Contrasting seasonality of the incidence of incisional surgical site infection after general and gastroenterological surgery: an analysis of 8436 patients in a single institute.

BACKGROUND: While seasonality of hospital-acquired infections, including incisional SSI after orthopaedic surgery, is recognized, the seasonality of incisional SSI after general and gastroenterological surgeries remains unclear. AIM: To analyse the seasonality and risk factors of incisional SSI after general and gastroenterological surgeries. METHODS: This was a retrospective, single-institute, observational study using univariate and multivariate analyses. The evaluated variables included age, sex, surgical approach, surgical urgency, operation time, wound classification, and the American Society of Anesthesiologists physical status (ASA-PS). FINDINGS: A total of 8436 patients were enrolled. General surgeries (N = 2241) showed a pronounced SSI incidence in summer (3.9%; odds ratio (OR): 1.87; 95% confidence interval (CI): 1.05-3.27; P = 0.025) compared to other seasons (2.1%). Conversely, gastroenterological surgeries (N = 6195) showed a higher incidence in winter (8.3%; OR: 1.38; 95% CI: 1.10-1.73; P = 0.005) than in other seasons (6.1%). Summer for general surgery (OR: 1.90; 95% CI: 1.12-3.24; P = 0.018) and winter for gastroenterological surgery (1.46; 1.17-1.82; P = 0.001) emerged as independent risk factors for incisional SSI. Open surgery (OR: 2.72; 95% CI: 1.73-4.29; P < 0.001) and an ASA-PS score ≥3 (1.64; 1.08-2.50; P = 0.021) were independent risk factors for incisional SSI in patients undergoing gastroenterological surgery during winter. CONCLUSION: Seasonality exists in the incisional SSI incidence following general and gastroenterological surgeries. Recognizing these trends may help enhance preventive strategies, highlighting the elevated risk in summer for general surgery and in winter for gastroenterological surgery.

Development of new osteonecrosis in systemic lupus erythematosus patients in association with long-term corticosteroid therapy after disease recurrence.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients are at high risk of developing osteonecrosis, as they require corticosteroid therapy for life. The purpose of this study was to use periodic MRI analysis to clarify (1) the incidence of new osteonecrosis associated with long-term corticosteroid therapy in SLE patients, and (2) the risk factors for delayed osteonecrosis in SLE patients. METHODS: We prospectively studied 291 joints (134 hips and 157 knees) in 106 SLE patients without osteonecrosis after initial corticosteroid therapy, with a mean follow-up period of 13.6 years and a follow-up rate of 71%. All patients had undergone periodic MRI examination of the hip and knee joints for >10 years. RESULTS: New osteonecrosis developed in 6 joints (3%) and only occurred after SLE recurrence in association with increased corticosteroid doses (to>30 mg/day [p=0.008]). New lesions were delayed for a mean 5.9 years after initial corticosteroid administration. The mean time from SLE recurrence to appearance of new lesions was 6.2 months. SLE recurrence occurred in 131 joints (45%), while SLE was well controlled in 160 joints (55%). CONCLUSIONS: We suggest that with respect to long-term effects, total cumulative dose and duration of corticosteroid therapy do not contribute to osteonecrosis. However, SLE recurrence is a risk factor for new osteonecrosis. We recommend MRI screening for osteonecrosis at SLE recurrence.

Effect of progesterone on recovery from nerve injury during leg lengthening in rats.

We investigated the effect of progesterone on the nerve during lengthening of the limb in rats. The sciatic nerves of rats were elongated by leg lengthening for ten days at 3 mm per day. On alternate days between the day after the operation and nerve dissection, the progesterone-treated group received subcutaneous injections of 1 mg progesterone in sesame oil and the control group received oil only. On the fifth, tenth and 17th day, the sciatic nerves were excised at the midpoint of the femur and the mRNA expression level of myelin protein P0 was analysed by quantitative real time polymerase chain reaction. On day 52 nodal length was examined by electron microscopy, followed by an examination of the compound muscle action potential (C-MAP) amplitude and the motor conduction velocity (MCV) of the tibial nerve on days 17 and 52. The P0 (a major myelin glycoprotein) mRNA expression level in the progesterone-treated group increased by 46.6% and 38.7% on days five and ten, respectively. On day 52, the nodal length in the progesterone-treated group was smaller than that in the control group, and the MCV of the progesterone-treated group had been restored to normal. Progesterone might accelerate the restoration of demyelination caused by nerve elongation by activating myelin synthesis.

