Relaxation of isolated rabbit arteries by fusaric (5-butylpicolinic) acid

The influence of fusaric (5-butylpicolinic) acid on vascular contractile or relaxing response was examined in different isolated arterial preparations of the rabbit. Prior exposure (10 minutes) to 1 x 10(-4) to 1 x 10(-3) M fusaric acid decreased contractile responses elicited with norepinephrine, histamine, serotonin, acetylcholine, angiotensin II and KCl in helical strips of rabbit aorta and superior mesenteric, carotid, renal, and femoral arteries. Fusaric acid produced a shift to the right and down in the dose-response curves to all tested agonists, and antagonized acetylcholine and serotonin most effectively among these agonists. These results indicate that fusaric acid antagonized nonspecifically these contractile agonists. When blood vessels were contracted with prostaglandin F2alpha, fusaric acid caused relaxation of rabbit aorta and superior mesenteric, carotid, renal, and femoral arteries in a dose-dependent fashion. Among blood vessels tested superior mesenteric arteries were relaxed the most effectively by fusaric acid. The concentration of fusaric acid which induced 50% relaxation of aortic strips was about 10-fold higher than that of papaverine. Propranolol and atropine did not affect fusaric acid-induced relaxation, suggesting that fusaric acid did not work through beta adrenergic or cholinergic receptors. Ethylene glycol bis(beta-aminoethyl-ether)-N,N'-tetraacetic acid which chelates with Ca++ caused blood vessel relaxation in doses similar to those of fusaric acid. As fusaric acid is known to chelate Ca++, a possible mechanism of fusaric acid to relax blood vessel through Ca++ depletion is discussed briefly.     

Regional variation in appearance of vascular contractile endothelin-B receptors following organ culture

OBJECTIVE: The aim of this study was to investigate the appearance of contractile endothelin (ET)-B receptors following organ culture in different vascular regions. METHOD: The contractile responses of vascular smooth muscle induced by ET-1 and the selective ETB receptor agonist sarafotoxin 6c (S6c) were investigated in circular segments representing eight vascular regions in the rat (aorta, femoral artery, mesenteric artery, branch of the mesenteric artery, proximal and distal parts of the caudal artery, femoral and mesenteric veins). To allow the ETB receptor to be expressed, the segments were placed in organ culture for 1 to 5 days. Pharmacological characterisation of the ET receptors was performed in mesenteric arterial segments. All contractile responses were measured in percentage of K(+)-induced contraction. RESULTS: ET-1 induced strong concentration-dependent contractions of all fresh (not cultured) segments. S6c had negligible effects on all fresh vessels with the exception of the mesenteric vein, where a small contraction was seen. After 1 day of organ culture all tested segments, with the exception of aorta and the proximal part of the caudal artery, showed concentration-dependent contractile responses to S6c which were further augmented after 5 days of culture. The ET-1-induced responses were only slightly affected by organ culture. Contractions induced by S6c were more enhanced in small arteries and veins than in larger arteries. Furthermore, the S6c-induced response was more pronounced in the mesenteric region as compared to the hindlimb. In fresh mesenteric arterial segments FR139317 (ETA receptor antagonist) and bosentan (ETA/ETB receptor antagonist) but not IRL 2500 (ETB receptor antagonist) shifted the ET-1-induced concentration-response curve in parallel to the right. In contrast, after organ culture the S6c-induced concentration-response curves were shifted parallel to the right in the following potency order: IRL 2500 > bosentan > FR139317. CONCLUSION: During normal conditions, the ETA receptor is the dominating mediator of endothelin-induced contraction in eight different vascular regions. Furthermore, this study indicates that most of the vessels have the ability to develop contractile ETB receptors and that this plasticity differs in vascular regions.     

Primary sensory nerves mediate in part the protective mesenteric hyperemia after intraduodenal acidification in rats

BACKGROUND: The mechanism of intraduodenal HCl-induced mesenteric hyperemia is unknown. In anesthetized rats, the hypothesis that the primary sensory nerves mediate the intraduodenal HCl-induced protective mesenteric hyperemia was tested. METHODS: The hyperemic response in the superior mesenteric artery (SMA) and superficial villus damage after intraduodenal bolus administration of saline, 0.03N, or 0.1N HCl were measured. These changes induced by 0.1N HCl after mucosal anesthesia (1% lidocaine) or afferent nerve ablation (125 mg/kg subcutaneous capsaicin) were evaluated. The duodenal villus damage induced by intraduodenal perfusion of 0.1N HCl after mucosal afferent nerve stimulation by intraduodenal capsaicin or afferent nerve ablation by subcutaneous capsaicin was examined. RESULTS: Intraduodenal bolus administration of HCl produced a dose-related increase in SMA blood flow and villus tip damage. The mesenteric hyperemia induced by 0.1N HCl was significantly reduced, but the villus tip damage was not altered by prior intraduodenal lidocaine or subcutaneous capsaicin. The deep duodenal villus damage produced by intraduodenal perfusion of 0.1N HCl was decreased by intraduodenal but increased by subcutaneous capsaicin. CONCLUSIONS: The capsaicin-sensitive afferent nerves mediate in part the HCl-induced mesenteric hyperemia. They protect against the deep but not the superficial duodenal villus damage induced by HCl.     

