Rapid Fall In Blood Pressure Research Articles

Renomedullary exosomes produce antihypertensive effects in reversible two-kidney one-clip renovascular hypertensive mice

The rapid fall in blood pressure following unclipping of the stenotic renal artery in the Goldblatt two-kidney one-clip (2K1C) model of renovascular hypertension is proposed to be due to release of renomedullary vasodepressor lipids, but the mechanism has remained unclear. In this study, we hypothesized that the hypotensive response to unclipping is mediated by exosomes released from the renal medulla. In male C57BL6/J mice made hypertensive by the 2K1C surgery, unclipping of the renal artery after 10 days decreased mean arterial pressure (MAP) by 23 mmHg one hr after unclipping. This effect was accompanied by a 556% increase in the concentration of exosomes in plasma as observed by nanoparticle tracking analysis. Immunohistochemical analysis of exosome markers, CD63 and AnnexinII, showed increased staining in interstitial cells of the inner medulla of stenotic but not contralateral control kidney of clipped 2K1C mice. Treatment with rapamycin, an inducer of exosome release, blunted the hypertensive response to clipping, whereas GW-4869, an exosome biosynthesis inhibitor, prevented both the clipping-induced increase in inner medullary exosome marker staining and the unclipping-induced fall in MAP. Plasma exosomes isolated from unclipped 2K1C mice showed elevated neutral lipid content compared to sham mouse exosomes by flow cytometric analysis after Nile red staining. Exosomes from 2K1C but not sham control mice exerted potent MAP-lowering and diuretic-natriuretic effects in both 2K1C and angiotensin II-infused hypertensive mice. These results are consistent with increased renomedullary synthesis and release of exosomes with elevated antihypertensive neutral lipids in response to increased renal perfusion pressure.

Need for prehospital management of hypertensive peaks

The purpose of the study was to analyze the situations requiring immediate pre-hospital management of high blood pressure cases according to the reason for the SAMU call, the medical history of the patient, the clinical context and the target organ damage. A retrospective study conducted at the SAMU, including 89 patients, during the period from January to December 2016. The inclusion criteria were: A known or non-hypertensive patient with a SAMU call reason including: malaise, headache, loss of consciousness, chest pain, dyspnea or cases of intoxication. The demographic parameters, the reason for calling the SAMU, the clinical examination data, the results of some additional tests and the toxicological assessments based on blood and urine samples, were recorded. A medical history of hypertension was found in 75% of cases. The mean age was 59 years [21–76 years] with a sex ratio M/F = 4.07. The physical examination performed on site showed high blood pressure in 39 cases (44%), heart failure in 11 cases (12%), chest and/or lumbar pain in 18 cases (20%), ischemic stroke in 18 cases (20%) and intoxication in 3 cases (3%). Pre-hospital management as well as transfer to a specialized department were necessary in all cases (cardiology or internal medicine department). In the management of hypertension, it is necessary to rely more on clinical tolerance than on the level of blood pressure to guide treatment. It is necessary to know how to diagnose a true hypertensive emergency associating generally very high blood pressure and a threatening clinical context justifying the use of an immediate treatment whose benefit must be greater than the risks incurred by a rapid fall in blood pressure.

A novel soluble guanylate cyclase activator with reduced risk of hypotension by short-acting vasodilation.

Cinaciguat, a soluble guanylate cyclase (sGC) activator, was under clinical development for use in acute decompensated heart failure (ADHF), but was discontinued due to occurrence of hypotension. We hypothesized that short‐term activation of sGC in ADHF patients would exert a vasodilative effect without hypotension irrespective of disease state, using a novel short‐acting sGC activator, TY‐55002. The objective of this study was to investigate the vasodilation and hemodynamic effects of TY‐55002 in comparison with those of cinaciguat. TY‐55002 and cinaciguat activated both normal and heme‐oxidized sGC in a dose‐dependent manner and caused rapid relaxation of phenylephrine‐contracted rat aorta. However, TY‐55002 had a milder effect than cinaciguat in enhancing the dose‐activity response between normal and oxidized sGC. Therefore, we suggest that the pharmacological effect of TY‐55002 is less subject than cinaciguat to oxidative stress associated with complications such as cardiovascular disease or diabetes. In normal dogs, the effects of intravenous TY‐55002 or cinaciguat on blood pressure were evaluated in conjunction with the plasma concentrations of the compounds, and pharmacokinetic (PK)‐pharmacodynamic (PD) analyses were carried out. The plasma‐to‐effect‐site transfer rate constant (Ke0) for TY‐55002 was three times greater than for cinaciguat. On the other hand, there was a small difference in blood half‐life (T1/2) between the compounds. It is possible that the rapid fall in blood pressure after the initial administration of TY‐55002 and the quick recovery after cessation were due to the pharmacodynamic property of the compound. In heart failure‐model dogs, TY‐55002 and cinaciguat improved the condition to the same degree, and the short‐term action of TY‐55002 was replicated. In conclusion, TY‐55002 is a novel short‐acting sGC activator, which offers the possibility of easy dose management without excessive hypotension. It therefore holds potential to serve as an innovative drug in the pharmacotherapy of ADHF.

