Meral Tuncer

5-HT1-like receptor-mediated contraction in the human internal mammary artery.

SummaryWe wished to characterize the 5-hydroxytryptamine (5-HT) receptors mediating vasoconstriction in the human internal mammary artery (IMA). Segments of the IMA obtained from patients undergoing coronary bypass surgery were suspended in an organ bath and exposed to 5-HT and sumatriptan (SUM), a

Hypertension increases the contractions to sumatriptan in the human internal mammary artery

BACKGROUND The internal mammary artery is the graft of choice for myocardial revascularization. The tendency to spasm increases toward the distal end of the internal mammary artery, which is the portion generally used for anastomosis. The distal internal mammary artery is more pharmacologically responsive to 5-hydroxytryptamine and several other vasoconstrictor agents than its midsection. METHODS We examined the effects of 5-hydroxytryptamine and a 5-hydroxytryptamine1-like receptor agonist sumatriptan on internal mammary artery segments (length, 3-4 mm) obtained from patients undergoing coronary artery bypass grafting. To unmask a 5-hydroxytryptamine1-like receptor-mediated contractile response, threshold concentrations of potassium chloride were used. RESULTS 5-Hydroxytryptamine induced concentration-dependent contractions in all, quiescent and potassium chloride precontracted, preparations. Sumatriptan induced marked contraction in some of the quiescent internal mammary artery rings, whereas it elicited marked and concentration-dependent contractions in all of the preparations given a moderate tone by a threshold concentration of potassium chloride. The sensitivity to sumatriptan was higher in potassium chloride-precontracted distal arteries than it was for the quiescent distal segments. Additionally, the sensitivity to and the efficacy of sumatriptan were much more markedly potentiated by precontraction in the preparations taken from hypertensive patients. CONCLUSIONS The more marked potentiation of the responses in arteries from hypertensive patients may be one of the factors influencing the patency rates.

Role of prostanoids in the increased vascular responsiveness and delayed tachyphylaxis to serotonin in the kidney of spontaneously hypertensive rats

The isolated and perfused kidney of the spontaneously hypertensive rat (SHR) exhibits an increased vascular reactivity and a delayed tachyphylaxis to serotonin (5-hydroxytryptamine) when compared with normotensive Wistar-Kyoto (WKY) rats. Experiments were designed to determine the involvement of products of cyclooxygenase in the augmented response and delayed tachyphylaxis to serotonin in the SHR kidney. Kidneys taken from male, 4-month-old SHR and WKY rats were studied in parallel and perfused with Tyrodes solution at constant, optimal flow rates. Vasoconstrictor responses were recorded as increases in perfusion pressure. The vasoconstrictor responses to serotonin, norepinephrine and angiotensin II were exaggerated in the SHR kidney compared with that of the WKY rat. Indomethacin did not affect the responsiveness to serotonin in the kidney of the SHR but increased the responses to the higher doses of the monoamine in the kidney of the WKY rats. Indomethacin accelerated the tachyphylaxis to serotonin in the SHR but delayed it in the WKY rats. Dazoxiben did not alter the responses to serotonin in the SHR. Responses to norepinephrine in the kidneys from both strains were not affected by indomethacin. The inhibitor of cyclooxygenase reduced the responses to angiotensin II in the kidneys from both hypertensive and normotensive animals. The basal and stimulated (serotonin, norepinephrine and angiotensin II) release of prostaglandins were measured by radioimmunoassay. The basal release of prostacyclin was lower, but that of thromboxane A2 higher, in the kidneys of SHR compared with those of WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

5-HT1-like and 5-HT2A receptors mediate 5-hydroxytryptamine-induced contraction of rabbit isolated mesenteric artery.

