Contractile Responses Of Mesenteric Arteries Research Articles

Intrauterine\ufeff growth restriction weakens anticontractile influence of NO in coronary arteries of adult rats

Intrauterine growth restriction (IUGR) is one of the most common pathologies of pregnancy. The cardiovascular consequences of IUGR do not disappear in adulthood and can manifest themselves in pathological alterations of vasomotor control. The hypothesis was tested that IUGR weakens anticontractile influence of NO and augments procontractile influence of Rho-kinase in arteries of adult offspring. To model IUGR in the rat, dams were 50% food restricted starting from the gestational day 11 till delivery. Mesenteric and coronary arteries of male offspring were studied at the age of 3 months using wire myography, qPCR, and Western blotting. Contractile responses of mesenteric arteries to α1-adrenoceptor agonist methoxamine as well as influences of NO and Rho-kinase did not differ between control and IUGR rats. However, coronary arteries of IUGR rats demonstrated elevated contraction to thromboxane A2 receptor agonist U46619 due to weakened anticontractile influence of NO and enhanced role of Rho-kinase in the endothelium. This was accompanied by reduced abundance of SODI protein and elevated content of RhoA protein in coronary arteries of IUGR rats. IUGR considerably changes the regulation of coronary vascular tone in adulthood and, therefore, can serve as a risk factor for the development of cardiac disorders.

Effects of different vasopressors on the contraction of the superior mesenteric artery and uterine artery in rats during late pregnancy

BackgroundHypotension after neuraxial anaesthesia is one of the most common complications during caesarean section. Vasopressors are the most effective method to improve hypotension, but which of these drugs is best for caesarean section is not clear. We assessed the effects of vasopressors on the contractile response of uterine arteries and superior mesenteric arteries in pregnant rats to identify a drug that increases the blood pressure of the systemic circulation while minimally affecting the uterine and placental circulation.MethodsIsolated ring segments from the uterine and superior mesenteric arteries of pregnant rats were mounted in organ baths, and the contractile responses to several vasopressor agents were studied. Concentration-response curves for norepinephrine, phenylephrine, metaraminol and vasopressin were constructed.ResultsThe contractile response of the mesenteric artery to norepinephrine, as measured by the pEC50 of the drug, was stronger than the uterine artery (5.617 ± 0.11 vs. 4.493 ± 1.35, p = 0.009), and the contractile response of the uterine artery to metaraminol was stronger than the mesenteric artery (pEC50: 5.084 ± 0.17 vs. 4.92 ± 0.10, p = 0.007). There was no statistically significant difference in the pEC50 of phenylephrine or vasopressin between the two blood vessels.ConclusionsIn vitro experiments showed that norepinephrine contracts peripheral blood vessels more strongly and had the least effect on uterine artery contraction. These findings support the use of norepinephrine in mothers between the time of neuraxial anaesthesia and the delivery of the foetus.

Activation of Nav channels by veratridine in mesenteric arteries: Contractile or relaxation responses?

Veratridine (VTD), a selective activator of voltage-gated Na + (Nav) channels, triggers contractile responses in mesenteric arteries (MA), by increasing intracellular Ca2+ mediated by Na + /Ca 2+ exchanger (NCX) in smooth muscle cells (SMC). However, VTD induces endothelium-dependent relaxation of retinal and cremaster arteries. These opposite VTD-responses gives rise to the question as to whether Nav channels play a role in vascular tone. We aim to characterize the contribution of Nav channels to vascular tone in MA. Since Nav channels are expressed in SMC, endothelial cells (EC) and nerve terminal endings of arteries, our aim is also to identify those which are responsible of VTD-evoked vasomotor responses. The VTD-induced contractile responses of first order mesenteric arteries (FOMA) and cecolic arteries (CA) of mice were recorded by wire myography. EC were used to characterize Ca 2+ responses using FURA-2 probe. Western blot and absolute RT-qPCR were used to characterize Nav channels and NCX expression. Nav1.2 channels are expressed in both SMC and EC of MA. VTD elicits contraction of FOMA, which is abolished by prazosin. Surprisingly, VTD induces relaxation of CA. This vasorelaxation is resistant to prazosin and supressed by atropine. VTD-induced relaxation is inhibited by eNO-synthase inhibitor (L-NNA) and NCX antagonists. Morever, NCX1 is the main NCX isoform expressed in EC. Finally, acetylcholine-induced Ca 2+ reponses are inhibited by NCX antagonists in endothelial cells. VTD induces opposite contractile responses in isolated mesenteric arteries. In fact, VTD activates Nav channels of sympathetic neurons in FOMA, and parasympathetic neurons in CA, leading to noradrenaline and acetylcholine release, respectively. Thus, the vascular tone of both arteries are differently regulated by the autonomic nervous system. Finally, acetylcholine triggers Ca 2+ -activation of eNO-synthase mediated by NCX1 in CA.