Redevelopment of a Rat Specific Rodenticide Norbormide

Norbormide is a rat specific toxicant. It causes vasoconstriction of small arteries and vasodilation of large arteries in rats, which results in a rapid fall in blood pressure and death from heart failure. It is an extraordinary compound in that it is only toxic to rats. The lack of toxicity of this compound to birds and other mammals is unique. It was originally researched in the 1960s and initially marketed in the USA. Problems with taste aversion slowed its continued use and sales it and was largely forgotten when anticoagulant rodenticides became more effective and popular. Following the emergence of anticoagulant resistance in some populations of rodents, residues of the second-generation anticoagulants in wildlife and concerns regarding humaneness, interest in non-anticoagulants, such as norbormide, has revived. Research has been conducted to help identify and understand a formulation of norbormide which is palatable, effective, and fast acting in rats. Further research is underway to determine methods for large scale synthesis of an improved form of norbormide. Field trials are planned in 2018/19. The ability to target rats with no risk to non-target species presents considerable advantages in many settings and warrants further investment and completion of the current scale-up phase of research and development.

Delayed orthostatic hypotension: A pilot study from India

Introduction:Orthostatic hypotension is defined as a sustained decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing compared with blood pressure from the sitting or supine position or by head-up tilt-table testing (1). When sustained blood pressure (BP) drop is after three minutes of upright posture it is called delayed orthostatic hypotension (delayed OH) (2).Aim of the Study:To detect the incidence of delayed orthostatic hypotension in patients referred to our autonomic lab.Materials and Method:BP was measured noninvasively at 1-minute intervals with an automated cuff sphygmomanometer over the right brachial artery for 45 minutes. The onset and duration of falls in blood pressure either systolic or diastolic or both were documented, and any associated symptoms were recorded. Only patients with sustained falls in BP were included. Drugs causing OH was stopped 48 hours before testing as per protocol followed in lab. We also looked into other autonomic function test abnormalities in patients with delayed OH.Inclusion criteria:Patients above age of 18 years referred for evaluation of autonomic function tests.Exclusion criteria:Patients with severe cardiac failure and cardiac arrhythmias were excluded and patients with rapid fall in BP and bradycardia (Neurally mediated syncope) were excluded.Results:Total 170 patients underwent tilt table testing. Orthostatic hypotension was seen within 3 minutes in seventy patients, fifty patients had delayed OH (BP fall after 3 minutes). There were twenty seven males and twenty three females in this group. Twenty nine of the 50 patients with delayed orthostatic hypotension, had symptoms during the tilt table procedure. Asymptomatic OH was more common in patients who developed OH after 10 minutes.Conclusion:This is a pilot study, first in India where we looked into the incidence of delayed orthostatic hypotension in patients undergoing tilt table testing in our autonomic lab. We found that fifty patients had delayed orthostatic hypotension which could have been missed on clinical evaluation. High clinical suspicion is needed to detect this disorder and tilt table testing should be done in suspicious cases since orthostatic hypotension is cause of high morbidity.