Increase in tumor vascular area due to increased blood flow by angiotensin II in rats.

For further elucidation of the microhemodynamics in tumor tissue, the "vascular level," percentage of the vascular area to tissue area, was measured in DONRYU rats. Changes in the vascular level due to angiotensin II were analyzed by a point-counting method in normal and tumor tissues within a rat transparent chamber. The vascular level in normal subcutis changed from 21.8 to 18.6% when the mean arterial pressure was elevated from 102.3 to 155.9 mmHg. The coefficient of change due to angiotensin II was 0.85. The vascular level in tumor tissue was distributed inhomogeneously from 0 to 48.5% with an average of 19.7%. It increased to 33.9% (range: 8.7-57.6%) with an elevation of the mean arterial blood pressure from 103.5 to 150.8 mmHg. The coefficient of change due to angiotensin II was 2.08 in tumor tissue. Moreover, the tumor vascular level increased at a higher rate in the areas with a lower vascular level.

A new approach to cancer chemotherapy: selective enhancement of tumor blood flow with angiotensin II.

Elevation of the mean arterial blood pressure to approximately 150 mmHg by infusion of angiotensin II resulted in an approximate 5.7-fold selective increase in blood flow in tumor tissue without increasing blood flow in normal tissue. This finding of no autoregulation of blood flow in tumor tissue was made in an experiment on inbred DONRYU rats with sc transplanted AH109A solid tumors (Yoshida ascites hepatoma). Changes in tissue blood flow were measured by a thermoelectrical method. In another experiment in which DONRYU rats with sc transplanted AH272 solid tumors were used, the chemotherapeutic effect of mitomycin C on main tumors and lymph node metastatic foci was markedly enhanced in rats with angiotensin-induced hypertension, as compared to its effect in rats without angiotensin-induced hypertension. Thus a new approach to cancer chemotherapy has been demonstrated in which the delivery to tumor tissue of systemically administered anticancer drugs can be selectively enhanced.

Role of dephosphorylation in accumulation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate in human lymphoblastic cell lines with reference to their drug sensitivity.

After a 3-day exposure to 0.1 microM 1-beta-D-arabinofuranosylcytosine (ara-C) in culture, growth was inhibited to 5.6% in MOLT-4F, 25% in Raji, and 91% in Daudi cells compared with control. Growth inhibition was more profound when exposure time was extended up to 7 days. Inhibition of DNA synthesis varied with sensitivity to ara-C. Plateau levels of intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were 35.5, 13.4, and 3.6 nmol/10(9) cells exposed to 0.1 microM ara-C in MOLT-4F, Raji, and Daudi cells, respectively, corresponding to the sensitivity to ara-C. The nucleotide levels at the plateau, however, did not correspond to the initial levels of the ara-CTP or to the calculated rate of ara-CTP synthesis, which decreased from Raji to MOLT-4F to Daudi cells. ara-C deamination had negligible effect on the differential accumulation of ara-CTP. ara-CTP degradation due to dephosphorylation was marked in Raji and Daudi cells but slight in MOLT-4F cells. The half-life of intracellular ara-CTP was 204, 26.4, 31.1 min in MOLT-4F, Raji, and Daudi cells, respectively. The ara-CTP level was considered to be maintained bimodally by synthesis and degradation of the nucleotide. This conclusion was supported by the fact that, in Raji and Daudi cells exposed to 0.1 microM ara-C in the presence of 1 mM hydroxyurea, the plateau levels of ara-CTP increased 3-fold through inhibition of the nucleotide degradation. Thus, not only ara-C phosphorylation but also subsequent ara-CTP dephosphorylation was important in the accumulation and maintenance of ara-CTP and in the sensitivity to ara-C.

Molecular cloning, expression, and site-directed mutations of oxidosqualene cyclase from Cephalosporium caerulens.

