Sule Oktay

Role of capsaicin-sensitive nerves in gastric and hepatic injury induced by cold-restraint stress.

The role of capsaicin-sensitive afferent fibers on cold-restraint stress-induced gastric and hepatic injury was examined at the macroscopic and ultrastructural levels. Wistar albino rats were treated with capsaicin either locally (intragastric, perivagal, and periceliac) or systemically (neonatal, intraperitoneal). Perineural and neonatal treatment with capsaicin was used to denervate afferent fibers, while intragastric capsaicin treatment would have activated mucosal afferent fibers just before the stress exposure. Capsaicin decreased significantly the formation of macroscopic gastric lesions caused by stress in all treatment groups. At the electron microscopic level, however, denervation of vagal afferent fibers with capsaicin was most effective in prevention of cellular injury in gastric mucosa. In the liver, systemic denervation of afferent fibers completely inhibited stress-induced cellular damage, while denervation of afferent fibers in vagus and splanchnic nerve was partially effective. Central neural pathways sensitive to capsaicin may mediate formation of both gastric and hepatic injury resulting from stress.

ROLE OF AFFERENT NEURONS IN STRESS INDUCED DEGENERATIVE CHANGES OF THE BLADDER

PURPOSE We investigated the role of afferent C fibers in morphological changes of the rat bladder during stress. MATERIALS AND METHODS Wistar albino rats were exposed to cold immobilization stress. Different routes of capsaicin administration before cold immobilization stress were studied. Capsaicin was given to neonates, around the vagus (perivagal) or celiac (periceliac), or perivagal plus periceliac. From each group samples of bladder were randomly chosen for morphological evaluation using electron microscopy. RESULTS Stress exposure led to pathological changes, including an increased number of mast cells, degenerated urothelium and dilated tight junctions, in the bladder. Capsaicin given neonatally and around the vagal and celiac ganglia prevented these stress induced degenerative bladder changes. CONCLUSIONS Activation of capsaicin sensitive afferent neurons locally and centrally may be involved in stress related pathological changes in the rat bladder.

NK-1 antagonist CP99994 inhibits stress-induced mast cell degranulation in rats.

Mast cells are implicated in stress‐induced inflammatory skin diseases such as psoriasis. Mechanisms of stress‐induced mast cell degranulation however, are not entirely clear. Here we explore the role of activation of a Substance P (SP) receptor (NK‐1) on mast cell degranulation upon exposure to stress in rats. A specific nonpeptide NK‐1 antagonist, CP99994 was used to treat the rats either peripherally or intracerebroventricularly. Because increased SP activity in the brain may mediate the stress response, we also examined cutaneous mast cell degranulation after central injection of SP. Stress, as well as SP injected centrally, increased mast cell degranulation. Both central and peripheral injection of CP99994 prevented stress‐induced mast cell degranulation. Surprisingly, the combination of stress with SP decreased mast cell degranulation, suggesting that high levels of SP may counteract the stress responses. Results in this animal model suggest that NK‐1 antagonists may be used therapeutically to treat stress‐induced inflammatory skin diseases; however, drug doses should be chosen carefully.

Calcium channel blockers prevent stress-induced ulcers in rats

Gastric mucosal damaged induced by cold and restraint stress caused increase in gastric lipid peroxidation (LP) and decrease in gastric glutathione levels. Two calcium-channel blockers, verapamil and nicardipine, prevented stress-induced increase in gastric LP, as well as ulcer formation. Both calcium-channel blockers protected against stress-induced ulcers, and inhibition of LP may be among their mechanisms of action.

Effects of a single dose of oral estrogen on left ventricular diastolic function in hypertensive postmenopausal women with diastolic dysfunction

Abstract Objective: To evaluate the acute effects of a single dose of oral estrogen on left ventricular diastolic function in hypertensive postmenopausal women with diastolic dysfunction. Design: Prospective, double-blind, placebo-controlled, clinical study. Setting: Cardiology and postmenopausal outpatient clinics of a university hospital. Patient(s): Thirty postmenopausal women with hypertension (diastolic blood pressure of >90 mm Hg) and left ventricular diastolic dysfunction (mitral E/A ratio [the ratio of peak velocity of early mitral diastolic filling to late diastolic filling] of 100 ms) were included in the study. Thirty normotensive postmenopausal women with normal left ventricular diastolic function served as the control group. Intervention(s): Conjugated equine estrogen (0.625 mg) was given orally. Left ventricular diastolic function was assessed by Doppler echocardiography at baseline and 3 hours after the administration of estrogen. Main Outcome Measure(s): Left ventricular diastolic filling as assessed by Doppler echocardiography. Result(s): Estrogen had no effect on heart rate or blood pressure in either study group. The baseline E/A ratios were 0.72 ± 0.26 and 1.22 ± 0.30, and the isovolumic relaxation times were 122 ± 18 ms and 89 ± 14 ms in the hypertensive and normotensive groups, respectively. Estrogen had no significant effect on any of the Doppler parameters in the normotensive group. In the hypertensive group, there was a trend toward normalization of the E/A ratio (from 0.73 ± 0.11 to 0.84 ± 20) and a significant improvement in the isovolumic relaxation time (from 124 ± 20 ms to 105 ± 13 ms) in response to the administration of estrogen compared with placebo. Conclusion(s): A single dose of oral estrogen caused a significant improvement in left ventricular diastolic filling in hypertensive postmenopausal women with diastolic dysfunction.