The contractions induced by 5-hydroxytryptamine (5-HT) and the 5-HT1-like receptor agonist, sumatriptan, were investigated in the open ring preparations of rabbit mesenteric artery in order to characterize the 5-HT receptors. 5-HT induced concentration-dependent contractions. Sumatriptan did not induce any contraction of unstimulated rings, whereas it elicited concentration-dependent contractions in preparations given a moderate tone by a threshold concentration of prostaglandin F2α (PGF2α). Pargyline, cocaine or normetanephrine were without significant effect on the contractions induced by 5-HT and sumatripan. The 5-HT concentration-effect curve was clearly biphasic. Methiothepin (0.01 μM) shifted the both phases of the concentration-effect curve to the right. Ketanserin (0.1 μM) shifted the second, low affinity, phase and prazosin did not alter concentration-effect curve to 5-HT. The sumatriptan concentration-effect curve was shifted by methiothepin (0.01 μM) to the right (pKB = 9.19) but not by ketanserin (1 μM). Concentration-effect curves to 5-HT and sumatriptan were not affected by the 5-HT3 receptor antagonist tropisetron (1 μM). These results suggest that 5-HT1-like type receptors are responsible for the first phase of 5-HT-induced contraction and 5-HT2A receptor for the second phase, in rabbit mesenteric artery. Sumatriptan-induced contractions appear to be mediated by 5-HT1-like type receptors in this artery. These results also suggest that this kind of amplification may be a common feature of vascular 5-HT1-like type receptor as has been shown in other vascular segments such as rabbit femoral, iliac and renal arteries, and guinea-pig iliac artery.

The effects of sildenafil on the functional and structural changes of ileum induced by intestinal ischemia–reperfusion in rats

There is evidence demonstrating the protective effect of cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors against ischemic injury in certain tissues. In this study, sildenafil, a potent inhibitor of PDE5, was tested for its beneficial effects in the prevention of disrupted ileal contractility and damage to tissue caused by intestinal ischemia-reperfusion in rats. Male Sprague-Dawley rats were divided into four groups: sham-operated; sham-operated with sildenafil pretreatment; ischemia-reperfusion with vehicle pretreatment; and ischemia-reperfusion with sildenafil pretreatment. The superior mesenteric artery was occluded for 45 min to induce ischemia. The clamp was then removed for a 60 min period of reperfusion. Sildenafil (1 mg/kg, i.v.) or saline was administered prior to the surgical procedure in the ischemia-reperfusion and sham-operated groups. Isometric contractions of the ileal segments in response to acetylcholine or electrical field stimulation (120 V, 2 ms pulse for 5 s, 1-20 Hz) were recorded. Additionally, levels of thiobarbituric acid reactive substances and myeloperoxidase activity were measured in addition to a histopathological examination of the ileal tissue. The contractions induced by both acetylcholine and electrical field stimulations were markedly inhibited after ischemia-reperfusion. Sildenafil pretreatment (1 mg/kg, i.v.) abolished the inhibition of responses to acetylcholine. The increased levels of thiobarbituric acid reactive substances and myeloperoxidase activity caused by ischemia-reperfusion were reversed to control levels with sildenafil pretreatment. Intestinal ischemia-reperfusion caused severe ischemic injury in rat ileum, which was prevented by sildenafil. These results suggest that sildenafil pretreatment has a protective effect against ileal dysfunction and damage induced by intestinal ischemia-reperfusion in the rat.

Response to the Endothelium-Dependent Vasodilator Acetylcholine in Perfused Kidneys of Normotensive and Spontaneously Hypertensive Rats

The possible role of endothelium-derived relaxing factor (EDRF) was investigated in resistance vessels of the kidney obtained from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Kidneys were studied in parallel and perfused with Tyrodes solution at constant optimal flow rates. In the presence of indomethacin, during vasoconstriction (increase in perfusion pressure) produced by prostaglandin F2 alpha, acetylcholine caused a graded dilatation (pressure fall) that was greater in kidneys of WKY than of SHR. Methylene blue and hydroquinone, but not oxyhemoglobin, inhibited the decreases in perfusion pressure induced by acetylcholine, but not those by papaverine. The results suggest that part of the renal vasodilatation induced by acetylcholine is mediated by endothelium-derived relaxing factor, and that the response is impaired in the resistance vessels of the hypertensive rat kidney.

The action of amyl nitrite and isosorbide dinitrate on the contractility of sphincter of Oddi of guinea-pigs

1. This study was designed to investigate whether relaxation of isolated guinea-pig sphincter of Oddi preparation by nitrates is mediated by guanylate cyclase activation indirectly by nitric oxide (NO), as in vascular tissues. 2. Sodium nitroprusside, isosorbide dinitrate and amyl nitrite induced dose-dependent relaxations of Oddis sphincter precontracted by potassium chloride (150 mM). Methylene blue (5 x 10(-5) M), an inhibitor of guanylate cyclase, did not significantly inhibit the relaxations caused by nitrovasodilators. 3. Unlike potassium chloride, acetylcholine (10(-7) - 10(-3) M) induced unsustained contractions which were significantly increased by methylene blue. NG-monomethyl-L-arginine (L-NMMA; 4 x 10(-4) M), an inhibitor of NO biosynthesis, also increased the contractile response to acetylcholine. 4. These results suggest that another mechanism rather than inhibition of guanylate cyclase is involved in the nitrovasodilators-induced relaxations and that acetylcholine releases a relaxing factor, possibly NO, that may modulate its own contraction in this preparation.