Activation of 5HT1A receptors in the nucleus tractus solitarius contributes to blood pressure compensation with blood loss and peripheral chemoreflex responses in the presence of acidosis

Caudal serotonin neurons and the 5‐HT1A receptor ( 1AR) agonist, 8‐OH‐DPAT, promote sympathetic‐mediated increases in cardiac output after blood loss. We hypothesize that the metabolic acidosis of hemorrhage activates serotonin neurons and 1AR in the nucleus tractus solitarius (NTS) to facilitate chemoreflex responses to carotid body hypoxia. Here, we tested ventilatory responses to hypoxic hypercapnia (10% O2, 5% CO2) and blood pressure responses to hemorrhage and subsequent 8‐OH‐DPAT administration in rats subjected to bilateral knockdown of the 1AR in the NTS. An adeno‐associated viral vector harboring a short hairpin RNA targeting the rat 1AR (1ARshRNA) or a scrambled shRNA (Scram) was injected into the caudal NTS of male Sprague Dawley rats. After 4 weeks, rats injected with the 1AshRNA (n=12) had lower cumulative minute ventilation during hypoxic hypercapnia vs. Scram‐injected rats (n=13, P<0.01). Rats injected with 1AshRNA (n=8) had a more rapid fall in blood pressure with blood loss and an attenuated blood pressure response to 8‐OH‐DPAT injection (30 nmol/kg, iv, P<0.01) vs. Scram‐injected rats (n=9). 1AshRNA injection decreased 1AR protein in the caudal NTS (−35%, P<0.05). Thus, the beneficial hemodynamic effect of 8‐OH‐DPAT and endogenous serotonin in hemorrhage is related to activation of 1AR in the NTS and possibly to facilitation of chemoreflex responses to hypoxia. Funded by AHA 10PRE4000023.

Temporal profile of arginine vasopressin release from the neurohypophysis in response to hypertonic saline and hypotension measured using a fluorescent fusion protein

Methods currently employed to study the release of hormones such as arginine vasopressin (AVP), while sensitive, suffer from a low temporal resolution such that the monitoring of AVP release on a moment-to-moment basis is not possible. Here, we describe a new approach to indirectly monitor the temporal profile of AVP release from the neurohypophysis of transgenic rats expressing an AVP-eGFP fusion gene. Using fibre-optic probes (termed ‘optrodes’) we were able to indirectly monitor AVP release via a reporter moiety in real-time. This method is a major advance over current methods used to monitor AVP release. Intravenous administration of hypertonic saline (3M NaCl) induced a rapid (latency of 2–3s) increase in fluorescence detected in the neurohypophysis that lasted on average for 60s – a response that was highly reproducible. Infusion of sodium nitroprusside induced a rapid fall in blood pressure accompanied by a rapid, stimulus-locked increase in fluorescent signal that returned to baseline with the recovery of blood pressure to pre-stimulus levels – again this response was highly reproducible. Withdrawal of blood (to simulate haemorrhage) also resulted in a stimulus-locked increase in fluorescence that return to baseline after the withdrawn blood was returned to the animal. In conclusion, we developed a highly sensitive approach that allows the indirect measurement of AVP release via the monitoring of a reporter gene in real-time. This technology can be adapted to permit the study of a whole array of neurohormones/chemicals in transgenic animals expressing a fluorescent reporter construct.

Impaired dynamic cerebral autoregulation during isometric exercise in patients with type 2 diabetes

Studies have shown that cerebral autoregulation (CA) is well maintained during physical activity in healthy adults. Whether type 2 diabetes (T2D) influences cerebral vascular control during exercise is currently unknown. This becomes an important question considering the associated vascular complications of diabetes. Thus, in six T2D patients (58±2 yrs) and four age matched controls (56±4 yrs) middle cerebral artery blood velocity, arterial blood pressure (BP), and end-tidal carbon dioxide (ETCO2) were measured at rest and during 2 min bouts of moderate (MEx) and high (HEx) intensity isometric handgrip performed at 20% and 40% maximum voluntary contraction, respectively. To estimate dynamic CA, the rate of regulation (RoR) was calculated from the change in cerebral vascular conductance during the rapid fall in BP following bilateral thigh cuff release performed at rest and 30s prior to the cessation of handgrip. The reduction in BP after cuff release was similar between groups and conditions (P>0.05). During MEx, the RoR was not significantly different from rest in T2D or controls. In contrast, although well maintained in controls during HEx, the RoR was reduced by 32±4% from rest in T2D patients (0.376±0.020/s rest vs. 0.256±0.019/s HEx; P<0.01). ETCO2 was unchanged throughout in both groups. These preliminary findings suggest that type 2 diabetes impairs dynamic CA during high intensity isometric exercise.

