Endothelium-derived relaxing factor (EDRF) and nitric oxide (NO). II. Physiology, pharmacology and pathophysiological implications.
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Arteriosclerosis↗
Biomedical subjects
T Hedner
Publications and source records attributed to T Hedner.
Endothelium-derived relaxing factor (EDRF) and nitric oxide (NO). I. Physiology, pharmacology and pathophysiological implications.
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Animals↗
Cardiovascular effects of irindalone, a new S2-serotonergic antagonist, in the rat.
Irindalone is a new antihypertensive agent with affinity to serotonin (5-HT2) receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative importance of the antagonism of central and peripheral alpha 1- and 5-HT2-receptors in the blood pressure lowering properties or irindalone after acute administration. In conscious Sprague-Dawley rats intravenous irindalone (0.05-1.5 mg/kg) dose-dependently reduced the blood pressure. In the same dose-range irindalone antagonized pressor responses to phenylephrine and electrical stimulation of the spinal sympathetic outflow (SNS) in the pithed rats, indicating that the acute blood pressure lowering effect is primarily related to the blockade of alpha 1-adrenoceptors. However, the concomitant 5-HT2-receptor blockade may contribute since irindalone in a dose (0.15 mg/kg) where it had no alpha-adrenoceptor blocking properties enhanced the hypotensive response to selective alpha 1-adrenoceptor blockade by prazosin (1 micrograms/kg). We found no evidence that central mechanisms contributed to the blood pressure lowering effect of irindalone. In anaesthetized rats irindalone (1 mg/kg) did not reduce the directly recorded sympathetic nerve activity. Intracerebroventricular administration of irindalone in conscious rats (10-100 micrograms) had no consistent effects on the blood pressure and did not enhance the hypotensive response to intracerebroventricularly administered prazosin (10 micrograms). Finally, the hypotensive response to irindalone was not influenced by depletion of central serotonin stores (by PCPA). It is concluded that the blood pressure lowering effect of irindalone following acute administration is related primarily to blockade of peripheral alpha-adrenoceptors but that the concomitant blockade of 5-HT2-receptors may contribute.
Animals↗
Local effects of substance P on respiratory regulation in the rat medulla oblongata.
The effect of substance P (SP) and the SP antagonist [D-Pro2,D-Trp7,9]-SP on basal ventilation was investigated in halothane-anesthetized rats. Microinjections of SP (0.4-1.5 nmol) into the ventrolateral medulla oblongata (VLM), (nuclei gigantocellularis, facialis, ambiguus, and reticularis lateralis) or into the dorsomedial medulla oblongata (DM, nucleus tractus solitarius) and its ventral surroundings dose dependently increased tidal volume (VT) and/or minute ventilation. In sensitive areas, the ventilatory stimulation was initiated within minutes, peaked around 8-10 min, and slowly returned to normal over 30-45 min after the injection. In the VLM sites, the increase in VT was generally accompanied by a decrease in respiratory frequency (f), whereas in the DM, f increased in parallel with VT. Furthermore, within the VLM, the respiratory response patterns differed with the definite location of the SP injection. A shortening of inspiratory time was observed in the ventromedial part, the ventrolateral portion of the nucleus paragigantocellularis and ventral to the nucleus facialis. In contrast, a lengthening of expiratory time was seen when SP was injected or applied more laterally along the ventral portion of nucleus facialis and near or directly on the ventral medullary surface. Application of [D-Pro2, D-Trp7,9]SP before or after SP completely antagonized the excitatory effects of SP on ventilation. The SP antagonist administered into the VLM decreased the ventilatory response to hypoxic breathing but caused no change during hyperoxic conditions.
Animals↗
Substance P in the ventrolateral medulla oblongata regulates ventilatory responses.