Propranolol-induced relaxation in the rat basilar artery

Propranolol is a non-selective beta-adrenergic receptor blocker used in the treatment of cardiovascular diseases and migraine prophylaxis. Although it has been shown that propranolol dilates the peripheral arteries of rat, its action in the central nervous system vasculature has not been investigated. In this study, the effects of propranolol in rat basilar artery were investigated. Basilar arteries from male Wistar rats were examined in a myograph system. The relaxant effects of propranolol, pindolol, atenolol, pizotifen and methysergide were examined in basilar arteries precontracted by serotonin or PGF2α. Only propranolol and pizotifen induced vasorelaxations; the pD2 values were 5.23±0.13 and 5.94±0.03; respectively. The vasorelaxation induced by propranolol and pizotifen was not affected by endothelium or the presence of l-NOARG and/or indomethacin. The calcium channel blocking activity of propranolol and pizotifen was compared with that of nifedipine in a calcium free solution with high K(+) (60mM) concentration. These drugs shifted the concentration-response curves of calcium induced contractions with pA2 values of 5.45±0.04; 7.14±0.09; and 9.22±0.06 respectively. The P2Y receptor agonist UTP was used to induce sustained and stable contractions in basilar artery segments. Nifedipine caused a marked, but an incomplete relaxation. Cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum calcium channels, but not propranolol or pizotifen abolished the remaining tonus after partial relaxations obtained with nifedipine. These results suggest that propranolol causes vasorelaxation by blocking the L-type voltage-gated calcium channels in the rat basilar artery.

Endothelial dysfunction in the mesenteric artery and disturbed nonadrenergic noncholinergic relaxation of the ileum due to intestinal ischemia-reperfusion can be prevented by sildenafil.

The aim of the present study was to evaluate the effects of sildenafil on endothelium-dependent mesenteric artery vasorelaxation and nonadrenergic noncholinergic (NANC) ileal responses in an experimental rat intestinal ischemia-reperfusion (I/R) model. The superior mesenteric artery was occluded for 45 min of ischemia and then the clamp was removed for 60 min of reperfusion. Sildenafil (1 mg/kg, i.v.) or saline was administered prior to surgery in the I/R and sham-operated groups. Acetylcholine-induced relaxation of the mesenteric arteries, which were precontracted via submaximal phenylephrine, decreased markedly after I/R. Sildenafil pretreatment reversed the acetylcholine-induced relaxation. In the ileum, NANC responses were significantly attenuated following I/R, which were increased by sildenafil pretreatment. These results indicate that pretreatment with sildenafil prevented both endothelial dysfunction in the mesenteric artery and impairment of ileal NANC responses in a rat intestinal I/R model.

Vasodilatation Induced by Nicotine in the Isolated Perfused Rat Kidney

1. In isolated perfused rat kidney, under a constant flow of 8-10 ml/min, mean basal perfusion pressure was found to be 82.57 +/- 8.96 mm Hg (n = 70). 2. After a bolus injection of 10 micrograms/0.1 ml phenylephrine (PE) which causes maximum vasopressor response, a 93.27 +/- 0.56 mm Hg increase in basal perfusion pressure was recorded (n = 70). In control experiments, a submaximum dose of PE (3 x 10(-6) M) caused a 68.37 +/- 0.47 mm Hg (n = 5) increase in perfusion pressure. 3. Nicotine, at a dose of 100 micrograms/0.1 ml, decreased the perfusion pressure raised by submaximum dose of PE. This nicotine-induced dilatation was 24.97 +/- 3.27% of maximum PE constriction (n = 5). 4. Nicotine-induced dilatation was not affected by atropine, guanethidine, hexamethonium, tetrodotoxin, capsaicin, indomethacin, quinacrine, NG-nitro-L-arginine, methylene blue, glibenclamide, tetraethylammonium, 4-aminopyridine and ouabain (n = 5).