Syncope du rire spasmodique. Une complication inhabituelle du syndrome pseudobulbaire

Introduction Spasmodic laughter is a classical sign of pseudobulbar palsy, but it has never been reported, to our knowledge, to provoke syncope. Case report A 63-year-old hypertensive and diabetic man with peripheral neuropathy and lacunar pseudobulbar palsy presented with three episodes of spasmodic laughter which had induced syncope. No new episode was observed after the beginning of low dose bisoprolol. Discussion Sustained or spasmodic laughter is accompanied by repetitive bursts of forced expiration, corresponding to short repetitive Valsalva maneuvers. Laughter-induced syncope is considered as one of the many Valsalva-type/vagally mediated syncopal attacks leading to rapid fall in blood pressure without compensatory tachycardia. The presence of autonomic diabetic neuropathy may also contribute to these attacks.

Severe hypoxia and renal sympathetic nerve activity in the preterm fetus

Low systemic blood flow occurs in the first day of life in one third of infants born before 30 weeks gestation, and is highly associated with impaired renal function. Although the mechanisms are poorly understood it is suggested that impaired perfusion is mediated by increased vascular resistance, and is associated with hypoxia. In preterm fetal sheep (103 days; term 147 days) we examined the hypothesis that increased renal sympathetic nerve activity (RSNA) is the primary mediator of increased renal vascular resistance (RVR) during and after severe hypoxia. During hypoxia, the initial increase in RVR was maximal after 4 min, then failed. In parallel with RVR changes, RSNA recorded using an adapted telemetry system (Telemetry Research Ltd), initially increased then became suppressed. This fall in RSNA corresponded closely with the start of a rapid fall in blood pressure, strongly suggesting fetal compromise. During recovery from hypoxia, there was a delayed increase in RVR. This increase was tightly correlated with a secondary increase in RSNA. These findings indicate, for the first time, that failure of RSNA is likely to mediate the fall in RVR during severe hypoxia, and that after hypoxia increased RSNA is likely to mediate renal hypoperfusion. These findings improve our understanding of the mechanisms which may underlie renal impairment in the preterm neonate. Supported by the Health Research Council of New Zealand.

Control Of Cutaneous Vascular Conductance During Presyncope In The Heat Stressed Human

Pronounced reductions in peripheral vascular resistance occur upon the onset of presyncope during orthostatic stress. This response contributes to the rapid fall in blood pressure associated with presyncopal symptoms. During pronounced orthostatic stress in the heat stressed individuals, cutaneous vascular conductance (CVC) remains above pre-heat stress baseline. It is unknown whether CVC increases at presyncope during combined heat and orthostatic stress. PURPOSE This project tested the hypothesis that CVC increases during orthostatic-induced presyncope in heat stressed individuals. METHODS Five healthy subjects experienced presyncope during lower body negative pressure while heat stressed (via water perfused suit). Forearm skin blood flow (SkBF), arterial blood pressure (catheterization of brachial artery), and heart rate (HR) were continuously measured. CVC was calculated from the ratio SkBF and mean arterial pressure (MAP) 1 min prior to presyncope and at presyncope. RESULTS Heat stress significantly increased skin and internal temperatures, CVC, and HR, without changing MAP. At presyncope HR (82±18 to 65±12 bpm; P=0.02) and MAP (71±11 to 54±4 mmHg; P=0.05) were reduced relative to the period prior to presyncope. However, there was no difference in CVC between these time points (0.88±0.22 to 0.91±0.31 AU/mmHg; P=0.81) despite a decrease in SkBF (62.3±16.2 to 48.6±15.2 AU; p < 0.01). CONCLUSIONS These finding do not support the hypothesis that CVC increases during presyncope, thereby suggesting that cutaneous vascular responses do not contribute to the reduction in blood pressure during vasovagal syncope in heat stressed subjects. Work supported by NIH HL67422 and HL61388

Control Of Cutaneous Vascular Conductance During Presyncope In The Heat Stressed Human