Local injection of substance P (SP) into the ventral portion of the nucleus gigantocellularis, nucleus reticularis lateralis, and nucleus retrofacialis of the ventrolateral medulla oblongata (VLM) or direct application on the ventral surface of the medulla oblongata caused marked stimulation of tidal volume (VT) and/or minute ventilation (VE). The ventilatory response to hypoxia was significantly blunted after SP in the VLM but not in the dorsal medulla oblongata (DM) (nucleus tractus solitarius). The SP antagonist [D-Pro2,D-Trp7,9]SP almost completely inhibited this response when applied locally to a wide area of the superficial layer of the VLM but not of the DM. Unilateral or bilateral application of 0.3-1.5 nmol of the SP antagonist in the VLM (corpus trapezoideum and the caudal region extending from the rootlets of the nucleus hypoglossus to the first cervical segment) markedly attenuated the response to a 5% CO2 inhalation. The inhibition of the CO2 response was seen after [D-Pro2,D-Trp7,9]SP in the rostral areas of the medulla oblongata corresponding to the corpus trapezoideum and the caudal region extending from the rootlets of the nucleus hypoglossus to the first cervical segment of the cervical cord. Electric somatosensory-induced ventilatory stimulation could be depressed by approximately 70% by [D-Pro2,D-Trp7,9]SP locally applied on the surface of the VLM. We conclude that SP is involved in the hypoxic, hypercapnic, and somatosensory ventilatory responses in the rat. However, these respiratory reflexes are mediated via different neuronal pools in the medulla oblongata, mainly the VLM.
Animals↗
Local application of somatostatin in the rat ventrolateral brain medulla induces apnea.
Local injections of the tetradecapeptide somatostatin (SOM) into the brain stem region were performed in anesthetized and decerebrate rats. SOM administration (0.6-1.8 nmol) into the nucleus paragigantocellularis and the nucleus reticularis lateralis of the ventrolateral medulla oblongata induced ventilatory depression and apnea. The occurrence of apnea was dose dependent and attributed to the anesthetic depth, and it was seen within 60-240 s after injection. In anesthetized rats the apnea was seen as a termination or a continuous decrease in tidal volume while respiratory frequency remained unaltered. SOM-induced apnea was caused by depression of central inspiratory drive. SOM injections into the dorsal medulla were ineffective in eliciting apnea, although a ventilatory depression but no apnea was induced in the awake unanesthetized state. In addition to its effect on basal ventilation, SOM administration in the ventrolateral medulla resulted in a blunted ventilatory response to hypoxic and hypercapnic stimuli in anesthetized rats. We conclude that SOM has potent inhibitory effects on respiration that are specifically located in the nucleus paragigantocellularis and the nucleus reticularis lateralis.
Animals↗
Effects of intravenous terbutaline on maternal circulation and fetal heart activity.
The effects of terbutaline on maternal circulation and fetal heart activity were studied in 15 healthy pregnant women admitted for external cephalic version. The two-step infusion of terbutaline (5-10 micrograms/min) resulted in increases in maternal heart rate (p less than 0.001), cardiac output (p less than 0.001), systolic arterial pressure (p less than 0.001) and pulse pressure (p less than 0.001), while diastolic arterial pressure (p less than 0.001) and total peripheral vascular resistance (p less than 0.001) were reduced. Mean arterial pressure was unchanged after the infusion. Fetal heart activity assessed by cardiotocography showed a gradual increase in baseline fetal heart rate (p less than 0.01) and an increased percentage acceleration time (p less than 0.05). Fetal movements also increased during the infusion (p less than 0.05). The terbutaline infusion had a positive inotropic effect and produced decreased systemic vascular resistance in the pregnant woman, and placental transfer of the drug resulted in increased fetal heart activity. The potential influence of the drug-induced changes in maternal hemodynamics on utero-placental perfusion require further investigation.
Adult↗
Renal and hemodynamic effects of isradipine in essential hypertension.
Twenty-three men with essential hypertension participated in a double-blind placebo-controlled study with a crossover design to evaluate the long-term (nine weeks) effects of isradipine on central and renal hemodynamics. Isradipine as monotherapy was titrated from 2.5 to 5 and then to 7.5 mg twice daily. At the end of the crossover periods, cardiac output (dye-dilution) and intraarterial blood pressure were assessed. Compared with placebo, isradipine reduced ambulatory blood pressure from 174/104 to 154/91 (p less than 0.001), whereas the heart rate was unchanged. The reduction of blood pressure was entirely due to a reduction (36 percent; p less than 0.001) of the peripheral resistance. The baroreceptor sensitivity did not change (RR intervals during infusion of phenylephrine) but, with isradipine, the setpoint was shifted to lower blood pressure levels. Renal plasma flow (para-amino hippurate clearance) increased (465 versus 391 ml/minute; p less than 0.05), but glomerular filtration rate ([51Cr]ethylenediaminetetraacetic acid clearance) did not change. Hence, the filtration fraction decreased. With isradipine, there was a post-dose increase in natriuresis (0.45 to 0.34 mmol/minute; p = 0.06). Side effects were mild.