A cDNA for oxidosqualene:lanosterol cyclase (OSLC) was cloned and sequenced from the fungus Cephalosporium caerulens, that produces a steroidal antibiotic, helvolic acid. A 2280 bp open reading frame encoded an M(r) 87078 protein with 760 amino acids. The cDNA was functionally expressed in the OSLC-deficient mutant GIL77 strain of Saccharomyces cerevisiae. A truncated recombinant enzyme (Delta49N) starting from the second methionine (M50) residue was completely inactive, suggesting that ca. 30 additional hydrophilic amino acid residues at the N-terminal are essential for the folding of the enzyme. Furthermore, the active site residues, H234 and D456 (numbering in S. cerevisiae OSLC), were chosen for site-directed mutagenesis experiments; H234E, H234Y, H234F, D456E, D456N, and D456H mutants were inactive, while H234W and H234K mutants retained lanosterol-forming activity.

The binding site for an inhibitor of squalene:hopene cyclase determined using photoaffinity labeling and molecular modeling.

BACKGROUND: The squalene:hopene cyclases (SHCs) are bacterial enzymes that convert squalene into hopanoids, a function analogous to the action of oxidosqualene cyclases (OSCs) in eukaryotic steroid and triterpenoid biosynthesis. We have identified the binding site for a selective, potent, photoactivatable inhibitor of an SHC. RESULTS: SHC from Alicyclobacillus acidocaldarius was specifically labeled by [3H]Ro48-8071, a benzophenone-containing hypocholesteremic drug. Edman degradation of a peptide fragment of covalently modified SHC confirmed that Ala44 was specifically modified. Molecular modeling, using X-ray-derived protein coordinates and a single point constraint for the inhibitor, suggested several geometries by which Ro48-8071 could occupy the active site. CONCLUSIONS: A covalent complex of a potent inhibitor with a squalene cyclase has been characterized. The amino acid modification and molecular modeling suggest that Ro48-8071 binds at the junction between the central cavity and substrate entry channel, therefore inhibiting access of the substrate to the active site.

Role of metabotropic glutamate receptors in ventrolateral medulla of hypertensive rats.

Evidence is accumulating for the role of metabotropic, as well as ionotropic, glutamate receptors in cardiovascular regulation. We sought to determine whether stimulation of metabotropic glutamate receptors in the rostral ventrolateral medulla would evoke enhanced cardiovascular responses in spontaneously hypertensive rats (SHR). Thus, we microinjected (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], a selective agonist of metabotropic glutamate receptors, into the rostral ventrolateral medulla of urethane-anesthetized adult SHR and age-matched Wistar-Kyoto (WKY) rats. Microinjection of (1S,3R)-ACPD (1 nmol/50 nL) produced increases in mean arterial pressure and splanchnic sympathetic nerve activity in SHR (+41 +/- 6 mm Hg and +34 +/- 4%, respectively) that were significantly greater than those observed in WKY rats (+18 +/- 3 mm Hg and +22 +/- 3%, P < .005 and P < .05, respectively). The pressor responses evoked by microinjection of L-glutamate (2 nmol), N-methyl-D-aspartate (20 pmol), or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (5 pmol) were also significantly (P < .001) augmented in SHR (+55 +/- 3, +61 +/- 7, and +53 +/- 5 mm Hg, respectively, in SHR versus +31 +/- 1, +30 +/- 3, and +28 +/- 2 mm Hg in WKY rats). Results indicate that stimulation of metabotropic, as well as ionotropic, glutamate receptors in the rostral ventrolateral medulla evokes enhanced cardiovascular responses in SHR, which may contribute to hypertension in this model.

Enhanced depressor response to nitric oxide in the rostral ventrolateral medulla of spontaneously hypertensive rats.

