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PubMed1991

Endogenous vasoconstrictor prostanoids: role in serotonin and vasopressin-induced coronary vasoconstriction.

A vasoconstrictor-induced prostacyclin (PGI2) production in a perfused rat heart was found, suggesting a mitigating role of PGI2 on coronary vasoconstriction. Treatment of the heart with cyclooxygenase inhibitors (aspirin or indomethacin) decreased PGI2 production by more than 90% and paradoxically reduced the vasoconstriction response. The attenuating effect of cyclooxygenase blockade suggested that endogenous prostanoids contribute to serotonin-, vasopressin- or U46619-induced vasoconstriction. Two prostaglandin (PG) H2/thromboxane A2 (TXA2) receptor antagonists, i.e., 13-azaprostanoic acid (13-APA) and SQ 29,548 were used to investigate putative endogenous vasoconstrictor prostanoids on the exogenously induced vasoconstriction. Retrogradely perfused (5-6 ml/min) rat hearts were rendered guiescent, yet responsive to stimuli, by local injection of lidocaine to the atrioventricular node. Changes in coronary vascular resistance (i.e., perfusion pressure at constant flow) were monitored and the cardiac effluent was collected for analysis of 6-keto PGF1 alpha (the stable metabolite of PGI2) as well as PGF2 alpha by radioimmunoassay. Three vasoconstrictors, i.e., serotonin, vasopressin and the TXA2/PGH2 analog U46619, as well as authentic PGD2, PGE2 and PGF2 alpha were infused. PGD2, PGE2 and PGF2 alpha exerted a dose-related coronary vasoconstriction, as did U46619, serotonin and vasopressin. Treatment with 13-APA (100 microM) or SQ 29,548 (100 nM) almost abolished U46619-induced vasoconstriction. The addition of PGH2/TXA2 receptor antagonists also significantly reduced the pressor effect of exogenously administered PGs, serotonin and vasopressin, with the exception that SQ 29,548 did not significantly antagonize PGE2-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Modification of local anesthetic toxicity by vasoconstrictors.

We studied the effects of epinephrine or levonordefrin on the toxicity (convulsions) and lethality of four local anesthetics in mice. Appropriate doses of procaine, lidocaine, tetracaine or bupivacaine--either alone or in combination with 15 mcg/kg epinephrine or levonordefrin--were injected intravenously into the tail vein of male mice. Dose-response curves were constructed from the data obtained, and the CD50 and LD50 values for each local anesthetic alone and in combination with each of the vasoconstrictors were calculated by probit analysis. Both epinephrine and levonordefrin decreased the toxicity and lethality of procaine with respect to dose. Epinephrine, but not levonordefrin, increased the toxicity and lethality of bupivacaine as well as the lethality of tetracaine. Neither vasoconstrictor significantly affected the toxicity of lidocaine in mice but in rats epinephrine markedly increased lidocaine's lethality under identical conditions. Tight physical restraint decreased the LD50 values of all four local anesthetics and eliminated any modifying effect of the vasoconstrictor.

Animals↗

PubMed1986

Augmentation of vasoconstrictor responses to serotonin by acute and chronic factors: inhibition by ketanserin.

Serotonin induces constrictor responses on smooth muscle tissues from several vascular regions mainly by its interaction with serotonin-S2 receptor sites. The individual sensitivity of various blood vessels to serotonin may vary considerably. Serotonin (e.g. released from aggregating platelets) also induces vascular contractions by amplifying the response to other vasoactive substances. The vascular reactivity to serotonin can be markedly augmented by acute hypoxia (95% N2, 5% CO2; canine coronary arteries) and by cooling from 37 degrees to 29 degrees C (rabbit tibial and canine saphenous arteries). Blood vessels become hyperreactive to the vasoconstrictor component of serotonin in a number of disease states. Isolated perfused kidneys from spontaneously hypertensive rats (SHR) exhibit direct and indirect (amplifying) vasoconstrictor responses to serotonin. The amplifying effect of serotonin is significantly more pronounced in 6-month-old than in 2-month-old SHRs. Both the direct and indirect vasoconstrictor responses to serotonin, whether or not augmented by acute or chronic conditions, are inhibited by the serotonin-S2 receptor antagonist, ketanserin (4 X 10(-10) to 4 X 10(-7) mol/l). Both the hypersensitivity of vascular tissue to serotonin and the amplifying effect of the amine may greatly contribute to hypertension and other cardiovascular disorders.