Differential mechanisms of action of the trace amines octopamine, synephrine and tyramine on the porcine coronary and mesenteric artery

Trace amines such as p-tyramine, p-octopamine and p-synephrine are found in low concentrations in animals and plants. Consumption of pre-workout supplements containing these plant-derived amines has been associated with cardiovascular side effects. The aim of this study was to determine the mechanisms of action of these trace amines on porcine isolated coronary and mesenteric arteries. Noradrenaline caused contraction of mesenteric arteries and relaxation of coronary arteries. In both tissues, all three trace amines induced contractions with similar potencies and responses were unaffected by the β-adrenoceptor antagonist propranolol (1 µM), the nitric oxide synthase inhibitor L-NNA (100 µM), or the TAAR-1 antagonist, EPPTB (100 nM). However, the contractile responses of mesenteric arteries, but not coronary arteries, were significantly reduced by depletion of endogenous noradrenaline. Mesenteric responses to all three amines were abolished in the presence of prazosin (1 µM) whereas residual contractile responses remained in the coronary artery which were inhibited by a high concentration (100 µM) of EPPTB. The results suggest complex responses of the coronary artery to the trace amines, with activity at α1-adrenoceptors and potentially TAARs other than TAAR-1. In contrast the actions of the amines on the mesenteric artery appeared to involve indirect sympathomimetic actions and direct actions on α1-adrenoceptors.

Testosterone plays a permissive role in angiotensin II-induced hypertension and cardiac hypertrophy in male rats.

Sex hormones contribute to sex differences in blood pressure. Inappropriate activation of the renin-angiotensin system is involved in vascular dysfunction and hypertension. This study evaluated the role of androgens (testosterone) in angiotensin II (Ang II)-induced increase in blood pressure, vascular reactivity, and cardiac hypertrophy. Eight-week-old male Wistar rats underwent sham operation, castration, or castration with testosterone replacement. After 12 weeks of chronic changes in androgen status, Ang II (120 ng/kg per minute) or saline was infused for 28 days via subcutaneous miniosmotic pump, and changes in blood pressure was measured. Vascular reactivity and Ang II receptor levels were examined in mesenteric arteries. Heart weight, cardiac ANP mRNA levels, and fibrosis were also assessed. Ang II infusion increased arterial pressure in intact males. The Ang II-induced increase in hypertensive response was prevented in castrated males. Testosterone replacement in castrated males restored Ang II-induced hypertensive responses. Castration reduced vascular AT1R/AT2R ratio, an effect that was reversed by testosterone replacement. Ang II-induced hypertension was associated with increased contractile response of mesenteric arteries to Ang II and phenylephrine in intact and testosterone-replaced castrated males; these increases were prevented in castrated males. Ang II infusion induced increased left ventricle-to-body weight ratio and ANP mRNA expression, indicators of left ventricular hypertrophy, and fibrosis in intact and testosterone-replaced castrated males, and castration prevented the increase in these parameters caused by Ang II. This study demonstrates that testosterone plays a permissive role in development and maintenance of Ang II-induced vascular dysfunction, hypertension, and cardiac hypertrophy.

Pressor response to angiotensin II is enhanced in aged mice and associated with inflammation, vasoconstriction and oxidative stress.