Possible impairment of the L-arginine-nitric oxide (NO) pathway in the rostral ventrolateral medulla of adult spontaneously hypertensive rats (SHR) was investigated by microinjecting N(G)-nitro-L-arginine methyl ester (L-NAME), NOC 18 (an NO donor), or L-arginine. Unilateral injection of L-NAME (10 nmol/50 nL) into the rostral ventrolateral medulla significantly increased mean arterial pressure (MAP) in both SHR and Wistar-Kyoto rats (WKY). The increases in MAP did not differ significantly between the two strains (15+/-3 versus 10+/-2 mm Hg, respectively; n=8). In contrast, microinjection of L-arginine elicited significant (P<.05) dose-dependent decreases in MAP in both strains, and these depressor responses were significantly greater in SHR than in WKY (in 10 nmol of L-arginine: -29+/-2 versus -15+/-2 mm Hg, respectively; n=8, P<.01). Similarly, microinjection of NOC 18 (10 nmol/50 nL) reduced MAP in both strains, and the depressor response was also significantly greater in SHR than in WKY (-38+/-7 versus -22+/-3 mm Hg, respectively; n=8, P<.05). These results suggest that the L-arginine-NO pathway in the rostral ventrolateral medulla is impaired in SHR and that this impairment may contribute to the increase in arterial pressure in this animal model of genetic hypertension.

Sympathetic control of arterial membrane potential by ATP-sensitive K(+)-channels.

Stimulation of perivascular nerve terminals leads to a release of various neurotransmitters such as norepinephrine, epinephrine, acetylcholine, nitric oxide, and calcitonin gene-related peptide (CGRP). Because some of these substances have been shown to cause smooth muscle hyperpolarization by direct or endothelium-dependent mechanisms, we hypothesized that the liberation of 1 or more of these transmitters may lead to neurogenic hyperpolarization in arterial muscle cells. The present study was designed to determine the presence or absence of neurogenic hyperpolarization and, if present, its underlying mechanisms in isolated rat mesenteric resistance arteries, through the use of conventional microelectrode techniques. The experiments were performed under the combined blockade of alpha-adrenoceptors and purinoceptors with phentolamine and suramin to eliminate depolarizing responses to nerve stimulation. Under these conditions, perivascular nerve stimulation (5 Hz, 30 seconds) evoked smooth muscle hyperpolarization (-3.3+/-0.3 mV, n=15), which was abolished by tetrodotoxin, indicating the neurogenic origin of the response. This neurogenic hyperpolarization was resistant to atropine, nitro-L-arginine, or CGRP8-37, a CGRP antagonist, but was abolished by guanethidine and beta-blocker propranolol. This hyperpolarization was also abolished by glibenclamide, an ATP-sensitive K(+) channel (K(ATP)) blocker, but was unaffected by apamin, a Ca(2+)-activated K(+) channel blocker. In separate experiments, exogenous norepinephrine caused glibenclamide-sensitive hyperpolarization in the presence of phentolamine. On the other hand, norepinephrine-induced depolarization in the absence of phentolamine was enhanced by propranolol. These findings suggest that neurally released catecholamines cause membrane hyperpolarization through the activation of K(ATP) by beta-adrenoceptors. Such hyperpolarization may play an important role in the control of arterial membrane potential by opposing alpha-adrenergic depolarization.

Central adrenomedullin augments the baroreceptor reflex in conscious rabbits.

We examined the roles of central adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP), and calcitonin gene-related peptide (CGRP) on the baroreceptor reflex in conscious rabbits. Intracerebroventricular injection of adrenomedullin (0.2 and 1 nmol/80 microL) elicited dose-related increases in arterial pressure and renal sympathetic nerve activity. On the other hand, a subpressor dose of intracerebroventricular infusion of adrenomedullin (1 nmol/300 microL per hour) caused significant increases in baroreflex sensitivities assessed by renal sympathetic nerve activity and heart rate compared with vehicle infusion (Gmax; -14.9+/-1.7 versus -8.0+/-0.7%/mm Hg, P<0.01, and -8.1+/-0.8 versus -5.1+/-0.5 bpm/mm Hg, P<0.01, respectively). Intracerebroventricular infusion of CGRP (1 nmol/300 microL per hour), which is structurally homologous to adrenomedullin, also enhanced the baroreflex controls of renal sympathetic nerve activity and heart rate. However, the intracerebroventricular infusion of PAMP (30 nmol/300 microL per hour) failed to alter the baseline levels of arterial pressure and baroreflex sensitivities. These results suggest that central adrenomedullin and CGRP, but not PAMP, participate in cardiovascular regulation to augment the baroreflex controls of renal sympathetic nerve activity and heart rate in conscious rabbits.