Pronounced reductions in peripheral vascular resistance occur upon the onset of presyncope during orthostatic stress. This response contributes to the rapid fall in blood pressure associated with presyncopal symptoms. During pronounced orthostatic stress in the heat stressed individuals, cutaneous vascular conductance (CVC) remains above pre-heat stress baseline. It is unknown whether CVC increases at presyncope during combined heat and orthostatic stress. PURPOSE This project tested the hypothesis that CVC increases during orthostatic-induced presyncope in heat stressed individuals. METHODS Five healthy subjects experienced presyncope during lower body negative pressure while heat stressed (via water perfused suit). Forearm skin blood flow (SkBF), arterial blood pressure (catheterization of brachial artery), and heart rate (HR) were continuously measured. CVC was calculated from the ratio SkBF and mean arterial pressure (MAP) 1 min prior to presyncope and at presyncope. RESULTS Heat stress significantly increased skin and internal temperatures, CVC, and HR, without changing MAP. At presyncope HR (82±18 to 65±12 bpm; P=0.02) and MAP (71±11 to 54±4 mmHg; P=0.05) were reduced relative to the period prior to presyncope. However, there was no difference in CVC between these time points (0.88±0.22 to 0.91±0.31 AU/mmHg; P=0.81) despite a decrease in SkBF (62.3±16.2 to 48.6±15.2 AU; p < 0.01). CONCLUSIONS These finding do not support the hypothesis that CVC increases during presyncope, thereby suggesting that cutaneous vascular responses do not contribute to the reduction in blood pressure during vasovagal syncope in heat stressed subjects. Work supported by NIH HL67422 and HL61388

Clinical relevance of the Bezold-Jarisch reflex.

THE idea that reflexes originating in the heart can play a role in normal physiology dates to the 1860s. Until the 1950s, these reflexes, and the Bezold–Jarisch reflex (BJR) in particular, were regarded largely as pharmacological curiosities with the only practical application of the study of the BJR being the clinical use of a veratrum alkaloid as an antihypertensive agent. Since the 1860s, it had been known that injection of minute amounts (0.005 mg) of veratrine or its pure alkaloid components (veratrum) initiates a reflex which causes a rapid fall in blood pressure and heart rate in association with apnea. This “Von Bezold reflex” was classically defined in association with arrest of breathing, but more recently, it has been called the BJR and includes the triad of bradycardia, hypotension, and peripheral vasodilation. It is now understood that certain inhibitory reflexes, which have origin with cardiac sensory receptors, play a role in cardiovascular homeostasis. Activation of a subset of these receptors by diverse stimuli increases parasympathetic nervous system activity, inhibits sympathetic activity and is responsible for eliciting the BJR. Some anesthesiologists have suggested that the BJR may explain cardiovascular collapse reported during regional anesthesia techniques. This review focuses on the physiology of the BJR and its possible physiologic role in a number of clinical situations. It also provides discussion of the limited relevance of this reflex in regional anesthesia. The topic of clinical management will not be addressed given the paucity of data on this matter, but suggestions for future experimental direction are offered.

Continuous cardiac baroreceptor measurement during tilt in healthy elderly subjects.

Abnormalities of cardiac baroreceptor sensitivity (BRS) may contribute towards the high prevalence of orthostatic hypotension and falls in the elderly. Most mathematical analyses used to determine BRS in the time or frequency domains assume a stationary physiological state and cannot be performed under dynamic change and therefore are not valid during tilt. We describe a new method of estimating BRS during tilt. Twenty-five healthy elderly volunteers with a mean age of 69 +/- 3 years underwent head-up tilt to 70 degrees, within 5 s, 3 times on 2 separate visits. Blood pressure (BP) and heart rate were recorded continuously using a Finapres beat-to-beat BP monitor and surface ECG. A continuous estimate of BRS was obtained by combining beat-to-beat linear regression with Legendre polynomial interpolation. The values for supine BRS prior to tilt on the two visits, calculated using the new regression method (10.4 +/- 8.2 ms/mmHg and 12.5 +/- 9.7 ms/mmHg) were similar to those using fast Fourier analysis (10.7 +/- 6.7 ms/mmHg and 12.4 +/- 7.1 ms/mmHg). A rapid fall in BP and pulse interval along with cardiac BRS values occurred with tilt within the first 20 s of onset on both visits and remained reduced up to 90 s post tilt (p < 0.01). The values for cardiac BRS obtained using continuous time domain analysis agree well with those calculated using spectral methods and can be used to assess the dynamic changes in BRS to rapid perturbations in BP such as that occur with tilt.