Antihypertensive Agents↗
Blood pressure control and haemodynamic adaptation with the dihydropyridine calcium antagonist isradipine: a controlled study in middle-aged hypertensive men.
Twenty-three middle-aged men (59 +/- 2 years) with sustained, essential hypertension (WHO Stage II) and with diastolic blood pressure exceeding 100 mmHg during a run-in placebo month were included in a trial designed to assess the clinical and haemodynamic effects of isradipine, a novel dihydropyridine calcium antagonist. The study was double-blind with a placebo-controlled crossover design. Isradipine as monotherapy was titrated in three, 3-week periods in doses of 2.5, 5 and 7.5 mg twice daily, or as apparently identical placebo capsules. A 3-week placebo wash-out period separated the two phases of the study. Clinical characteristics were followed during each treatment phase and an invasive haemodynamic examination was performed on the last day of the final active or placebo dose. In the haemodynamic investigation, cardiac output was measured using a dye-dilution technique and blood pressure via a catheter in the brachial artery. Plasma renin activity (PRA) was assessed by radio-immunoassay of generated angiotensin I and arterial noradrenaline concentrations using high-performance liquid chromatography (HPLC). Baroreceptor sensitivity was calculated from R-R intervals of the ECG and beat-to-beat systolic blood pressure during increasing bolus injections of phenylephrine. During optimal therapy with isradipine (7.5 mg twice daily), highly significant decreases in supine systolic (from 174 +/- 4 to 154 +/- 3 mmHg) and diastolic blood pressures (from 104 +/- 2 to 91 +/- 1 mmHg) were observed. Heart rate was unchanged (79 +/- 3 versus 81 +/- 2 beats/min) during chronic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Atrial natriuretic peptide (ANP) in relation to blood pressure: a study in middle-aged men with normal and elevated blood pressure.
In order to investigate the potential role of atrial natriuretic peptide (ANP) in mild to moderate essential hypertension, a study was conducted in groups of normotensive and hypertensive middle-aged men born in 1926 and 1927. Venous plasma concentrations of immunoreactive ANP (irANP) were studied in relation to measurements of cardiac structure and function, urinary electrolytes as well as some cardiovascular hormones. Plasma irANP did not differ between normotensive controls (31 +/- 14 pmol l-1) and borderline or untreated hypertensive patients. However, irANP concentrations were slightly but significantly (P less than 0.05) lower in the borderline (26 +/- 8 pmol l-1) compared to the untreated established hypertensives (35 +/- 14 pmol l-1). No relationships were found between irANP and blood pressure, indices of left ventricular structure and function or hormone parameters in subgroups or the whole study group. Our data do not support the view that plasma irANP is increased in uncomplicated essential hypertension, since our groups of borderline or established hypertensive middle-aged men without major cardiac involvement did not differ in irANP concentrations compared to normotensive controls. Thus, during the development or in the early stages of essential hypertension, ANP secretion does not seem to be abnormal.
Antihypertensive Agents↗
Central sympathoinhibitory effect of ketanserin in the spontaneously hypertensive rat.
The sympathoinhibitory effects of ketanserin were investigated in the spontaneously hypertensive rat. In conscious rats ketanserin (0.1-10.0 mg/kg intravenously caused dose-related reductions in blood pressure and heart rate (carotid artery). The heart rate reduction was prevented by chemical sympathectomy (reserpine) and in anaesthetized rats the heart rate reduction was correlated to a reduction in the directly recorded preganglionic sympathetic activity in the left renal nerve. Ketanserin had no presynaptic effects on the sympathetic nerve terminals as evidenced by the lack of effect on the tachycardia induced by electrical stimulation of the sympathetic outflow in pithed rats. In rats, catecholamine-depleted by reserpine, the heart rate reduction was prevented, and in atropine-pretreated animals there was a partial blockade of the bradycardic effect. We conclude that the lack of reflexogenic tachycardia in response to the hypotension induced by ketanserin treatment is partly due to a preganglionic inhibition of sympathetic nerve activity.
Animals↗
Relationship between renal sympathetic activity and diuretic effects of atrial natriuretic peptide (ANP) in the rat.