Aging is commonly associated with chronic low-grade inflammation and hypertension but it is unknown whether a cause-effect relationship exists between them. We compared the sensitivity of young adult (8-12 w) and aged (23-31 mo) male C57Bl6J mice to develop hypertension in response to a slow-pressor dose of angiotensin II (Ang II; 0.28 mg/kg/d; 28 d). In young mice, the pressor response to Ang II was gradual and increased to 142±8 mmHg over 28 d. However, in aged mice, Ang II promptly increased SBP and reached 155±12 mmHg by 28 d. Aging increased renal but not brain expression of Ang II receptors (At1ar and At2r) and elevated AT1R:AT2R expression ratio in mesenteric artery. Maximal contractile responses of mesenteric arteries to Ang II were enhanced in aged mice and were not affected by L-NAME, indomethacin or tempol. Mesenteric arteries and thoracic aortae from aged mice exhibited higher Nox2-dependent superoxide production. Despite having higher renal expression of Nlrp3, Casp-1 and Il-1β, Ang II-induced hypertension (SBP: 139±7 mmHg) was unaffected by co-infusion of the NLRP3 inflammasome inhibitor, MCC950 (10 mg/kg/d; SBP: 145±10 mmHg). Thus, increased vascular AT1R:AT2R expression, rather than NLRP3 inflammasome activation, may contribute to enhanced responses to Ang II in aging.

Effects of Nuclear Factor-E2-related factor 2/Heme Oxygenase 1 on splanchnic hemodynamics in experimental cirrhosis with portal hypertension

ObjectiveWe explored the effects of Nuclear Factor-E2-related factor 2 (Nrf2) and Heme Oxygenase 1 (HO-1) on splanchnic hemodynamics in portal hypertensive rats. MethodsExperimental cirrhosis with portal hypertension was induced by intraperitoneal injection of carbon tetrachloride. The expression of proteins was examined by immunoblotting. Hemodynamic studies were performed by radioactive microspheres. The vascular perfusion system was used to measure the contractile response of mesentery arterioles in rats. ResultsNrf2 expression in the nucleus and HO-1 expression in cytoplasm was significantly enhanced in portal hypertensive rats. Portal pressure, as well as regional blood flow, increased significantly in portal hypertension and can be blocked by tin protoporphyrin IX. The expression of endogenous nitric oxide synthase and vascular endothelial growth factors increased significantly compared to normal rats, while HO-1 inhibition decreased the expression of these proteins significantly. The contractile response of mesenteric arteries decreased in portal hypertension, but can be partially recovered through tin protoporphyrin IX treatment. ConclusionsThe expression of Nrf2/HO-1 increased in mesenteric arteries of portal hypertensive rats, which was related to oxidative stress. HO-1was involved in increased portal pressure and anomaly splanchnic hemodynamics in portal hypertensive rats.

Fludrocortisone and Hydrocortisone, Alone or in Combination, on In Vivo Hemodynamics and In Vitro Vascular Reactivity in Normal and Endotoxemic Rats

Hydrocortisone enhances the pressor response to catecholamines in healthy volunteers and septic shock patients. Similar data do not exist for fludrocortisone. We assessed the effects of single administrations of fludrocortisone and hydrocortisone on systolic blood pressure until 2 hours after treatments injection and on in vitro vascular contraction of mesenteric artery rings to phenylephrine at 3 hours, in normal and endotoxemic rats. Intravenous fludrocortisone (5 and 20 μg/kg) and hydrocortisone (4 and 20 mg/kg) were administered in 16 groups (8 without and 8 with lipopolysaccharide-induced endotoxemic shock) of 10 Wistar rats according to four 2 × 2-factorial designs. Fludrocortisone and hydrocortisone similarly increased systolic blood pressure (P < 0.001 for both) but more in endotoxemic than in normal animals. Fludrocortisone and hydrocortisone significantly modified contractile response to phenylephrine (P = 0.039 and P = 0.007, respectively). At dose 1, fludrocortisone had no effect and hydrocortisone decreased contraction, whereas, at dose 2, both fludrocortisone and hydrocortisone increased contraction, especially in endotoxemic rats and with additive effect. Our results show that single intravenous administrations of fludrocortisone and hydrocortisone increase blood pressure and contractile response of mesenteric arteries to phenylephrine. The magnitude of these effects depends on dose and pathophysiological conditions and is higher in endotoxemic than in normal rats.

