates pulmonary edema.

Efficacy and safety of sublingual nifedipine in hypertensive emergencies

Hypertensive emergencies are a diverse group of disorders characterized by a marked elevation of systemic arterial pressure that is associated with acute end-organ dysfunction. The efficacy and safety of sublingual nifedipine were evaluated in 16 men and 14 women (mean age 65 ± 14 years) who had hypertensive emergencies. Before treatment, mean systolic blood pressure was 224 ± 23 mm Hg, mean diastolic blood pressure was 125 ± 18 mm Hg, and the average mean arterial pressure was 158 ± 16 mm Hg. Administration of 10 or 20 mg of sublingual nifedipine initiated a smooth and predictable decline in blood pressure values within five minutes and produced a peak effect between 30 and 60 minutes. At 30 minutes, the decreases in the systolic blood pressure, diastolic blood pressure, and mean arterial pressure for the group were 49 ± 24 mm Hg, 31 ± 17 mm Hg, and 39 ± 20 mm Hg, respectively, all of which were highly significant (p <0.001). By 60 minutes, nifedipine had decreased the diastolic blood pressure to less than 120 mm Hg in 97 percent of patients, less than 110 mm Hg in 93 percent, and less than 100 mm Hg in 67 percent. Fourteen patients required other antihypertensive medications within the first 12 hours for the antihypertensive effect to be maintained. In this group, the systolic, diastolic, and mean arterial pressures were significantly lower than baseline values (p <0.001) at the time that the other drugs were started (which occurred at a mean of 4.3 ± 3.2 hours after entry into the study). The response to nifedipine correlated with the blood pressure value prior to treatment, but did not correlate with age, gender, or the type of hypertensive emergency. Twenty mg of nifedipine produced a significantly greater antihypertensive effect than did 10 mg during the first 20 minutes (176 ± 15 mm Hg versus 201 ± 18 mm Hg systolic; p = 0.009) and appeared to be more efficacious clinically. In only two of 30 patients (7 percent) was the blood pressure response considered inadequate, and all 10 patients with pulmonary edema or myocardial ischemia showed clinical improvement within 60 minutes of treatment. In one patient, flushing and another symptom suggestive of transient symptomatic hypotension developed after treatment with nifedipine. These results suggest that sublingual nifedipine is a safe, effective, and practical agent for treating patients with hypertensive emergencies.

Rebound cardiovascular responses following stimulation of canine vagosympathetic complexes or cardiopulmonary nerves.

Electrical stimulation of a canine vagosympathetic complex or a cardiopulmonary nerve can elicit a variety of negative chronotropic and inotropic cardiac responses, with or without alterations in systemic arterial pressure. In the period immediately following cessation of such a stimulation "rebound" tachycardia, increased inotropism above control values in one or more regions of the heart, and (or) elevation in systemic arterial pressure can occur. These "rebound" phenomena are abolished by propranolol or ipsilateral chronic sympathectomy. It is proposed that "vagal" poststimulation "rebound" of the canine cardiovascular system is primarily the result of activation of sympathetic neural elements present in the vagosympathetic complexes or cardiopulmonary nerves.

A canine model of neurogenic pulmonary edema.

The purpose of this study was to evaluate the usefulness of the intracisternal administration of veratrine as a model of neurogenic pulmonary edema (NPE) in the alpha-chloralose-anesthetized dog. Veratrine (40-60 micrograms/kg) was injected into the cisterna magna of 17 animals, and systemic arterial, pulmonary arterial, and left ventricular end-diastolic (LVEDP) pressures were followed for 1 h. Eleven animals developed alveolar edema. In these animals, systemic arterial pressure increased to 273 +/- 9 (SE) Torr, pulmonary arterial pressure to 74.5 +/- 4.9 Torr, and LVEDP to 42.8 +/- 4.5 Torr, and large amounts of pink frothy fluid, with protein concentrations ranging from 48 to 93% of plasma, appeared in the airways. Postmortem extravascular lung water content (Qwl/dQl) averaged 7.30 +/- 0.46 g H2O/g dry lung wt. Six animals escaped developing this massive degree of edema after veratrine (Qwl/dQl = 4.45 +/- 0.24). These animals exhibited similar elevated systemic arterial pressures (268 +/- 15 Torr), but did not develop the degree of pulmonary hypertension (pulmonary arterial pressure = 52.5 +/- 6.7 Torr, LVEDP = 24.8 +/- 4.0 Torr) observed in the other group. These results suggest that both hemodynamic and permeability mechanisms may play a role in the development of this form of edema and that veratrine administration may provide a useful model of NPE.

Baroreflex regulation of hindquarter vascular resistance during acute blood volume expansion.

The baroreflex control of hindquarter vascular resistance in response to a 30% blood volume expansion (BVE) was examined in constant-flow perfused hindlimbs of chloralose-urethan-anesthetized rats. Volume expansion initially increased both systemic arterial pressure (SAP) and central venous pressure (CVP) while decreasing hindquarter vascular resistance. After these initial changes, there was a parallel return of hindquarter-vascular resistance and CVP to pre-expansion levels, suggesting that cardiopulmonary afferents play a major role in the vascular resistance adjustments to volume expansion. This notion was supported in a separate set of experiments in which CVP was elevated selectively while SAP was held constant. This manipulation elicited a decrease in hindquarter vascular resistance, which was significantly attenuated following vagal cardiopulmonary denervation. The return of hindquarter vascular resistance following BVE also occurred in the presence of elevated SAP in rats with vagotomy and aortic nerve denervation, i.e., only the carotid sinus baroreflexes intact, but the time course was much faster compared with preparations with cardiopulmonary receptors intact. No response of hindquarter vascular resistance to BVE was observed in rats with both sinoaortic and cardiopulmonary baroreceptors denervated. These findings suggest that the return of hindquarter vascular resistance following BVE involves a gradual increase in sympathetic outflow to the hindquarters resulting from both a decrease in cardiopulmonary afferent activity and a rapid adaptation of arterial baroreflexes.