Single L-type calcium channels in smooth muscle cells from resistance arteries of spontaneously hypertensive rats.

The amplitude of the whole-cell L-type Ca2+ channel current recorded from vascular smooth muscle cells is reportedly greater in spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY). However, no study has examined properties of single Ca2+ channels in arterial cells from these strains. To further test the hypothesis that activation of L-type Ca2+ channels in arterial smooth muscle cells would be enhanced in SHR, we recorded single Ca2+ channel currents in resistance mesenteric artery cells from SHR and WKY (8 to 9 weeks of age) using a cell-attached patch clamp technique. With 50 mmol/L Ba2+ in the recording pipette, the depolarizing pulse from a holding potential of -40 mV evoked the single L-type Ca2+ channel current. Opening of the single channels was more frequent in cells from SHR than from WKY. Single-channel conductance (20 pS) and open time (1 ms at 0 mV) did not differ in the two strains. The results suggest that an increased amplitude of the whole-cell current can be attributed to the enhanced opening of single Ca2+ channels in the arterial smooth muscle cells from SHR compared with WKY.

Impaired isoproterenol-induced hyperpolarization in isolated mesenteric arteries of aged rats.

Stimulation of vascular beta-adrenoceptors leads to membrane hyperpolarization, presumably via the beta-adrenoceptor/G(s) protein/adenylate cyclase signaling cascade; the ionic mechanisms of this phenomenon remain unclear. beta-Adrenoceptor-mediated vascular relaxation is impaired with aging; however, little is known concerning whether beta-adrenoceptor-mediated hyperpolarization is altered with aging. We sought to determine the ionic mechanisms of isoproterenol-induced hyperpolarization in the rat mesenteric resistance artery, as well as the age-related changes in isoproterenol-induced hyperpolarization and their underlying mechanisms. Isoproterenol-induced hyperpolarization was inhibited by high-K(+) solution and glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K(+) channels (K(ATP)), but not by apamin, iberiotoxin, or charybdotoxin, inhibitors of Ca(2+)-activated K(+) channels. Isoproterenol-induced hyperpolarization was markedly less in aged rats (>/=24 months) than in adults rats (12 to 20 weeks) (3x10(-6) mol/L; -3.1 versus -9.9 mV; P<0.001; n=8 to 9). Cholera toxin (10(-9) g/mL), an activator of G(s), evoked hyperpolarization only in adult rats. Hyperpolarization to forskolin, a direct activator of adenylate cyclase, was also reduced to some extent in aged rats (10(-5) mol/L; -8.8 versus -13 mV; P<0.05; n=6), whereas hyperpolarization to levcromakalim, a K(ATP) opener, was comparable in both groups. These findings suggest that isoproterenol elicits hyperpolarization via an opening of K(ATP) in the rat resistance artery and that isoproterenol-induced hyperpolarization is attenuated in aged rats mainly because of a defective coupling of beta-adrenoceptors to adenylate cyclase and partly because of a defect at the level of adenylate cyclase, but not because of an alteration of K(ATP) per se.

Antihypertensive treatment and the responsiveness to glutamate in ventrolateral medulla.

We have recently reported that the cardiovascular responses to excitatory amino acids are augmented in the rostral ventrolateral medulla of spontaneously hypertensive rats (SHR). In the present study, we investigated whether the responsiveness to excitatory amino acids would be normalized by antihypertensive treatment. Thus we treated 4-week-old SHR and age-matched Wistar-Kyoto (WKY) rats with either enalapril (25 mg/kg per day in drinking water) or vehicle for 8 weeks. At 12 weeks of age, systolic blood pressure in the untreated SHR (248+/-9 mm Hg) was significantly (P<.01) higher than that in the enalapril-treated SHR (140+/-4 mm Hg), untreated WKY rats (148+/-4 mm Hg), and enalapril-treated WKY rats (117+/-1 mm Hg). The pressor responses to L-glutamate (2 nmol) microinjected into the rostral ventrolateral medulla were similar in enalapril-treated and untreated SHR (40+/-5 and 47+/-3 mm Hg, respectively, NS), and these responses were significantly greater than that seen in the untreated WKY rats (24+/-2 mm Hg, P<.01). On the other hand, the pressor response to either N-methyl-D-aspartate, an ionotropic glutamate receptor agonist, or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a metabotropic glutamate receptor agonist, in the enalapril-treated SHR was slightly but significantly smaller than that in the untreated SHR but was still markedly greater than those in untreated and enalapril-treated WKY rats. These results suggest that the augmented responsiveness to excitatory amino acids in the rostral ventrolateral medulla of SHR may be at least partly genetically determined and cannot be normalized by the treatment with enalapril.