Contribution of Rho kinase to blood pressure elevation and vasoconstrictor responsiveness in type 2 diabetic Goto–Kakizaki rats

The RhoA-Rho kinase (ROCK) pathway contributes to a number of diabetic complications including cardiomyopathy and nephropathy. In this study, we investigated whether it contributes to elevated blood pressure and vascular contractile dysfunction in type 2 diabetes. Blood pressure was measured in Goto-Kakizaki rats, a nonobese model of type 2 diabetes, before and after treatment with the ROCK inhibitor fasudil. Vasoconstrictor responsiveness in the absence and presence of ROCK inhibitors as well as ROCK pathway activity was measured in isolated mesenteric resistance vessels from these animals. Blood pressure was elevated in diabetic rats compared with age-matched Wistar controls, and was normalized by treatment with fasudil. Contractile responses of mesenteric arteries from diabetic rats to phenylephrine and U-46619, as well as relaxant responses to acetylcholine, were unaltered. However, vasoconstrictor responses were more sensitive to ROCK inhibition with either Y-27632 or H-1152 than were responses of control arteries. No differences were found in expression of RhoA, ROCK1, or ROCK2 or in basal ROCK activity between arteries from control and diabetic rats. U-46619 produced a similar magnitude of increase in ROCK activity that was completely blocked by H-1152 in arteries from both groups of animals. These data suggest that ROCK contributes to the increase in blood pressure in type 2 diabetic Goto-Kakizaki rats, and that vasoconstrictor responses of small mesenteric arteries from these animals are more dependent on ROCK than are responses of control arteries.

Bimodal effects of chronically administered neurokinin B (NKB) on in vivo and in vitro cardiovascular responses in female rats

The in vivo cardiovascular effects of acutely administered neurokinin B (NKB) have been attributed both to direct effects on vascular tone and to indirect effects on central neuroendocrine control of the circulation. We proposed: 1) that a modest long-term increase in plasma NKB levels would decrease mean arterial pressure (MAP) due to attenuated peripheral vascular tone, and 2) that chronic high-dose NKB would increase MAP, due to increased sympathetic outflow which would override the peripheral vasodilation. We examined the in vivo and in vitro cardiovascular effects of chronic peripheral NKB. Low- (1.8 nmol/h) or high- (20 nmol/h) dose NKB was infused into conscious female rats bearing telemetric pressure transducers. MAP, heart rate (HR) and the pressor responses to I.V. phenylephrine (PE, 8 μg) and angiotensin II (Ang II, 150 ng) were measured. Concentration–response curves of small mesenteric arteries were constructed to PE using wire myography. Low-dose NKB reduced basal MAP (88 ± 2 mm Hg to 83 ± 2 mm Hg), did not affect resting HR, reduced the pressor responses to PE, and attenuated the maximal constriction of mesenteric arteries to PE and KCl. By contrast, high-dose NKB increased basal MAP (86 ± 1 mm Hg to 89 ± 1 mm Hg), increased HR (350 ± 3 beats/min to 371 ± 3 beats/min), increased the pressor responses to Ang II and, contrary to our hypothesis, increased the maximum contractile responses of mesenteric arteries to PE and KCl. The cardiovascular effects of NKB are thus dose-dependent: whereas chronic low-dose NKB directly modulates vascular tone to reduce blood pressure, chronic high-dose NKB induces an increase in blood pressure through both central (indirect) and peripheral (direct) pathways.