Solving the Microgram/Kilogram Puzzle

ou work as a critical care nurse in a university teaching facility, and this evening you're moonlighting at a local community hospital. During your CCU shift here, Alexander Schmitt, age 43 and weighing 220 lbs. (100 kg), is admitted from the ED with a diagnosis of acute anterior wall myocardial infarction. In the ED, his EKG showed acute S-T elevation in leads V2 through V4. The ED nurse had initiated streptokinase by physician order; a heparin bolus of 5,000 units, a heparin drip at 1,000 units/hr, and a nitroglycerin drip at 10 mcg/min were ordered as well. Mr. Schmitt also received one baby aspirin and 15 mg metoprolol. You assess his vital signs: BP, 101/58 mmHg; P, 102 beats per minute; R, 20 per minute; and T, 98.4oE Mr. Schmitt rates his chest pain at about 5 or 6 on a 1-to-10 scale. You note that the nitroglycerin drip (50 mg/250 cc) is infusing at 50 cc/hr, and the heparin drip (25,000 units/250 cc) at 10 cc/hr. You're familiar with different concentrations of nitroglycerin in your own hospital, where the drug is available in the manufacturer's premixed bags. You realize that here you'll need to check the calculations for the nitroglycerin dose and rate. Per the physician's orders, you administer morphine sulfate 2 mg Iv to relieve Mr. Schmitt's pain. Moments later, he rates his chest pain at only 1 or 2. At the nurses' station, you check the order and begin calculating the dose and rate of nitroglycerin. Within minutes, Mr. Schmitt calls your name; something's wrong, he says. His vital signs have changed: Blood pressure is 92/54 mmHg; pulse is 110 beats per minute; respirations are 22 per minute. You auscultate his heart and lungs and hear an S3 and crackles in all lung fields. Mr. Schmitt stops talking to you mid-sentence-his level of consciousness is decreasing. Blood pressure has now dropped to 88/40 mmHg; pulse has risen to 120 beats per minute; respirations are 24 per minute. You immediately stop the nitroglycerin drip and call to the physician in charge. She orders a dopamine drip (400 mg/250 cc) at 5 mcg/kg/min, or 19 cc/hr. Mr. Schmitt's vital signs begin to improve, and the physician orders resumption of the nitroglycerin drip at 10 mcg/min (3 cc/hr). Your immediate discontinuation of nitroglycerin probably saved Mr. Schmitt's life. He showed signs of acute heart failure, and his MI may have been extending. Inaccurate calculation of the drip rate-50 cc/hr was far too high for this concentration-resulted in a nitroglycerin overdose, precipitating a rapid fall in blood pressure and acute cardiac symptoms. Vasoactive medications are usually administered as micrograms per kilogram of body weight per minute. It's important to carefully calculate the dosage at the beginning of a shift and to check any drips already infusing.

Anesthesia for Liver Transplantation

Advances in surgical and anesthetic techniques have provided great success in liver transplantation, with more than 4,000 liver transplantations performed annu ally in the United States. Indications for transplanta tions include the various forms of cirrhosis, commonly resulting from hepatitis B or C, alcoholism, or acute hepatic failure from drug toxicity or poisoning. Cadav eric donor livers are resected and may be transplanted up to 24 hours later while the recipient is prepared for surgery. These operations may last 10 hours and require large amounts of blood products. Extrahepatic prob lems from their end-stage liver disease are common and affect nearly all organ systems. Intraoperative monitor ing of acid-base status, electrolytes, intravascular vol ume, and coagulation parameters is essential. Preexist ing coagulopathies from liver disease, complications of massive transfusions and fibrinolysis from the new liver create complex coagulation disturbances requiring prompt diagnosis and treatment. Metabolic (lactic) aci dosis is common and severe. Reperfusion of the donor liver can result in a dramatic and rapid fall in blood pressure as well as hyperkalemia.