Animals↗

PubMed1987

Reciprocal potentiation of a vasoconstrictor response between 5-hydroxytryptamine and clonidine in the perfused mesenteric vascular bed of the rat.

The interaction between 5-hydroxytryptamine (5-HT) and clonidine, an alpha 2-adrenoceptor agonist, was investigated in the isolated perfused mesenteric vascular bed of the rat. Clonidine itself did not cause vasoconstriction even at 300 micrograms. However, clonidine in the presence of 5-HT (10 and 100 nM) caused a marked vasoconstriction in a dose range of 0.1 micrograms to 300 micrograms. Prazosin inhibited the clonidine response, whereas yohimbine did not. The potency of prazosin against clonidine was less than that against an alpha 1-adrenoceptor agonist phenylephrine. Therefore, it is suggested that clonidine activated alpha 1-like adrenoceptors. 5-HT also potentiated the vasoconstrictor response to perivascular nerve stimulation, exogenous norepinephrine (NE) and phenylephrine. Calcium entry blockade by nicardipine (0.1 microM) reduced the response to clonidine in the presence of 5-HT, whereas that to phenylephrine in the presence or absence of 5-HT was not reduced. On the other hand, clonidine (0.01-1 microM) potentiated the vasoconstrictor effect of 5-HT more than NE did. Ouabain (1 microgram/ml) enabled clonidine to exhibit an agonistic action, and also enhanced the contractile response to 5-HT. In conclusion, 5-HT modulated the vasoconstrictor effect of clonidine, and the vasoconstriction with 5-HT was also facilitated by clonidine reciprocally. It is possible that a partial depolarization of the cell membrane is the common mechanism for their reciprocal potentiation.

Animals↗

PubMed1982

Interrelations between prostaglandins and vasoconstrictor hormones: contribution to blood pressure regulation.

Angiotensin II and norepinephrine promote formation of prostaglandins (PG), e.g., PGE2 and PGI2, that are capable of counteracting the vasoconstrictor actions of these pressor hormones. During activation of the renin-angiotensin and/or the sympathetic nervous systems, the administration of prostaglandin synthesis inhibitors causes vasoconstriction in renal and probably in extrarenal vasculatures, which suggests that antagonism of vasoconstrictor systems by prostaglandins is a feature of processes controlling arterial vascular tone. It follows, then, that endogenous prostaglandins may contribute to the regulation of blood pressure by opposing hormone-induced vasoconstriction. This implies that an uncompensated reduction in prostaglandin synthesis could cause blood pressure to rise. However, reports that prostaglandin synthesis inhibitors cause elevation of blood pressure conflict with reports that they do not. Obscuring the interpretation of such studies is the fact that inhibitors of prostaglandin synthesis also lower plasma renin activity, which may offset any tendency of blood pressure to rise consequent to reduced synthesis of antihypertensive prostaglandins. Hence it is premature to draw any firm conclusion regarding the full extent of the contribution of prostaglandins to blood pressure control. Nonetheless, the reviewed evidence commands consideration of the antagonism of the action of vasoconstrictor hormones by one or more prostaglandins as a feature of antihypertensive mechanisms.

Angiotensin II↗

PubMed1993

Effect of vasoconstrictor pre-treatment on obstruction, secretion and sneezing after nasal challenge with threshold and suprathreshold allergen doses.

Acute nasal allergen challenge produces airway obstruction which varies in amount and timing with the allergen dose delivered. To see whether different mechanisms might contribute variably to mucosal swelling with different amounts of allergen, we challenged sensitive volunteers with threshold and 10-times threshold allergen doses, with and without topical vasoconstrictor pre-treatment. The vasoconstrictor effectively eliminated obstruction at both allergen dose levels, suggesting that acute vascular changes were responsible for all the measurable obstruction seen with acute allergen provocation. Alpha-adrenergic vasoconstrictor pre-treatment was associated with increased weight of secretion and numbers of sneezes.

Administration, Intranasal↗

PubMed1996

Inhibition of prostaglandin synthesis in newborn pigs increases cerebral microvessel prostaglandin F2 alpha and prostaglandin E2 receptors, their second messengers and vasoconstrictor response to adult levels.