Differential modulation by mu- and delta-opioids on baroreceptor reflex in conscious rabbits.

We examined the role of central mu- and delta-opioids on both neurohormonal responses and baroreceptor reflex in conscious rabbits. Both intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-selective agonist, and [D-Ala2,D-Leu5]-enkephalin, a delta-selective agonist, caused dose-related increases in arterial pressure and renal sympathetic nerve activity, whereas intravenous injection of the same maximum dose of these peptides as that used in the intracerebroventricular experiment did not cause any cardiovascular and neuronal responses. On the other hand, increases in plasma epinephrine, norepinephrine, and glucose levels induced by intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin were significantly greater than those by [D-Ala2,D-Leu5]-enkephalin. Both enkephalins did not cause any responses in plasma renin activity, plasma vasopressin, and serum sodium and potassium concentrations. The sensitivity of the baroreceptor reflex control of renal sympathetic nerve activity using a logistic model was enhanced by a subpressor dose of intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 pmol/kg) but not by [D-Ala2,D-Leu5]-enkephalin. Conversely, a mu-selective dose of intravenous naloxone (0.1 mg/kg) attenuated baroreceptor reflex sensitivity. Intravenous naloxone methobromide, which has been shown not to cross the blood-brain barrier, did not change baroreceptor reflex sensitivity, suggesting that naloxone acts at the central nervous system. In conclusion, in conscious rabbits, 1) intracerebroventricular mu- and delta-receptor agonists caused pressor responses and 2) mu-opioid agonist altered baroreceptor reflex control of renal sympathetic nerve activity and produced changes in sympathoadrenal responses.

Angiotensin II increases norepinephrine turnover in the anteroventral third ventricle of spontaneously hypertensive rats.

We evaluated the effect of angiotensin II (Ang II) administered by intracerebroventricular injection on norepinephrine turnover in the anteroventral third ventricle in adult spontaneously hypertensive rats (SHR, n = 35) and age-matched Wistar-Kyoto rats (WKY, n = 38). Ang II (100 ng) or saline (vehicle control) was administered into the cerebral ventricle 30 minutes after injection of alpha-methyl-p-tyrosine (250 mg/kg IP). Norepinephrine turnover was assessed by evaluation of the norepinephrine concentration before and 1 hour after such administration. The pressor response to Ang II administration was significantly greater in SHR than in WKY (+43 +/- 3 versus +23 +/- 2 mm Hg, P < .01). Baseline norepinephrine turnover (response to saline) was reduced in the ventral median preoptic nucleus of SHR. Ang II significantly increased norepinephrine turnover in the organum vasculosum lamina terminalis and ventral median preoptic nucleus of SHR (organum vasculosum lamina terminalis: 40 +/- 5% by Ang II versus 18 +/- 6% by saline, P < .05; ventral median preoptic nucleus: 32 +/- 3% by Ang II versus 21 +/- 2% by saline, P < .05) but not of WKY (37 +/- 5% versus 29 +/- 5%, P = NS, and 30 +/- 2% versus 32 +/- 3%, P = NS, respectively). Thus, norepinephrine turnover in the anteroventral third ventricle region induced by intracerebroventricular administration of Ang II was increased in SHR. This effect may contribute to the enhanced pressor response to central Ang II seen in this model.

Central effect of endothelin on neurohormonal responses in conscious rabbits.