Role of the PKC/CPI‐17 pathway in enhanced contractile responses of mesenteric arteries from diabetic rats to α‐adrenoceptor stimulation

Protein kinase C (PKC) may contribute to enhanced contractile responses of arteries from streptozotocin-diabetic rats to stimulation of G-protein coupled receptors. This was investigated by comparing the effects of PKC inhibitors on contractile responses of mesenteric arteries from diabetic and age-matched control rats to noradrenaline (NA) and endothelin-1 (ET-1). The effects of NA and ET-1 on the distribution of three isoforms of PKC implicated in contraction were also determined. In addition, the effect of NA on phosphorylation of CPI-17, a substrate for PKC, was investigated. Contractile responses of endothelium-denuded arteries from diabetic rats to NA were enhanced, but were normalized by PKC inhibition. In contrast, contractile responses to ET-1 were not significantly different, and were blocked to a similar extent by PKC inhibition, in arteries from control and diabetic rats.NA produced only a small increase in particulate levels of PKCepsilon in control arteries (to 125+/-8% of levels in untreated arteries), but a significant increase in particulate PKCalpha (to 190+/-22%) and a much greater increase in particulate PKCepsilon (to 230+/-19%) in arteries from diabetic rats. ET-1 increased particulate PKCalpha and epsilon to a similar extent in arteries from control and diabetic rats.NA significantly enhanced CPI-17 phosphorylation from a basal level of 22+/-10 to 71+/-7% of total in arteries from diabetic rats, and this was prevented by PKC inhibition. NA had no detectable effect on CPI-17 phosphorylation in arteries from control rats. These data suggest that NA-induced activation of PKC and CPI-17, its downstream target, is selectively enhanced in arteries from diabetic rats, and mediates the enhanced contractile responses to this agonist.

Age-dependent changes in blood pressure and arterial reactivity in obese Zucker rats

The purpose of the present investigation was to determine whether there is an association between changes in arterial reactivity to vasoactive agents and the development of hypertension in obese Zucker rats. At 20 weeks of age, obese rats were mildly hypotensive compared to their lean littermate controls. Maximum contractile responses of endothelium-intact mesenteric arteries from these rats to noradrenaline, endothelin-1 and KCl were depressed, although there was no change in relaxation to acetylcholine. By 32 weeks of age, obese rats had developed hypertension compared to their lean littermate controls. Maximum contractile responses of mesenteric arteries from 32-week-old obese rats to noradrenaline and endothelin-1 were no longer significantly different than control, although contractile responses to KCl remained depressed. In addition, there was a small increase in sensitivity to endothelin-1, while endothelium-dependent relaxation to acetylcholine was impaired. In contrast, there were no changes in contractile responses of endothelium-intact aortas from either 20- or 32-week-old obese rats to noradrenaline, endothelin-1 or KCl, while endothelium-dependent relaxation of this artery to acetylcholine was slightly enhanced at both ages. Therefore, changes in the reactivity of the mesenteric artery but not the aorta from obese Zucker rats parallel changes in blood pressure in these animals.

Differences in K + current components in mesenteric artery myocytes from WKY and SHR

Previous studies have documented increased K + permeability of arterial smooth muscle in hypertension and suggested a role in altered arterial contractile function. To characterize the mechanisms responsible for these alterations, we determined the contribution of K + current (I K) components to whole cell I K in freshly dispersed myocytes and tetraethylammonium (TEA)-induced contractile responses in mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Tetraethylammonium produced a larger tonic contractile response in SHR with a lower threshold compared to WKY (ie, 0.1 v 1 mmol/L), which was due in part to the larger Ca 2+ current in SHR. Whole cell I K recorded by perforated patch methods was similar at a holding potential (HP) of −60 mV (I K60), but were larger in SHR when recorded from a HP of −20 mV (I K20). The selective blocker iberiotoxin (IbTX) was used to separate the contribution of voltage- (K V) and calcium-dependent (K Ca) components of I K60. The I K60 and I K20 component inhibited by 100 nmol/L IbTX (ie, K Ca) was larger in SHR than in WKY myocytes, whereas the IbTX-insensitive I K60 component (ie, K V) was larger in WKY. In the presence of IbTX, 1 and 10 mmol/L TEA inhibited a larger fraction of I K60 in SHR myocytes compared with WKY. The activation properties of the TEA-sensitive and TEA-insensitive K V components determined by fitting a Boltzmann activation function to the current-voltage data, exhibited both group and treatment differences in the half maximal activation voltage (V 0.5). The V 0.5 of the TEA-sensitive K V component was more positive than that of the TEA-insensitive component in both groups, and values for the V 0.5 of both TEA-sensitive and TEA-insensitive components were more negative in SHR than WKY. These results show that SHR myocytes have larger K Ca and smaller K V current components compared with WKY. Furthermore, SHR myocytes have a larger TEA-sensitive K V component. These differences may contribute to the differences in TEA contractions, resting membrane potential, Ca 2+ influx, and K Ca current reported in hypertensive arteries.