We recently reported that the density of prostaglandin (PG) F2 alpha and E2 receptors (FP and EP) on the cerebral microvasculature of the newborn is less than on that of the adult animal. This study tests the hypothesis that higher levels of PGF2 alpha and PGE2 in the newborn than in the adult brain might down-regulate FP and EP and their functions in the cerebral microvasculature. Newborn pigs (1-2 days old) were treated with ibuprofen (40 mg/kg i.v.) every 6 h for 48 h; and cerebrovascular FP and EP density, receptor-coupled second messenger production and cerebral vasoconstrictor responses to PGF2 alpha and PGE2 were determined. The results showed that ibuprofen treatment in the newborn increased brain microvascular FP and EP densities to levels found in the brains of adult pigs. This up-regulation of prostaglandin receptors was also observed in isolated newborn brain microvessels incubated for 48 h with ibuprofen. PGF 2 alpha, fenprostalene (PGF2 alpha analog), PGE2, 17-phenyl trinor PGE2 (EP1 receptor subtype agonist) and M&B 28,767 (EP3 agonist) caused a significantly greater increase in inositol 1,4,5-triphosphate production in brain microvessels of ibuprofen-treated than in brain microvessels of saline-treated newborn pigs. The cerebral vasoconstrictor effects of PGF2 alpha, 17-phenyl trinor PGE2 and M&B 28,767 were also significantly increased in newborn pigs treated with ibuprofen to levels comparable to those of adults. However, the steady-state level of FP mRNA in cerebral microvasculature did not differ between saline-treated newborn, ibuprofen-treated newborn and adult pigs. It is concluded that the low FP and EP densities in newborn brain microvessels are a result of high levels of brain prostaglandins and that these receptors, receptor-coupled second messengers and cerebral vasoconstrictor responses to FP, EP1 and EP3 stimulation can be up-regulated to adult levels by decreasing endogenous prostaglandin production. The changes in receptor levels were not related to steady-state levels of receptor mRNA in brain microvessels.

Animals↗

PubMed1997

Differentiation of muscarinic receptors mediating negative chronotropic and vasoconstrictor responses to acetylcholine in isolated rat hearts.

The primary goal of this study was to determine the extent that selective muscarinic receptor antagonists could discriminate between the chronotropic and coronary vasoconstrictor responses to acetylcholine in isolated rat hearts perfused at constant flow rate. Bolus injections of acetylcholine caused dose-dependent decreases in heart rate and increases in perfusion pressure. The ED50 (95% confidence) of acetylcholine for decreasing rate was 0.463 (0.336-0.640) nmol and the dose that increased perfusion pressure by 30 mm Hg (ED30 mmHg) was 3.19 (2.00-5.08) nmol. The M2 selective antagonist methoctramine (3.16 microM) produced a 307-fold increase in the ED50 for bradycardia but had no significant effect on the pressor response to acetylcholine. In marked contrast, the M3 antagonist hexahydrosiladifenidol displayed a distinct preference for inhibiting coronary vasoconstrictor responses to acetylcholine. When present at 316 nM, this drug produced a 66-fold increase in the ED30 mmHg but only a 6-fold increase in the ED50 for bradycardia. The M1 selective antagonist pirenzepine (316 nM) produced a 5- to 7-fold increase in both parameters. Pretreatment with pertussis toxin (25 microg/kg, i.p.) essentially eliminated acetylcholine-evoked bradycardia although pressor responses persisted with some reduction. These observations demonstrate that cardiac and coronary vascular effects of acetylcholine can be clearly discriminated with specific muscarinic antagonists. Furthermore, they provide evidence that the M3 receptor subtype mediates the vasoconstrictor effect of acetylcholine on resistance vessels in rat heart.

Acetylcholine↗

PubMed2004

Radiotherapy combined with transarterial infusion chemotherapy and concurrent infusion of a vasoconstrictor agent for nonresectable advanced hepatic hilar duct carcinoma.

