Evidence for central reorganization of ventilatory chemoreflex pathways in the cat during regeneration of visceral afferents in the carotid sinus nerve

There are two sets of peripheral arterial chemoreceptors in the cat, the carotid bodies innervated by the carotid sinus nerve and the aortic bodies with afferents in the aortic depressor nerves. Reflex stimulation of ventilation in response to hypoxia is abolished acutely after interrupting the sensory pathway from the carotid body chemoreceptors in the cat even though the reflex pathway from the aortic body chemoreceptors is intact. However, in chronically maintained preparations, there is a restoration of the hypoxic response which is mediated by the aortic chemoreflex pathway. It was proposed that restoration was due to a ‘central reorganization’ of chemoreflex pathways which followed interruption of the sensory pathway from the carotid bodies and that the reorganization enhanced the efficacy of the aortic ventilation chemoreflex. This proposal was tested in the present experiments by measuring reflex ventilatory and cardiovascular responses to electrical stimulation of the sensory nerves containing aortic and carotid chemoreceptor afferents following bilateral interruption of carotid sinus nerves and carotid body resection. Responses measured acutely (1–6 h) after interruption were compared with those measured 60–80 and 110–140 days later. At 60–80 days, a chemoreflex response (increase in tidal volume of ventilation) to stimulation of the interrupted carotid sinus sensory pathway was markedly attenuated while the response to stimulation of the uninterrupted pathway in aortic depressor nerves was enhanced. At 110–140 days, the tidal volume response to carotid sinus nerve stimulation was greatly enhanced while the aortic depressor nerve response declined from the elevated level. There were significant but less pronounced changes in the response of other ventilatory and cardiovascular variables to aortic depressor nerve and carotid sinus nerve stimulation.The results support the idea that there is a ‘central reorganization’ of chemoreflex pathways which is reflected functionally by changes in the efficacy of reflexes evoked from aortic depressor nerve and carotid sinus nerve. The changes are analagous to those occurring in somatic reflexes during regeneration of sensory nerves. It is suggested that the changes in efficacy of carotid sinus nerve reflexes are due to a degenerative loss of synapses of the central projections of interrupted carotid sinus nerve sensory axons (degenerative atrophy) and subsequent regenerative like changes (regenerative proliferation) in the central projections. The changes in the efficacy of aortic depressor nerve reflexes may be attributed to formation of new synapses by converging central projections of this uninterrupted pathway (reactive synaptogenesis) and subsequent regression of the newly formed synapses.     

The thrombin inhibitor argatroban does not influence the endothelium-dependent relaxant and contractile responses of isolated rabbit carotid arteries

Atherosclerotic endothelial dysfunctions are associated with a reduced NO production, which is probably due to impaired NO synthase (eNOS) activity or a deficiency of the substrate L-arginine. In the present studies, the influence of argatroban on isolated rabbit carotid arteries was investigated to determine whether the arginine derivative argatroban can improve the endothelium-dependent relaxation.

Rings from rabbit carotid arteries were placed in 10 ml organ baths for isometric tension recording. Endothelial integrity was assessed by the acetylcholine-induced relaxation of PGF₂-precontracted rings; after mechanical removal of the endothelium the relaxation was abolished. Preincubation of the vessels in vitro with L-NAME, an inhibitor of the eNOS, diminished significantly the acetylcholine-induced relaxation by more than 50%. After i.v. application of L-NAME (100 mg/kg) in rabbits, relaxation in response to acetylcholine was significantly reduced compared to the control when the vessels were studied ex vivo in an organ bath. The contractile effects of phenylephrine and 5-HT were slightly enhanced.

Argatroban is a selective, potent, synthetic thrombin inhibitor; after i.v. application at doses of 0.5 and 1.0 mg/kg, a significant prolongation of the plasma coagulation time (measured as thrombin time and a PTT) of up to 60 min was found in rabbits.

In vitro argatroban did not affect the acetylcholine-induced relaxation or the contractile response to phenylephrine and 5-HT. After i.v. application, the ex vivo experiments in the organ bath showed that after 30 min the relaxant responses of the carotid arteries to acetylcholine and the contractile effects of phenylephrine and 5-HT were not influenced by pretreatment with argatroban. The present studies suggest that argatroban has no vascular effects in vitro and ex vivo in normal rabbits.     

Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers

Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.     