Long-term endothelin receptor blockade improves cardiovascular function in diabetes

To evaluate the potential contribution of endothelin-1 (ET-1) toward the cardiovascular complications of diabetes, the present study examined the effects of chronic ET receptor blockade with bosentan on heart function and vascular reactivity in streptozotocin (STZ)-induced diabetic rats. Wistar rats were divided into four groups: control, control bosentan-treated, diabetic, and diabetic bosentan-treated. After chronic bosentan treatment, cardiac function and vascular reactivity were assessed. Exvivo working heart function was determined in terms of rate of contraction (+dP/dt), rate of relaxation (−dP/dt), and left ventricular developed pressure (LVDP). Contractile responses to ET-1 were determined in isolated superior mesenteric arteries. In addition, ET-1-like immunoreactivity was determined in ventricular and vascular tissues by immunohistochemistry. Cardiac function was depressed in the untreated-diabetic group. Bosentan treatment improved working heart function; hearts from the diabetic bosentan-treated group exhibited improved LVDP and −dP/dt. The contractile responses of mesenteric arteries to ET-1 were exaggerated in the untreated-diabetic group. Long-term bosentan treatment normalized these responses. Immunohistochemical analyses revealed increased ET-1-like immunoreactivity in ventricular and vascular tissues from untreated diabetic rats. These data show the beneficial effects of ET A/B receptor blockade on cardiovascular function in STZ-diabetic rats. An altered ET-1 system may contribute toward the pathogenesis of cardiovascular dysfunction in diabetes.

Impaired contractile response of mesenteric arteries in Crohn's disease.

Crohn's disease is associated with vascular injury and dysregulation of the intestinal immune system which together can provide disturbance of mesenteric circulation functional properties. To evaluate the vascular reactivity of mesenteric arteries from patients with Crohn's disease. Phenylephrine-induced contractions were assessed from 10 patients with Crohn's disease and 8 control organ donors. NG-nitro-L-arginine-methyl-ester (L-NAME) was used to test the presence of inducible NO synthase. Endothelium dependent and independent relaxation was assessed using acetylcholine, bradykinin, calcium ionophore A23187 and sodium nitroprusside. The contractile response to phenylephrine was significantly decreased in arteries without endothelium from patients with Crohn's disease. Exposure to the NO synthase inhibitor L-NAME restored the contractile response to phenylephrine. Relaxation remained unaltered in both groups. These data provide direct evidence for fading of contraction caused by phenylephrine in Crohn's disease. The restored mesenteric artery tone by a specific NO synthase inhibitor suggests that an increased production for NO in vascular smooth muscle might be responsible of this altered vascular reactivity.