BACKGROUND: The treatment of patients with advanced hepatic hilar duct carcinoma is a challenging problem. The current study was performed to evaluate the outcome of patients with advanced hepatic hilar duct carcinoma who received external beam radiotherapy (EBRT) combined with transarterial chemotherapy and infusion of a vasoconstrictor. METHODS: Between April 1993 and December 2002, 23 patients with histopathologically confirmed hilar duct carcinoma entered the study. The median total dose of EBRT was 41.4 grays (Gy). Transarterial chemotherapy was performed twice during EBRT. It was comprised of an infusion of a cocktail of 20 mg of epirubicin, 10 mg of mitomycin C, and 500 mg of 5-fluorouracil and was administered 1 minute after injection of epinephrine via a catheter introduced in the hepatic arteries. After the combined treatment, the patients underwent biliary endoprosthesis after evaluation of the initial response to treatment by percutaneous transhepatic cholangiography (PTC). The initial responses based on PTC were classified into four categories: CR, no stenosis; PR, relief of stenosis/obstruction; NC, no change; and PD, progressive stenosis/obstruction. The outcome parameters were survival rates and time, as well as frequency and type of complications. RESULTS: Excluding 1 patient who discontinued the treatment, the initial responses of 22 patients were 1 CR (5%), 8 PR (36%), 11 NC (50%), and 2 PD (9%). The response rate was 41%. The overall survival rates at 1 year, 2 years, and 3 years after treatment were 59%, 36%, and 18%, respectively. CONCLUSIONS: The combination of radiotherapy, transarterial infusion chemotherapy, and concurrent infusion of a vasoconstrictor can be delivered safely with good efficacy for patients with advanced hilar duct carcinoma.

Aged↗

PubMed1987

Endothelial cells in culture produce a vasoconstrictor substance.

We report that cultured vascular endothelial cells release into the culture medium a vasoconstrictor peptide, a substance we call an endothelium-derived constricting factor (EDCF). Conditioned medium from cultured bovine aortic and pulmonary artery endothelial cells caused sustained, dose-dependent isometric constriction of vascular rings isolated from bovine coronary and pulmonary arteries and rat and guinea pig pulmonary arteries and aortas. The medium also caused vasoconstriction when infused into isolated, perfused rabbit hearts and rat kidneys. Conditioned medium from bovine aortic intimal explants also contained constrictor activity, whereas medium from denuded intimal explants, cultured microvascular endothelial cells, vascular smooth muscle cells, or lung fibroblasts did not. Constrictor activity increased progressively in the culture medium over 2-12 h of incubation. Thrombin stimulated the release of constrictor activity; hypoxia, anoxia and meclofenamate had no effect and the calcium ionophore A23187 inhibited EDCF release. The EDCF caused a characteristic slow-onset and sustained constriction of the vascular rings that relaxed slowly over 60-90 min following removal. The constriction was not affected by inhibitors of arachidonic acid metabolism or by antagonists of serotonergic, histaminergic, alpha-adrenergic, opioid, leukotriene, angiotensin II, or substance P receptors; constriction was reversed partly by verapamil and acetylcholine and completely by nitroprusside and isoproterenol. EDCF was heat stable, not extractable into organic solvents, and completely destroyed by trypsin and neutral protease. Cycloheximide blocked the production of EDCF. These properties and the results of polyacrylamide gel filtration experiments suggested that EDCF was a peptide with a molecular weight of 3,000 daltons. These findings show that endothelial cells in culture produce a vasoconstrictor substance and support the idea that endothelial cell products play a role in mediating vascular tone.

Animals↗

PubMed1975

Simple isolated perfused artery preparation: vasoconstrictor evaluation.

Small mesenteric arteries free of all extraarterial tissues were obtained from anesthetized dogs and perfused in vitro with Krebs solution. Vasoconstrictor responses of these arteries to intraarterial levarterenol and epinephrine were dose related and equivalent to those of arteries surrounded by fat and other tissues. Responsiveness was stable for at least 60 min. This simple preparation is useful for the study of vasoconstrictor phenomena uncomplicated arterial tissue.

Animals↗

PubMed1996

Anatomical differences in responsiveness to vasoconstrictors in the mesenteric veins from normal and portal hypertensive rats.

The present study evaluates the effects of pre-hepatic portal hypertension, induced in rats by partial portal vein ligation, on the responsiveness of rostral (proximal) and caudal (distal) rings from the mesenteric vein. The anatomical origin of the sample influenced the response to vasoconstrictors in sham-operated animals, and this pattern of reactivity was specifically modified in portal-ligated rats. In veins from sham-operated rats, contraction induced by a submaximal concentration of KCl (60 mM) was greater in proximal than in distal rings. Vasopressin and 5-hydroxytryptamine contracted mainly distal rings, methoxamine showed a greater effect on proximal rings, and endothelin-1 and angiotensin-II contracted vein rings independently of their anatomical origin. In veins from portal hypertensive rats, response to KCl (60 mM) were increased in distal rings, and all rings exhibited enhanced reactivity to vasopressin and 5-hydroxyptyptamine as well as attenuation of the response to methoxamine. Responses to endothelin-1 were decreased in proximal vein rings from portal hypertensive rats whereas responses to angiotensin-II were not influenced by the anatomical origin. Incubation with atropine, propranolol or indomethacin, did not modify the responses to vasopressin and 5-hydroxytryptamine in tissues from either sham-operated or portal hypertensive animals. Likewise, the hyporeactivity to methoxamine and endothelin-1 in rings from portal hypertensive rats persisted in the presence of the nitric oxide inhibitor NG-nitro-L-arginine methyl ester. These results suggest the physiological existence of anatomical differences in the responsiveness to vasoconstrictors throughout the mesenteric vein and that changes in the responsiveness of the mesenteric vein induced by portal hypertension are specific for each agonist and possibly result from individual variations at a receptor or post-receptor level.

