Comparison of the antihypertensive effects of carvedilol and metoprolol on resting and exercise blood pressure

The present study was conducted to assess the efficacy and safety of carvedilol 50 mg as compared to metoprolol 200 mg at rest and during and after a standardized bicycle ergometric exercise test. Carvedilol is a novel non-selective -blocker without intrinsic sympathomimetic activity possessing vasodilatory properties primarily due to an ₁-antagonism in the same dose range. Both drugs were effective in reducing systolic and diastolic blood pressure at rest and during and after exercise. The reduction of diastolic blood pressure was much stronger under carvedilol treatment than under metoprolol treatment at all measurement points. Carvedilol was even effective in the treatment of patients whose blood pressure was unsatisfactorily controlled by metoprolol. This shows the importance of the vasodilation component of carvedilol. No serious adverse events were observed. Carvedilol therefore promises very well as a powerful and safe drug for the treatment of essential arterial hypertension.     

Long-term hemodynamic effects of antihypertensive treatment

The cardinal hemodynamic disorder in established essential hypertension is increased total peripheral resistance. During exercise, the increase in stroke volume of the heart is abnormal. A 20-year follow-up study of the hemodynamics in essential hypertension demonstrated a progressive increase in total peripheral resistance and deterioration of the heart pump function. Long-term treatment with antihypertensive agents modifies the circulatory system in different ways. Vasodilators (angiotensin converting enzyme inhibitors, ₁-blockers, and calcium antagonists) all reduce total peripheral resistance, and in general, cardiac output, heart rate, and stroke volume remain unchanged. Calcium antagonists like verapamil and diltiazem reduce the heart rate approximately 10% during exercise, but since stroke volume increases, cardiac output is unchanged. Chronic treatment with conventional -blockers induces a permanent reduction in cardiac output and heart rate during exercise. In contrast, carvedilol — a ₁,₂-blocker with ₁-blocking activity — prevents the immediate increase in total peripheral resistance during acute -blockade. In 19 patients followed by hemodynamic measurements over 6–9 months, blood pressure was well controlled by carvedilol. During exercise, total peripheral resistance decreased 6% (P<0.05), and=" the=" reductions=" in=" heart=" rate=" and=" cardiac=" index=" were=" less=" than=" on=" conventional=">-blockade. Echo-Doppler studies showed a significant reduction in the intraventricular septum of 13%.     

Inhibition of histamine synthesis influences the development of hypertension in spontaneously hypertensive rats

Young (3-week old) and adult (7-week old) spontaneously hypertensive rats (SHR) and normotensive rats (WKY) were treated with -fluoromethylhistidine (-FMH) for 29 and 13 days, respectively. Treatment of SHR and WKY with -FMH led to a pronounced decrease in the histidine decarboxylase activity and in the histamine concentration in all brain areas studied. In adult SHR, the development of hypertension was not influenced by -FMH. In young SHR, -FMH elicited a transient delay in the development of hypertension followed by a short-lasting tendency for increased blood pressure. It is concluded that histaminergic neurons of the brain play, if at all, only a secondary role in the development of hypertension in SHR.This work was supported by the Fonds zur Förderung der wissenschaftlichen Forschung.     

Pharmacological profile of β-adrenoceptor blockers with vasodilating properties, especially carvedilol — rationale for clinical use