Defective Endothelium-Dependent Relaxation in Fructose-Hypertensive Rats

The present study examined the endothelium-dependent and -independent responses of isolated mesenteric arteries to acetylcholine and the endothelium-independent vasodilator sodium nitroprusside in mesenteric arteries from fructose-induced hypertensive rats. Fructose feeding resulted in hyperinsulinemia and elevated blood pressure when compared to controls (plasma insulin, 5.9 +/- 0.4 v control 3.6 +/- 0.4 ng/mL, P < .05; systolic blood pressure, 154 +/- 5 v control 127 +/- 7 mm Hg, P < .05). The maximum contractile response of mesenteric arteries to norepinephrine did not differ between the control and fructose groups, either with or without the endothelium. In arteries with intact endothelia, precontracted with the approximate ED50 of norepinephrine, the percent maximum relaxation produced by acetylcholine in hypertensive rats was lower than the control arteries (62 +/- 7 v control 95 +/- 5, P < .05) without any change in sensitivity. In arteries precontracted with norepinephrine, the endothelium-independent vasodilator sodium nitroprusside produced a dose-dependent relaxation in arteries obtained from control and fructose groups, both with and without the endothelium. The maximum relaxation produced by sodium nitroprusside did not differ between control and fructose arteries, either with or without the endothelium; however, removal of the endothelium caused an increase in sensitivity of this agonist. These data suggest that in the insulin resistant and hyperinsulinemic fructose-hypertensive rats, there is a defective endothelium-dependent yet preserved endothelium-independent relaxation.

Endothelial dysfunction of resistance arteries of spontaneously hypertensive rats.

Vascular relaxations are impaired in adult spontaneously hypertensive rats (SHRs) because of increased production of endothelium-derived, cyclooxygenase-dependent contractile factors. The objectives of the present study were to determine whether alterations in endothelial function precede the development of hypertension in SHRs and to characterize the contractile factor(s) produced by SHR endothelial cells. Mean systolic blood pressures were minimally (6 mm Hg) higher at 4 weeks of age in SHRs than in Wistar-Kyoto (WKY) rats. Endothelium-mediated relaxations of mesenteric and renal resistance arteries from SHRs and WKY rats were compared in myographs and arteriographs in paired experiments. Acetylcholine (ACh, 10(-9) to 10(-7) M) induced endothelium-dependent relaxations in precontracted mesenteric and renal resistance arteries that were similar in SHRs and WKY rats. At higher concentrations of ACh (10(-6) to 10(-5) M), relaxations were replaced by contractile responses in SHR but not in WKY rat resistance arteries. The contractile responses were endothelium dependent and were inhibited by indomethacin in both mesenteric and renal arteries. Thus, endothelial dysfunction precedes and may contribute to the development of accelerated hypertension in SHRs. SQ 29548, a prostaglandin H2 (PGH2)-thromboxane A2 receptor antagonist, blocked the contractile responses in renal but not in mesenteric resistance arteries. The contractile responses in mesenteric arteries were inhibited by 3-amino-1,2,4-triazole (10(-3) M), an inhibitor of superoxide production via the cyclooxygenase pathway. We conclude from these data that the endothelium-derived contracting factor (EDCF) produced in SHR renal arteries is most likely PGH2 whereas the contractile factor produced in mesenteric arteries is superoxide.

Augmented inositol phosphate production in mesenteric arteries from diabetic rats

The effects of noradrenaline (NA) on contraction and phosphoinositide metabolism were compared in mesenteric arteries from rats with chronic streptozotocin-induced diabetes and from age-matched control rats. Maximum contractile responses of mesenteric arteries from diabetic rats to NA (30 μM) were significantly greater than control in both the presence and absence of extracellular Ca 2+. Basal incorporation of [ 3H]myoinositol into total [ 3H]inositol phosphates was greater in diabetic than control mesenteric arteries. NA (30 μM) resulted in a time-dependent increase in total [ 3H]inositol phosphate production, which was also significantly greater in diabetic than in control preparations. The increase in total [ 3H]inositol phosphates produced by NA in both control and diabetic arterie was blocked by the α 1-adrenoceptor antagonists, prazosin. Absolute levels of inositol 1,4,5-trisphosphate (I(1,4,5)P 3), measured by protein binding assay, were also increased in response to 30 μM NA in both control and diabetic arteries. Although basal I(1,4,5)P 3 levels were not significantly different, NA-induced increases in I(1,4,5)P 3 were significantly greater in diabetic than in control arteries at each time-point measured. These data indicate that phosphoinositide metabolism is enhanced in mesenteric arteries from rats with chronic streptozotocin-induced diabetes in response to a maximum concentration of NA. Augmented production of the second messengers I(1,4,5)P 3 and presumably, 1,2-diacylgylcerol may contribute to the enhanced maximum contractile responses of the diabetic arteries to NA.