Animals↗

PubMed1992

Evidence for direct vasoconstrictor activity of melatonin in "pressurized" segments of isolated caudal artery from juvenile rats.

Responses of isolated, 60 mmHg 'pressurized' segments of the distal caudal artery of adult and juvenile Wistar rats to melatonin and the selective alpha 2-adrenoceptor agonist 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate (UK-14304) were examined using the Halpern pressure myograph. Melatonin showed no direct vasoconstrictor activity in vessels from adult rats, whereas UK-14304 produced moderate vasoconstriction (pD2-7.43 +/- 0.09). In the presence of phenylephrine-induced tone, melatonin produced a variable but small constrictor response (less than 10 microns reduction in diameter) in some vessels; the response to 1 mumol/l UK-14304 was less than in the absence of tone. In vessels isolated from juvenile rats, melatonin caused concentration-dependent vasoconstriction with a maximum response about 70% of the maximum response elicited by UK-14304. Vessels from juvenile rats were more sensitive to melatonin (pD2-9.40 +/- 0.07) than they were to UK-14304 (pD2-8.12 +/- 0.14). In the presence of phenylephrine-induced tone, the vasoconstrictor responses to both melatonin and IK-14304 were markedly less; the sensitivity to melatonin was not different from that seen in the absence of tone. These findings indicate that 'pressurized' segments of the isolated distal caudal artery may provide a simple and convenient, functional model of melatonin receptors. The findings also appear to implicate melatonin in thermoregulatory processes in juvenile rats.

Aging↗

PubMed1978

Comparative study of the vasoconstrictor activity of halopredone acetate in a modified McKenzie test.

The vasoconstrictor activity of four steroids, administered in solution and in the commercially available form, were compared in healthy volunteer subjects. Evaluation was based on conventional visual observations and photometric measurement of reflectance. Statistical analysis showed that halopredone acetate had less vasoconstrictor action on healthy skin than fluocinolone acetonide, beta-methasone valerate and hydrocortisone acetate. The halopredone acetate results were identical to those of th excipient, although it was found that halopredone acetate cream (Topicon) had a marked anti-inflammatory effect in animals and on human dermatoses. The validity of the McKenzie test, as an unequivocal screening procedure for the potency of topical steroids is discussed, and the accuracy and precision of photometric evaluation is emphasized.

Administration, Topical↗

PubMed1987

Vasoconstrictor effects of endogenous digitalis-like factors extracted from urine of hypertensive patients.

The vascular effects of endogenous digitalis-like factors (EDLFs) extracted from the urine of hypertensive patients were investigated in isolated and perfused intermediate auricular and mesenteric arterial preparations of dogs. EDLFs produced a transient vasoconstriction in a dose-related manner in intermediate auricular arteries but only a slight constriction in mesenteric arteries. Ouabain induced a long-lasting vasoconstriction with tachyphylaxis in intermediate auricular arteries, but it did not constrict mesenteric arteries. EDLF-induced vasoconstrictions were reproducible and were not modified by alpha-adrenoceptor blockade. They were slightly suppressed by a potent calcium entry blocker, verapamil, in doses which markedly suppressed KCl-induced vasoconstrictions. Noradrenaline- and KCl-induced vasoconstrictions were not significantly modified by either EDLF or ouabain. From these results, it is concluded that EDLF has clear vasoconstrictor properties which are not due to adrenergic or calcium entry mechanisms and that there are differences in the vasoconstrictor effects of EDLFs with respect to different vascular beds. This is similar to what was found with ouabain.

Animals↗

PubMed1994

Identification of the Ca2+ current activated by vasoconstrictors in vascular smooth muscle cells.