Clinical relevance of 24 h blood pressure control by 1,4-dihydropyridines

Plasma drug concentration and hemodynamic responses to dihydropyridines correlate closely. Differences in pharmacokinetic profile lead therefore to marked differences in blood pressure (BP) control over 24 h and sympathetic tone and side effects, and also appear to determine effects on left ventricular hypertrophy (LVH) and outcome in patients with coronary artery disease (CAD). Fast-absorbed and short-acting agents (eg, nifedipine capsules) cause intermittent control of BP with rapid decreases in BP after each dose. This rapid fall in BP causes, after each dose, an increase in sympathetic activity, which over subsequent hours gradually disappears. In contrast, long-acting formulations, such as nifedipine gastrointestinal therapeutic system (GITS), or agents with a long elimination half-life, such as amlodipine, provide, during long-term treatment, stable hemodynamic and BP effects with little or no activation of the sympathetic nervous system. Intermittent hemodynamic responses and the resulting sympathetic hyperactivity with the rapid-acting agents are possible explanations for outcome of treatment as it relates to regression of LVH and cardiac events in patients with CAD.

L-Canavanine restores blood pressure in a rat model of endotoxic shock

Administration of lipopolysaccharide to anaesthetised rats produced a reduction in mean arterial pressure, an increase in heart rate, and death at 4–6 h. Intravenous infusion of N G -nitro- L-arginine methyl ester (50 mg/kg), an inhibitor of constitutive and inducible nitric oxide (NO) synthase, 60 min after challenge with lipopolysaccharide, caused an immediate increase in blood pressure followed by a precipitous fall in pressure, and death. In contrast, intravenous infusion of L-canavanine (100 mg/kg), reported to be a selective inhibitor of inducible NO synthase in vitro, 60 min and 180 min after lipopolysaccharide challenge, produced an increase in mean arterial pressure and reversed the lipopolysaccharide induced hypotension. However, in lipopolysaccharide challenged animals protected from hypotension by administration of L-canavanine (60 min post challenge), intravenous infusion of N G-nitro- L-arginine methyl ester at 180 min post challenge caused an immediate rise in mean arterial pressure, followed by a rapid fall in blood pressure and heart rate, and sudden death. In contrast, a second dose of L-canavanine at 180 min post challenge maintained blood pressure for the duration of the experiment. These findings indicate that inhibition of both constitutive and inducible NO synthase during endotoxaemia is lethal. However, the use of a selective inhibitor of inducible NO synthase restores mean arterial pressure to baseline, and offers a therapeutic approach to managing hypotension in shock.

Sublingual Captopril and Nifedipine in Immediate Treatment of Hypertensive Emergencies

<h3>To the Editor.—</h3> In their article in the April 1991 issue of theArchives, Angeli et al¹compared the efficacy of sublingual captopril and nifedipine in immediate treatment of hypertensive emergencies. The authors imply that the sublingual route is the optimal means of orally administering nifedipine in hypertensive emergencies. However, a few studies have shown that nifedipine is poorly absorbed through the oral mucosa,²and, thus, the efficacy of sublingual nifedipine may be attributed to its ultimate gastric absorption. The bite-and-swallow method is the most efficacious route of administering nifedipine orally. The authors also state that there is general medical consensus that prompt control of blood pressure is required in hypertensive emergencies. The fact is that while sublingual nifedipine produces a rapid fall in blood pressure within 5 to 10 minutes,³it can also cause symptomatic hypotension in the acute treatment of severe hypertension.⁴Cerebral infarction

Management of hypertensive emergencies: Changing therapeutic options

Rapid lowering of severe hypertension is essential to prevent irreversible damage to vital organs. The patient's clinical status should be evaluated, noting particularly cardiac, neurologic, and renal functions. Choice of treatment should be based on speed and efficacy of action and on hemodynamic, vascular, and renal consequences. It is also important to preserve circulatory homeostasis and vital organ function. Sodium nitroprusside, labetalol, diazoxide, and hydralazine have been used parenterally for rapid control of severe hypertension, but they do not always produce optimal, balanced hemodynamic effects. Calcium antogonists have been advocated because of their beneficial circulatory effects. Nicardipine, a new dihydropyridine calcium antagonist, produces significant antihypertensive effects, and when given intravenously, results in a rapid fall in blood pressure. Studies have confirmed that nicardipine is effective and safe in the management of severe hypertension and hypertensive crises. Because the aim of rapidly controlling severe hypertension is to prevent target organ dysfunction, nicardipine therapy offers a useful additional option in the clinical management of severe hypertension and hypertensive crises.