The rationale for the combined use of -adrenoceptor antagonists and vasodilators is to improve the efficacy of the antihypertensive therapy and to reduce the incidence of side effects. If suitable coagents are selected and used at appropriate doses, the disadvantages of each separate component (compromised blood flow to individual organs, increase in total peripheral resistance, unfavorable lipid profile for -blockers; stimulation of counter-regulatory mechanisms, retention of water and electrolytes for vasodilators) can be balanced. In addition, the favorable effects of each (reduction in cardiovascular morbidity and mortality for -blockers, and favorable hemodynamic profile for vasodilators) may be used to advantage. Such a treatment rationale can be accomplished by a free combination or by using a dual-acting drug. From the practical point of view, the latter may be preferable. The basic requirement for such a drug is that the two effects are evoked in the same dose range. Carvedilol is a dual-acting drug designed to produce -blockade and vasodilatation in the same dose range. The vasodilatation is mediated predominantly by specific ₁-adrenoceptor blockade; at markedly higher concentrations additional vasodilating actions can be observed. These effects resemble those of Ca²⁺ -antagonistic properties. However, they do not contribute to the acute blood-pressure-lowering activity, but may be responsible for the increased blood flow to some organs. At -blocking doses, carvedilol reduces the total peripheral resistance, and blood flow to the kidneys is preserved. Cardioprotection has been demonstrated in a variety of experimental investigations     

The effects of asphyxia on afferent activity recorded from the cervical vagus in the duck

Summary The rats with chronic renal hypertension caused by constricting one renal artery, exhibit a decrease in the activity of Na–K-ATPase in the outer medulla of the untouched kidney, as compared to this activity in the kidneys of intact normotensive rats and in the untouched kidney of the rats where renal artery constriction did not result in hypertension.There were no differences between the control normotensive Wistar rats and the spontaneously hypertensive rats (SHR) in the prehypertensive and early hypertensive stages (at the age of 6–8 weeks) as far as the activities of Na–K-ATPase and oxidoreductases (SDH and LDH) in the renal cortex, the outer and inner medulla are concerned. The spontaneously hypertensive rats with chronic hypertension had at the age of 16–20 and 27–29 weeks lower activity of Na–K-ATPase, SDH, and LDH in the outer renal medulla than the control normotensive Wistar rats.The experimental results indicate that in chronic arterial hypertension there is a decrease in the activity of Na–K-ATPase, in the outer renal medulla, which suggests a reduction in the resorption capabilities of the ascending Henle's loop with respect to sodium and water.     

Amelioration of established collagen-induced arthritis (CIA) with anti-IL-1

Inflammatory cytokines have been implicated in the pathogenesis of rheumatoid arthritis (RA). To investigate the role of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in arthritic processes we studied the effect of neutralizing antibodies against murine IL-1 and TNF in murine collagen-induced arthritis (CIA). Combined i.p. injection of anti-IL-1 and anti-IL-1 (anti-IL-1,), given before onset of the disease, completely prevented CIA. In contrast, treatment with anti-TNF at this time point only delayed the onset of arthritis. Remarkably, a single injection of anti-IL-1, was also highly effective in suppressing established arthritis, reducing both inflammation and cartilage destruction. Suppression was most pronounced with the combination of anti-IL-1 and , but anti-IL-1 alone also gave significant relief. Specific antibodies against TNF had no effect on established CIA. Of interest, anti-IL-1, treatment started after onset of CIA completely normalized chondrocyte synthetic function, which was highly suppressed in the non-treated group. It is concluded that IL-1 and TNF are important cytokines during the onset of CIA and that IL-1 is the key mediator of inflammation and cartilage damage in established CIA.     

Transport of sulphate in rat jejunal and rat proximal tubular basolateral membrane vesicles