The effects of various adrenergic agonists and antagonists on the diuretic/natriuretic effects of rANP (103-125) were investigated in conscious and anaesthetized normotensive rats. Pharmacological sympathetic inhibition by reserpine completely inhibited the diuretic/natriuretic effects of ANP. However, surgical renal nerve denervation did not influence the renal response to ANP. Further studies using various pharmacological agents which interfere with adrenergic activity revealed that the diuretic mechanism of action differed between conscious and anaesthetized animals. In the anaesthetized group only, dopamine (D1) blockade reduced ANP-induced diuresis. In the conscious as well as anaesthetized rats, however, pre-synaptic dopamine (D2) stimulation and alpha 2-adrenergic receptor blockade effectively inhibited the renal response to ANP. The results of this study are compatible with the notion that ANP acts indirectly within the kidney via interaction with dopamine-containing neuronal or non-neuronal structures in the kidney.
Adrenergic alpha-Agonists↗
Renal interaction between sympathetic activity and ANP in rats with chronic ischaemic heart failure.
The diuretic and natriuretic effects of r-alpha-ANP (99-126) were investigated in rats with chronic ischaemic heart failure (IHF) produced by left coronary artery ligation. The plasma concentration of immunoreactive ANP (IrANP) was significantly higher, 91.8 +/- 16.0 pm in the IHF rats compared to 31.0 +/- 4.9 pm in sham-operated controls. In the control rats, ANP infusion (0.25-1.0 micrograms kg 1 mm 1) increased urine flow rate (V) and urinary sodium (UNa V) excretion. At the highest dose level, both V and UNa V were increased approximately fivefold. The diuresis and natriuresis seen in the control group after the infusion of ANP were blunted in the IHF rats. A bilateral surgical renal denervation in the IHF rats did not alter the renal dopamine levels, but induced a significant decrease in renal noradrenaline content, and almost completely restored the renal responsiveness to the ANP infusions. We conclude that renal denervation reversed the blunted renal excretory response to ANP in IHF rats. Thus, in experimental IHF, there seems to be a functional antagonism between efferent renal sympathetic nerve activity and ANP.
Animals↗
Cerebrospinal fluid concentrations of neurotensin and corticotropin-releasing factor in pediatric patients.
Cerebrospinal fluid (CSF) concentrations of neurotensin (NT) and corticotropin-releasing hormone (CRF)-like immunoreactive materials (LIM) were measured in 22 infants and children 6 days to 15 years of age. For both neuropeptides there was a marked age-related exponential decline in CSF concentrations. The most prominent decrease in CSF neuropeptide concentrations was seen during the first 24 months of postnatal life. From 1 year and on there was no or only minimal age-associated alteration in CSF neuropeptide concentrations. In this group of children (1-15 years) mean CSF concentrations of NT-LIM and CRF-LIM were 36.8 +/- 4.32 and 65.9 +/- 4.63 pg/ml, respectively. As CSF neuropeptide concentrations are apparently independent of circulating serum concentrations, they may reflect functional activity of neuropeptide-containing neurons and therefore may be of value in the assessment of the role of peptides in the human central nervous system function and behavior.
Adolescent↗
CSF and plasma pharmacokinetics of pethidine and norpethidine in man after epidural and intrathecal administration of pethidine.
The disposition of pethidine and its main metabolite, norpethidine, in cerebrospinal fluid (CSF) and plasma was studied in 11 thoracic surgery patients after lumbar epidural (100 mg; n = 6) or lumbar intrathecal (25 mg; n = 5) administration of pethidine. Pethidine appeared more slowly in plasma after intrathecal than after epidural administration (tmax 2.3 h and 14 min, respectively), but systemic bioavailability was similar. The CSF concentrations of pethidine were higher than those in plasma after both routes of administration. The maximal CSF/plasma concentration ratio was 6000 to 45,000 after intrathecal administration but was only 26 to 97 after the epidural route. Pethidine was rapidly distributed in CSF; nine to ten h after the intrathecal and epidural injections the CSF/plasma concentration ratios were 12 to 89 and 2 to 33, respectively. The calculated bioavailability in CSF of epidural pethidine was 10.3%. The terminal elimination half-life of pethidine was 6.0 h (CSF) and 5.4 h (plasma) after intrathecal administration and 8.6 h (CSF) and 8.8 h (plasma) after epidural injection. The volume of distribution of unchanged pethidine in the subarachnoid space was 13 ml.kg-1 and clearance from the CSF was 15 microliters.kg-1.min-1. In all patients receiving intrathecal pethidine and in some patients after epidural pethidine, CSF norpethidine concentrations were higher than those in plasma; the maximum CSF norpethidine was 102 to 1211 ng.ml-1 and 14 to 210 ng.ml-1 and the maximum CSF/plasma norpethidine concentration ratios were 21 to 652 and 0.6 to 14 times after intrathecal and epidural administration, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Female↗
Atrial natriuretic peptide and catecholamines in peripheral blood as indicators of cardiac dysfunction in the general population.