Protein kinase C‐mediated contractile responses of arteries from diabetic rats

1. The role of protein kinase C (PKC) in mediating enhanced contractile responses of aortae and mesenteric arteries from male rats with 12-14 week streptozotocin-induced diabetes to noradrenaline (NA) was investigated using the PKC activator, phorbol 12,13-dibutyrate (PDB), and the PKC inhibitor, staurosporine. 2. Maximum contractile responses of aortae and mesenteric arteries from diabetic rats to NA were significantly enhanced compared with responses of arteries from age-matched control animals. The maximum NA responses were increased by 59.6 +/- 7.9% in aortae and by 54.9 +/- 7.4% in mesenteric arteries from diabetic animals, compared to their respective controls. 3. Pretreatment of aortae and mesenteric arteries from both control and diabetic animals with staurosporine (5 x 10(-8) M) caused marked inhibition of contractile responses to a maximum concentration of NA (10(-5) M in aortae; 3 x 10(-5) M in mesenteric arteries). In the presence of staurosporine, no difference was observed in the magnitude of contractile responses of arteries from control and diabetic rats to NA. 4. Maximum contractile responses of mesenteric arteries from diabetic rats to PDB were significantly increased (by 45.0 +/- 4.9%) compared to responses of arteries from control animals. In contrast, no significant difference was found in the magnitude of contractile responses or aortae from control and diabetic rats to PDB. 5. Staurosporine (5 x 10(-8) M caused marked attenuation of contractile responses of arteries from control and diabetic rats to a maximum concentration of PDB (3 x 10(-6) M). In the presence of staurosporine, the difference in magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB was abolished. 6. Contractile responses of aortae and mesenteric arteries from control and diabetic rats to PDB were reduced in the absence of extracellular Ca2", and in the presence of the Ca2 + channel blockers, nifedipine (3 x 10-6 M) or verapamil (3 x 10-6 M). Under these conditions, no difference was found in the magnitude of contractile responses of mesenteric arteries from control and diabetic rats to PDB. 7. These data suggest that enhanced contractile responses of aortae and mesenteric arteries from streptozotocin-induced diabetic rats to NA may result, at least in part, from increased activation of PKC. In addition, increased activation of PKC-mediated processes, which are dependent on the presence of extracellular Ca2+, may further contribute to the enhanced contractile responses of diabetic mesenteric arteries to NA.

Functional and Histological Changes in Mesenteric Arteries and Aortas from Monkeys Fed a High Cholesterol Diet

Treatment of Japanese monkeys for 8 months with a high fat, high cholesterol diet produced atherosclerotic lesions in the aorta and mesenteric arteries, such as fatty dots, streaks and plaques, intimal thickening with accumulation of spindle-shaped cells and macrophages and endothelial cell flattening. Contractile responses of mesenteric arteries from control and atherosclerotic monkeys to electrical stimulation of adrenergic nerves, norepinephrine and angiotensin II did not differ, whereas contractions caused by serotonin in the atherosclerotic monkey arteries were significantly greater. Ketanserin and cinanserin suppressed the serotonin-induced contraction. Relaxations caused by adenosine and K+ (5 mM) were moderately attenuated in atherosclerotic monkey mesenteric arteries, and those by acetylcholine were reduced only slightly or not affected in the arteries or aortas. Relaxations of control and atherosclerotic arteries in response to nitroglycerin, isoproterenol and prostaglandin I2 did not differ. The relaxant response to K+ was reversed to a contraction by ouabain. Acetylcholine-induced relaxations were dependent on the endothelium and suppressed by atropine. Diet-induced atherosclerosis appears to potentiate contractions mediated via serotonergic 5-HT2 receptors and to attenuate relaxations possibly caused by activation of the elec-trogenic Na+ pump in the smooth muscle cell membrane. Endothelium-dependent relaxations via muscarinic receptors would not evidently be affected in mesenteric arteries and aortas from atherosclerotic Japanese monkeys.