Basolateral membrane vesicles were isolated by a Percoll density gradient centrifugation method from small intestinal and renal proximal tubular epithelial cells. Transport of sulphate across the basolateral membrane was analyzed by measuring the uptake of tracer sulphate.In both membrane preparations, preloading the vesicles with sulphate-or hydroxyl-anions stimulated tracer sulphate uptake (trans-stimulation); an inwardly directed sodium gradient did not stimulate sulphate influx whether in the absence or in the presence of sulphate- or hydroxyl-iontrans-stimulation. Under sulphate trans-stimulation conditions, DIDS (10^–4 mol/l) inhibited sulphate influx.In intestinal membranes, trans-stimulation of sulphate influx was obtained by preloading the vesicles with chloride, in renal membranes by preloading with bicarbonate. Under sulphate trans-stimulation conditions, in intestinal membranes, sulphate influx was strongly inhibited by chloride, in renal membranes, chloride inhibition was absent. Under bicarbonate trans-stimulation conditions, in renal membranes, sulphate transport was inhibited by lactate.It is concluded that small intestinal and renal proximal tubular basolateral membrane vesicles contain a transport mechanism for sulphate that cannot be energized by a sodium gradient. The transport system in small intestinal basolateral membranes seems to be different from that in renal membranes. It is suggested that the observed interaction between inorganic and organic anion transport in renal basolateral membranes is indirect.Abbreviations DIDS 4,4-Diisothiocyano-2,2-disulfonic acid stilbene - DTT dithiothreitol - HEPES N-2-hydroxyethylpiperazine-N-ethanesulfonic acid - MES N-morpholinoethanesulfonic acid - PAH p-aminohippuric acid - PMSF phenylmethylsulfonyl fluoride - SITS 4-acetamido-4-isothiocyanostilbene-2,2-disulfonate - TMA tetramethylammonium - Tris tris(hydroxymethyl)aminomethane     

Influence of central neuronal histamine on the pituitary-adrenocortical activity stimulated by neurotransmitters

The effect of brain neuronal histramine and its receptors on monoaminergic stimulation of the hypothalamic-pituitary-adrenal (HPA) activity, measured indirectly through corticosterone secretion, was investigated in conscious rats. Pretreatment with -fluoromethylhistidine, (-FMH) a histamine synthesis inhibitor, did not markedly affect the increase in serum corticosterone levels induced by intracerebroventricular (icv) injection of muscimol, a GABA_A receptor agonist and noradrenaline, an - and -adrenergic agonist, and slightly diminished the corticosterone response to isoprenaline, a -adrenergic agonist. -FMH totally abolished the increase in serum corticosterone induced by carbachol, a cholinergic muscarinic receptor agonist and significantly diminished the rise in corticosterone levels induced by clonidine, an ₂-adrenergic agent. Pretreatment with the histamine receptor antagonists mepyramine and cimetidine also considerably reduced the carbachol-induced corticosterone response and the response induced by clonidine.These results indicate that brain neuronal histamine is considerably involved in stimulation of the HPA axis by cholinergic muscarinic and ₂-adrenergic agonists, but not by GABA_A and ₁- and -adrenergic agonists.     

Immunoreactivity of the JK-132 monoclonal antibody directed against basement membrane collagen in normal and diabetic glomeruli

The possible involvement of basement membrane-associated collagen (recognized by the monoclonal antibody JK-132) in the evolution of diabetic nephropathy was studied in kidney specimens from seven patients with noninsulin-dependent diabetes mellitus, and its distribution was compared with those of antibodies against 1 to 4 chains of type IV collagen. JK-132, a monoclonal antibody against basement membrane-associated collagen, reacted immunohistochemically exclusively with the mesangial matrix of the glomerular capillary. In contrast, antibodies to the 1 and 2 chains (IV) reacted strongly with mesangial matrix, and less strongly with the glomerular basement membrane (GBM). Antibodies to the 3 and 4 chains (IV) reacted mainly with GBM. In diabetes, JK-132 reacted most extensively with the expanded mesangial matrix, its staining intensity increasing with progression of the diabetic glomerulosclerosis. Antibodies to the 1 and 2 chains (IV) reacted prominently with the expanded mesangial matrix but less strongly with the GBM. Antibodies to the 3 and 4 chains reacted intensely with the thickened GBM. These results suggest that basement membrane-associated collagen differs from 1 to 4 chains of type IV collagen and that basement membrane-associated collagen is a good marker of mesangial expansion in diabetic nephropathy.     