1. From a screened cohort of 644 67-year-old men, drawn from the population of Gothenburg, 42 men with presumed cardiac dyspnoea were selected and compared with 45 random controls. 2. Cardiac function was evaluated by echocardiography and other non-invasive methods, and the potential of peripheral venous concentrations of immunoreactive atrial natriuretic peptide (IrANP), noradrenaline and adrenaline in revealing cardiac dysfunction was investigated. 3. Concentrations of venous IrANP and noradrenaline were both significantly, but weakly, related to the degree of dyspnoea and to pulmonary congestion. 4. IrANP, but not catecholamines, was also related to other indices of heart failure. The correlations were, however, due solely to increased immunoreactivity in men with severe dyspnoea; in most subjects with mild to moderate dyspnoea the level of IrANP was similar to that of the controls. 5. It is concluded that, in a population sample, the peripheral venous level of IrANP is more closely related to cardiac function than are catecholamines. Yet, the level of IrANP is not a very sensitive marker of cardiac dysfunction, suggesting that stimulation of alpha-human atrial natriuretic peptide release is a late phenomenon in the development of cardiac failure.
Aged↗
Effects of a new serotonin antagonist, ketanserin, in experimental and clinical hypertension.
Ketanserin is an agent whose main pharmacologic action is antagonism of serotonin (5-hydroxytryptamine, 5HT) receptors of the 5HT2 subtype. It also has weak alpha 1-adrenergic blocking properties, which may contribute to the acute blood pressure lowering effects seen in animal models of hypertension. During chronic treatment of hypertension in animals, the 5HT2 antagonistic properties, or a combination of 5HT2 and alpha 1-antagonistic effects, seems to be responsible for ketanserin's hypotensive action. Studies of patients with hypertension have demonstrated the therapeutic effects of ketanserin in monotherapy and combination therapy. In humans, the drug has a terminal half-life of 12-25 hours, and a twice daily dosage will lower blood pressure over the day. Ketanserin is a vasodilator that acts on both resistance and capacitance vessels. Chronic treatment with the drug causes minimal reflex changes in cardiovascular function, as well as sustained blood pressure reduction comparable with the effects of beta-adrenergic blockers or diuretics. In elderly patients, the therapeutic effects of ketanserin appear to be greater, and side effects are less frequent compared with beta-blockers and diuretics. In addition to its antihypertensive action, ketanserin also produces other effects that may be important in reducing cardiovascular morbidity and mortality in patients with hypertension. Some studies have shown a reduction in total and low-density lipoprotein (LDL) cholesterol, and a rise in high-density lipoprotein (HDL) cholesterol. Ketanserin also reduces ex vivo platelet aggregation and inhibits the serotonin-induced platelet release reaction. Worldwide experience with ketanserin in the treatment of hypertension indicates that it is a safe and effective agent for long-term therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Topical anesthesia with lidocaine aerosol in the control of postoperative pain.
Postoperative pain was assessed in patients undergoing inguinal hernia repair. Ten patients received lidocaine aerosol in the surgical wound before skin closure, ten patients received placebo aerosol devoid of lidocaine, and ten patients were untreated. The lidocaine-treated group had significantly lower pain scores and meperidine requirements during the first postoperative day compared to the control groups. During the second day after surgery, these variables did not differ between groups. Wound anesthesia, assessed by palpation of the wound 24 h after surgery by a blinded investigator, was significantly more pronounced in the group treated with lidocaine aerosol than in the control groups. Similarly, in patients undergoing bilateral herniorraphy, wound pain following palpation was significantly reduced on the lidocaine-treated side compared to the untreated side. Patients in the group receiving lidocaine aerosol indicated less pain in connection with mobilization than untreated patients, but not compared to patients treated with placebo aerosol. Plasma substance P (SP) and beta-endorphin (BE) measured in lidocaine-treated patients and in untreated patients before and after drug administration showed no significant differences regarding SP, while BE was significantly increased 1 h after surgery in the untreated group. Plasma lidocaine concentrations were well below toxic levels. Results show that lidocaine aerosol used as topical anesthetic in the surgical wound is simple to use, and results in a long-lasting reduction of pain after a single administration. Moreover, postoperative mobilization is facilitated, and the requirement for postoperative analgesics is reduced. Wound healing was normal, and no adverse reactions to lidocaine were reported.
Adult↗