Lack of association of the common TaqIB polymorphism in the cholesteryl ester transfer protein gene with angiographically assessed coronary atherosclerosis

The anti-atherogenic effect of cholesteryl ester transfer protein (CETP) genetic variants associated with lowered enzyme activity is controversial. Moreover, in a few studies, this effect has been evaluated in the presence of a certain risk factor constellation. We addressed this issue in a case-control study, where 415 subjects with angiographically documented coronary artery disease (CAD +), 397 subjects without CAD (in 215, CAD was excluded by coronarography (CAD-)), and 188 healthy population controls, were screened for the CETP TaqIB polymorphism. The prevalence of the low-activity TaqIB2 allele was 0.396 in CAD+, and 0.428 and 0.416 in CAD- and population controls, respectively (p = 0.40). Its presence was significantly associated with increased high-density lipoprotein cholesterol (HDL-C) in population controls (1.40 +/- 0.40 mmol/l in B1B1, 1.52 +/- 0.39 mmol/l in B1B2 and 1.58 + 0.46 mmol/l in B2B2; p < 0.03 for trend), but not in the other groups. The CETP TaqIB polymorphism accounted for < 1% of the HDL-C variance in the whole cohort (p = 0.048). After adjustment for other risk factors, the CETP TaqIB2 allele was found not to be associated with significant changes in CAD risk independently of an assumed either dominant (odds ratio (OR) 0.97; 95% confidence interval (CI) 0.66-1.44; p = 0.89) or recessive effect (OR 0.68; 95% CI 0.42-1.12; p = 0.13). The CETP TaqIB polymorphism did not show a significant interaction with other risk factors in influencing CAD risk. Our findings do not support the hypothesis that a genetic variant resulting in lowered CETP activity is associated with reduced risk of coronary atherosclerosis.     

Endothelial Regulation of Vascular Repair: Role of bFGF in Paracrine Pathways

Vascular repair following injury is mediated by both endothelial and smooth muscle cells often through paracrine pathways. Basic fibroblast growth factor (bFGF) is present at sites of vascular injury. The role of bFGF in regulating reendothelialization through an effect on centrosome redistribution in cell migration is discussed. The role of bFGF in neointimal formation, especially as it relates to smooth muscle cell proliferation, is reviewed. It is concluded that bFGF appears to be an important agent regulating the early responses of the artery wall to injury. Presented in part at the Molecular Endocrine Pathology Symposium at the International Academy of Pathology XXI International Congress, Budapest, Hungary, October 20–25, 1996.     

B cells and atherosclerosis in systemic lupus erythematosus

Introduction: Cardiovascular (CV) events, as a result of accelerated atherosclerosis, are an important cause of mortality in patients with Systemic lupus erythematosus (SLE). The etiology of SLE is multifactorial and still unclear; among other potential culprits, excessive B cell activation seems to play a crucial role. Accumulating evidence supports a contributory role of B cells in the pathogenesis of atherosclerosis as well.

Areas covered: This article focuses on the contribution of both B cells and autoantibodies in the pathogenesis of atherosclerosis in both general and lupus populations. Review of the published literature on experimental models has also been performed.

Expert opinion: Distinct B cell subsets seem to exhibit separate effects on the progression of atherosclerosis, with B2 B cells displaying a mainly atherogenic phenotype, while B1 B cells are mostly viewed as atheroprotective. Selective B2 inhibition by anti-B cell therapies seems a promising therapeutic strategy against atherosclerosis development in the setting of lupus.     

Growth hormone effect on accumulation of arterial basement membrane-like material studied on rabbit aortic myomedial cell cultures

Summary The effect of human growth hormone on arterial basement membrane-like (BM) material was studied. BM-like material was obtained from the cell layer of cultured aortic myomedial cells using a sonication-differential centrifugation technique. After the addition of small amounts of growth hormone (1 ng/ml) to the cultures, we observed a 26% increased incorporation of amino acids into BM-like material (2p<0.005). However, further increase in the incorporation was not observed using either 3 ng or 10 ng growth hormone per ml. Growth hormone inhibited removal/degradation of BM-like material by 16% (2p<0.01). However, pinocytosis rate and activity of major lysosomal enzymes: cathepsin D, acid phosphatase and -N-acetyl-glucosaminidase were unchanged. Incorporation of glycosaminoglycans as evaluated by [³⁵SO₄]-labelling was reduced by 8% when cells were exposed to growth hormone (2p<0.01). The present study demonstrates an effect of growth hormone on the turnover and composition of BM-like material in cultured arterial myomedial cells.     

Prognostic value of early somatosensory evoked potentials during carotid surgery: Relationship with electroencephalogram,stump pressure and clinical outcome

Summary The authors have reported on the prognostic value of continuous monitoring of somatosensory evoked potentials (SEP) in a survey of 25 patients who underwent carotid surgery. SEP recordings were correlated with the EEG, stump pressure (SP) values and clinical outcome. A non-cephalic reference was used for SEP recordings to allow the analysis of both subcortical and cortical components. During surgery the conduction time between SEP peaks relating to the subcortical components remained stable or showed minimum variations in all patients. During carotid clamping, SEP variations were observed in 9 out of 25 cases (36%). The application of an intraluminal shunt was accompanied by the return to normal values in 7 out of 9 patients. In the remaining two cases SEP abnormalities continued post-operatively and were accompanied by new neurological deficits. EEG changes during carotid clamping were associated with SEP modifications in 6 out of 7 cases, although they were not always correlated. Results confirm that SEP recordings provide useful data concerning the function of the CNS in anaesthetized patients and that, being sensitive to CBF changes, SEP monitoring acts as an indicator of cerebral ischaemia.Presented in part at the Third International Evoked Potentials Symposium, Berlin-West, September 28th–October 1st, 1986.