Comparison of the properties of five pox virus strains isolated from monkeys

Summary Five strains of monkey pox viruses were compared with respect to their cultural characteristics in primary and continuous cell cultures and the lesions developed in embryonated eggs and in rabbit skin as well as to their hemagglutinating activity.Four strains (Copenhagen 65-31 65-32 and 7-61) appeared to be similar in their properties. The cytopathogenic effect (CPE) was identical to that induced by vaccinia virus. There was no detectable virus multiplication in an pig kidney cell line (PEK). All four strains produced small, white, compact, hemorrhagic pock-like lesions on the chorioallantoic membrane.The strain 64–7275, isolated from healthy monkeys kidneys, had all properties of variola virus. It multiplied in the PEK cell line with a CPE. The lesions on the CAM were more compact without hemorrhage. In rabbit skin no detectable reaction occurred after infection with this strain.     

Regulation of interleukin-1β and tumor necrosis factor secretion by the human monocytic leukemia cell line,THP-1

Activated macrophages synthesize and release the potent polypeptides, interleukin-1 (IL-1) and tumor necrosis factor (TNF). In an effort to identify the cellular signals which control cytokine production by activated macrophages, we have developed anin vitro model employing the human THP-1 cell line. In the present study, THP-1 cells primed by 1.6 M phorbol 12-myristate-13-acetate (TPA) for 4 hr demonstrated a dose-and time-dependent release of IL-1 and TNF upon activation by 20 g/ml LPS. BSA/anti-BSA-coated latex beads were also a potent stimulus for IL-1 secretion. Moreover, the combination of a suboptimal concentration of LPS (200 ng/ml) plus interferon- (0.03–333 U/ml) greatly enhanced IL-1 production. Resting THP-1 monocytes not primed by TPA did not secrete IL-1 or TNF. These distinct patterns of cytokine production may be related to the developmental stages of macrophage activation.     

Does TNF-α directly increase endothelial cell monolayer permeability?

The effects of dexamethasone (DEX) and methyl ester (l-NAME) on the tumour necrosis factor- (TNF-)-induced increase in permeability of human umbilical vein endothelial cell (HUVEC) monolayer to [¹²⁵I] labelled bovine serum albumin (BSA) were examined. Preincubation of HUVEC monolayers with DEX (1M, 2 h) completely abolished the effect of TNF- (5 ng/ml, 18 h). Administration of DEX 2 h after TNF- also reduced the effect of TNF-, whilel-NAME (5 ng/ml, 1 mM, 18 h) had no significant effect.The observed inhibition of the TNF--induced permeability increase on preincubation with DEX would suggest a role for nitric oxide (NO) in mediating the permeability response. However, this is not confirmed by the experiments withl-NAME. The inhibition caused by DEX administered after TNF- would suggest alternative mechanisms by which DEX may be acting in addition to inhibition of NO synthase induction.     

Mechanism of modulation of single sodium channels from skeletal muscle by the β 1-subunit from rat brain

We studied the molecular mechanism of the rat skeletal muscle -subunit (_I) gating kinetics modulation by the brain ₁-subunit by heterologous expression of single sodium channels from _I and ₁ in Xenopus laevis oocytes. Coexpression of ₁ reduced mean open time at –10 mV to 21% when compared to channels expressed by _I alone. Channels formed by _I exerted multiple openings per depolarization, which occurred in bursts, in contrast to the channels formed by the _I/₁ complex that opened in average only once per depolarizing voltage pulse. Macroscopic current decay (mcd), as evidenced by reconstructed open probability vs. time , was greatly accelerated by ₁, closely resembling mcd of sodium currents from native skeletal muscle. Generally was larger for channels expressed from the pure _I subunit.From our single channel data we conclude that ₁ accelerates the inactivation process of the sodium channel complex.     

The bulbar respiratory centre in the rabbit

In anesthetized rabbits, spirogram and diaphragmatic activity were examined during electrical stimulation of the bulbar lateral reticular formation. The activity of bulbar respiratory neurons was recorded contra-or ipsilaterally to the stimulation site. One volley of repetitive stimuli per breath was delivered during either inspiration or expiration.