It has been shown that endothelin-1 (ET-1) binding sites exist in the central nervous system and that the injection of intracerebroventricular ET-1 induces a pressor response. Therefore, we determined the neurohormonal and cardiovascular responses to intracerebroventricular ET-1 (25 pmol/kg) in conscious rabbits with chronically instrumented electrodes on the renal sympathetic nerve. Intracerebroventricular ET-1 provoked a prompt increase in arterial pressure and in renal sympathetic nerve activity within 5 minutes, and peak values were obtained at 20 and 40 minutes, respectively. Plasma epinephrine and norepinephrine reached peak values at 5-20 minutes. Plasma vasopressin and plasma glucose levels also increased significantly, but plasma osmolality, hematocrit, and serum sodium and potassium concentrations did not show any changes. Arterial blood gas analysis showed respiratory alkalosis. However, pretreatment with intravenous pentolinium (5 mg/kg), a ganglion blocking agent, abolished these neurohormonal and cardiovascular responses. Conversely, the same dose of intravenous ET-1 (25 pmol/kg) as that used in the intracerebroventricular experiment failed to cause any cardiovascular or renal sympathetic nerve responses. These results suggest that intracerebroventricular ET-1 acts in the central nervous system and causes a pressor response mainly through the enhancement of sympathoadrenal outflow.

Intima-media thickness of the carotid artery in hypertensive subjects and hypertrophic cardiomyopathy patients.

While hypertension is known to cause left ventricular and vascular hypertrophy, the relationship between alterations of vascular and cardiac structures in patients with hypertrophic cardiomyopathy has not been fully clarified. We measured intima-media thickness of carotid arteries by ultrasonography in patients with hypertrophic cardiomyopathy (n = 16), normotensive subjects (n = 358), and hypertensive subjects (n = 386) in a cohort of 7940 male employees of a bus company. Our object was to determine whether vascular alteration occurs in hypertrophic cardiomyopathy similarly as in hypertension. Hypertrophic cardiomyopathy (wall thickness > or = 15 mm; asymmetrical hypertrophy without hypertension) was screened with family history and electrocardiography followed by echocardiography. The intima-media thickness in patients with hypertrophic cardiomyopathy (mean, 0.61 mm) did not differ from that of normotensive subjects (0.60 mm) but was significantly less than that of hypertensive subjects with left ventricular hypertrophy (wall thickness > or = 14 mm; n = 22; 0.73 mm). In a scatterplot of intima-media thickness versus interventricular septal thickness, these two parameters were significantly correlated in normotensives and hypertensives. The patients with hypertrophic cardiomyopathy distributed outside the 95% confidence range of the normotensive and hypertensive subjects. In summary, the increase in intima-media thickness of the carotid artery paralleled left ventricular hypertrophy in normotensive and hypertensive subjects. Patients with hypertrophic cardiomyopathy had a normal intima-media thickness regardless of the hypertrophied left ventricle. Thus, information on intima-media thickness may be useful in differentiating hypertensive left ventricular hypertrophy from hypertrophic cardiomyopathy.

Stretch-activated channels in arterial smooth muscle of genetic hypertensive rats.

Electrical and contractile responses of small arteries to mechanical stress are reportedly enhanced in spontaneously hypertensive rats (SHR), compared with those in Wistar Kyoto rats (WKY). We have previously shown that stretch-activated cation channels exist in arterial smooth muscle membrane, of which opening causes Na+ and Ca2+ influx and membrane depolarization. We thus hypothesize that activation of stretch-activated channels is enhanced in arterial smooth muscle of SHR compared with WKY. To test this hypothesis, stretch-activated currents were recorded in single smooth muscle cells of resistance mesenteric arteries from SHR and WKY (16 to 24 weeks of age). In the whole-cell recording, membrane stretch was applied by inflating the cell with positive pressure to the recording pipette. Cell-inflation evoked Gd3+-sensitive cation currents. This current appeared with less stretch stimulation and its amplitude was larger in SHR cells compared with WKY cells. In the cell-attached recording, suction to the recording pipette evoked single stretch-activated channel currents (conductance of 32 pS with 150 mmol/L Na+), which were blocked by Gd3+. Channels were activated with less negative pressure and their availability was greater in SHR cells than in WKY cells. Results suggest that the activation of stretch-activated channels is enhanced in smooth muscle of resistance arteries from SHR compared with WKY, which may contribute to the enhanced vascular responses to mechanical stress in SHR.