The noncontractile aortic cell line A7r5 was chosen to study the effect of the vasoconstrictor peptide vasopressin on transmembrane Ca2+ movements, using conventional whole-cell patch recording techniques. Conditions in which previously characterised vasoconstrictor-modulated currents were suppressed revealed a tiny inward current component (-18 +/- 2 pA, n = 50, at -61 mV in 110 mM CaCl2). The vasopressin-activated inward current was absent when Ca2+ was absent from the extracellular solution, and the current amplitude increased with [Ca2+] (0.01-110 mM), with an apparent dissociation constant for Ca2+ of 9.7 mM. It was highly selective for Ca2+ over monovalent cations (permeability ratio Ca/Cs greater than 17). It was not voltage gated, except that the current/potential characteristic showed some inwards rectification. Amplitudes of the evoked inward currents had the same order of magnitude in Sr2+ and Ca2+, whereas they were much smaller in Mn2+, suggesting that this pathway is highly permeable to Sr2+ but poorly permeable to Mn2+. Inward currents evoked in Ca2+ were inhibited by other cations with the following order of potency: La3+ > Cd2+ > Co2+ approximately Ni2+ approximately Mn2+. The channel producing this current corresponds most probably to the ionic pathway originally called the receptor-operated calcium channel, which produces a long-lasting, constrictor-induced plateau of increased intracellular free calcium concentration in smooth muscle.

Animals↗

PubMed1997

Interactions between vasoconstrictors in isolated human cerebral arteries.

This study investigates whether different endogeneous vasoconstrictors exert synergistic effects in isolated human cerebral arteries, because potentiation of contractile effects may play a role in the pathogenesis of cerebral vasospasm. Isolated human pial arteries obtained from macroscopically intact tissue during brain tumour operations were mounted onto a wire myograph. Concentration-response curves of 5-hydroxytryptamine (5-HT) were constructed in the absence and presence of threshold concentrations of the thromboxane A2 (TXA)-analog U46619, and endothelin-1 (ET-1). Threshold concentrations of U46619 markedly enhanced the maximum contractile effect of 5-HT. The response to 5-HT remained markedly increased even after washout of U46619. Threshold concentrations of ET-1 increased the maximum response to 5-HT, and markedly shifted the dose-response curve to the left. Even after washout of ET-1, the dose-response curve of 5-HT remained shifted to the left. The increase of the contractile effect of 5-HT in the presence of U46619 did not correlate with the relaxant action of the endothelium-dependent vasodilator carbachol. Thus, synergism between contractile substances such as 5-HT, U46619, or ET-1 is seen in human cerebral arteries, and responses to 5-HT are potentiated even after washout of ET-1 and U46619. The potentiation does not depend on the endothelial function. We conclude that synergistic responses between endogeneous vasoconstrictors such as 5-HT, TXA and ET-1 may be involved in the pathogenesis of cerebral vasospasm after subarachnoid haemorrhage.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2003

Increased vasoconstrictor reactivity and decreased endothelial function in high grade varicocele; functional and morphological study.

The pathophysiology of human varicocele is not fully understood. We investigated vasoconstrictor reactivity, endothelial function and morphological changes in different grades of varicocele to clarify the pathophysiology. Contractile responses to phenylephrine, norepinephrine, serotonin and histamine were determined in isolated human varicose spermatic veins using the organ bath technique. Endothelial function was tested with acetylcholine-induced relaxation after phenylephrine-induced precontraction in the absence and presence of nitric oxide synthase inhibitor, L-NAME, and cyclooxygenase inhibitor, indomethacin. The cyclic guanosine monophosphate (cGMP) level was measured in the spermatic vein and peripheral plasma. Morphological changes were evaluated with light microscopy. Phenylephrine, norepinephrine, serotonin and histamine induced concentration-dependent contractions. The maximum contractions for all of these agents except norepinephrine were significantly higher in grade III than grade I and II (P<0.05). The sensitivity to phenylephrine was significantly higher in grades II and III than in grade I (P<0.05). In the presence of L-NAME and indomethacin, the difference from respective control phenylephrine-induced contractions was higher in grade I and II than grade III. Acetylcholine did not induce stable relaxation but the level of cGMP, which is responsible for the vasorelaxant effect of NO, in veins was lower in grades II and III than grade I (P<0.05). Vessel wall thickness increased in grade II and dilatation developed in grade III when compared to grade I (P<0.05). Our findings suggest that endothelium produces less vasorelaxant which results in the more enhanced effects of vasoconstrictor substances in grade III, indicating that endothelial dysfunction develops at high grades of varicocele.

Endothelium, Vascular↗