Modulation of the pressor response elicited by carbachol and electrical stimulation of the amygdala by muscarinic antagonists in conscious rats

The nature of the muscarinic receptor involved in mediating cardiovascular changes caused by unilateral microinjection of carbachol (5 nmol) into, and electrical stimulation (200–300 μA) of, the amygdaloid complex was investigated in conscious, unrestrained female Sprague‐Dawley rats. Unilateral microinjection of carbachol (5 nmol; n=6) and electrical stimulation (200–300 μA, 80 Hz, 30 s; n=4) caused a significant rise in blood pressure of 21±4 mmHg and 25±5 mmHg, respectively. These changes were associated with no overall effect on heart rate. The effects of electrical stimulation were found to be repeatable. Pretreatment i.c.v. with pirenzepine (5–20 nmol; n=6–7 for each dose), dose‐dependently inhibited the rise in blood pressure induced by carbachol, whereas AF‐DX 116 (100 nmol; n=6) failed to have any effect on the carbachol‐induced pressure response. Neither antagonist alone had any effect on resting baseline variables. Unilateral microinjections of atropine sulphate (1–100 nmol; n=4–6 for each dose), pirenzepine (0.03–10 nmol; n=4 for each dose) or AF‐DX 116 (10–60 nmol; n=4–5 for each dose), into the amygdala, dose‐dependently inhibited the rise in blood pressure caused by electrical stimulation (200–300 μA). The ID50 values were 1.05, 0.23 and 39.5 nmol, respectively. Although pirenzepine seemed to be more potent than atropine, this difference was not significant. It is concluded that the rise in blood pressure elicited by unilateral microinjection of carbachol into, or electrical stimulation of, the amygdaloid complex is mediated by M1‐muscarinic receptors.

Inhibition of cholecystokinin-induced gallbladder contraction by atropine and pirenzepine in man

The effect of pirenzepine on cholecystokinin (CCK)-stimulated gallbladder contraction in man was compared with that of atropine. Following pretreatment with atropine, pirenzepine or physiological saline in a random order, 6 healthy male volunteers were infused for 75 min with CCK-octapeptide in doses that are reported to mimic physiological plasma concentrations. Gallbladder volumes were determined by real-time ultrasonography. Pirenzepine inhibited CCK-induced gallbladder volume reduction significantly up to 30 min (p less than 0.01) and the magnitude of this inhibition was similar to that of atropine. The results demonstrate that M1 neural muscarinic receptors are involved in the anticholinergic inhibition of CCK-induced gallbladder contraction in man.

Drug utilization and teratogenicity risk categories during pregnancy

A limited number of studies have investigated in detail the use of drugs during pregnancy. Researchers in the present study investigated the details of drug utilization in pregnant women during the month before pregnancy, at the time that they became aware of the pregnancy, and during the first trimester. Face-to-face interviews were conducted with 359 pregnant women who were admitted to the fetal medicine unit at a university hospital for diagnosis and follow-up. A questionnaire was used to document sociodemographic characteristics and details of drug use. Drugs were categorized according to the US Food and Drug Administration fetal risk classification. Mean maternal age was 29.9±5.1 y, and mean gestational age was 19.6±9.5 wk. Many of the pregnant women studied (46.6%) were university graduates, and most (61.9%) had a relatively high annual income. Mean gestational age when participants first learned of their pregnancy was 39.8±16.4 d. One hundred seventeen participants (32.6%) used drugs during the month before conception, 54 (15%) at the time when they learned of their pregnancy, 180 (50.1 %) at the time of the interview, and 289 (80.5%) during the first trimester. The percentages of drugs in categories D and X used by these subjects were 14%, 13.5%, 2.9%, and 5.9%, respectively. Most of the drugs were hormones. The total rate of drug utilization was not high before and during the first trimester of pregnancy. A considerable number of women were using drugs from the D and X categories; however, these numbers decreased significantly when women learned of their pregnancies. Intake of folic acid, vitamins, and iron was very low during the preconception period and was not high enough during the first trimester; this suggests that particular attention should be paid to the use of beneficial “safe” drugs during the preconception and early pregnancy periods.

Influence of Pirenzepine on Gallbladder Contraction in Man Induced by Sham Feeding or an Intraduodenal Meal

Pirenzepine, an M1 muscarinic receptor antagonist, was tested for its ability to antagonize sham feeding- and intraduodenal fatty meal-stimulated gallbladder contraction in man. Intravenously administered pirenzepine abolished sham feeding-induced gallbladder contraction. Pirenzepine also inhibited contraction induced by intraduodenal meal, but this inhibition was of a lesser magnitude than the inhibition of sham feeding-induced contraction. The results demonstrate that the cephalic phase of gallbladder contraction is probably mediated by M1 muscarinic receptors while the duodenal phase of gallbladder contraction is partially mediated by M1 receptors.

The Protective Effect of 5-HT3 Receptor Antagonist in Thyrotropin Releasing Hormone-Induced Gastric Lesions

The present study examined 1) oxidative stress and gastric lesions induced by thyrotropin releasing hormone (TRH) 2) The effect of a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, ICS 205930 on protective effect of calcitonin on gastric lesions produced by TRH. Calcitonin (5 micrograms/10 microliter) was injected i.c.v. 10 min before TRH (10 micrograms/10 microliter, i.c.v.) injection or ICS 0.5 mg/kg, (i.p.) was given 60 min prior to calcitonin or TRH to rats. Ulcer index, lipid peroxidation (LP) and glutathione (GSH) levels were quantified 3 h after TRH injection in the stomach, liver and brain. TRH caused mucosal lesions (UI: 10.0 +/- 2.0 mm) without changing gastric GSH and LP. JCS did not alter the protective effect of calcitonin against TRH-induced lesions but attenuated. TRH-induced lesion formation. The oxidative effects of calcitonin or ICS were similar to TRH but both drugs attenuated gastric lesion formation. Hence, oxidative changes in tissues studied are not directly involved in TRH-induced lesions.