Inhibitory effects of Hoe 140 on vasodilator responses to bradykinin in the mesenteric vascular bed of the cat

The effect of Hoe 140, a bradykinin B2 receptor antagonist, on vasodilator responses to bradykinin was investigated in the mesenteric vascular bed of the cat under constant flow conditions. Injections of bradykinin into the mesenteric vascular bed induced dose-related decreases in perfusion pressure which were reduced significantly following administration of Hoe 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) (100 micrograms/kg i.v.). The inhibitory effects of Hoe 140 were longer than 3 h in duration and vasodilator response to acetylcholine and S-nitroso-N-acetylpenicillamine and vasoconstrictor responses to norepinephrine, angiotensin II, and the thromboxane mimic, U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxymethano-prostaglandin F2 alpha) were unchanged by the B2 receptor antagonist. Hoe 140 had little effect on baseline systemic arterial and mesenteric arterial perfusion pressures. These results suggest that Hoe 140 is a potent, highly selective, long-acting bradykinin B2 receptor antagonist with little agonistic activity in the mesenteric vascular bed of the cat.     

Effect of stretch on the contractile response of isolated portal vein smooth muscle

The character of spontaneous activity of the isolated preparation was shown to be affected only by the first stretching stimulus which was due to release of the intracellular Ca. Active contractile responses to stretching at the peak of the contracture due to perfusion of the preparations with the Krebs sodiumless solution, are directly correlated with the speed of the stretching. Stretching of the preparations in calciumless solution elicited no active response.     

Effect of vitamin D metabolites and analogs on renal and intestinal calbindin-D in the rat

The effects of endotoxin (20 mg kg-1 i.p.) on the mesenteric vascular responses to acetylcholine, bradykinin, sodium nitroprusside, and to transient occlusion of the superior mesenteric artery were examined in rats anesthetized with pentobarbitone. Mesenteric vasodilator responses to close arterial injections of acetylcholine and bradykinin were reduced at 1.5 h after endotoxin and almost abolished by 4 h; responses to sodium nitroprusside were unaffected. Occlusion of the superior mesenteric artery for 30, 60, or 120 s produced, on release of the occlusion, a time-dependent vasodilator response in the mesenteric circulation (post-occlusion hyperemia). This hyperemia was markedly reduced by nitro-L-arginine methyl ester (L-NAME); L-NAME did not modify acetylcholine-induced vasodilation. Endotoxin-pretreatment did not modify mesenteric post-occlusion hyperemia 1.5 h after administration but markedly reduced the response by 2.5 h. The administration of L-NAME to endotoxin-treated rats did not further attenuate the hyperemic responses. Mesenteric vasoconstrictor responses to phenylephrine were not modified by endotoxin, although systemic pressor responses to this agent were impaired. We concluded that endotoxin impairs endothelium and nitric oxide-dependent vasodilator responses in the mesenteric circulation.     

Mechanisms of the regional hemodynamic effects of a mu-opioid receptor agonist microinjected into the hypothalamic paraventricular nuclei of conscious unrestrained rats

The present study was undertaken to characterize the mechanisms of the hemodynamic responses to microinjection of the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly5-ol]enkephalin (DAMGO) into the paraventricular nucleus of the hypothalamus, in conscious rats chronically instrumented with pulsed Doppler flow probes. We found that i.v. pretreatment with phentolamine had no effect on the tachycardia elicited by DAMGO (1 nmol); however, the pressor response was reversed to a state of hypotension, the renal and superior mesenteric vasoconstrictions were attenuated and the hindquarter vasodilation was potentiated. In the presence of propranolol, the pressor response and renal vasoconstriction were unchanged, whereas the superior mesenteric vasoconstriction was reduced and the hindquarter vasodilation was abolished. Moreover, in those animals we observed bradycardia followed by tachycardia. Combined i.v. pretreatment with phentolamine and propranolol abolished the pressor and heart rate responses to DAMGO but had no effect on the renal and superior mesenteric vasoconstrictions, although the hindquarter vasodilation was reduced. Intravenous pretreatment with a vasopressin V1 receptor antagonist or captopril had no effect on the cardiovascular responses to DAMGO. Together, these results indicate that the hypertension observed after injection of DAMGO into the paraventricular nucleus of the hypothalamus was secondary to alpha adrenoceptor-mediated vasoconstrictions in renal and superior mesenteric vascular beds and to beta adrenoceptor-mediated vasodilation in the hindquarter vascular bed, whereas the involvement of circulating vasopressin or angiotensin seems less obvious from the present findings. However, we cannot exclude the possibility that nonadrenergic, nonvasopressinergic and nonangiotensinergic vasoconstrictor mechanisms were acting in the renal and superior mesenteric vascular beds.     

Tissue and species variation in the vascular receptor binding of 3H-P1075, a potent KATP opener vasodilator

A high-affinity receptor site for 3H-P1075 previously observed in rat aorta has been proposed to mediate the vasorelaxation effects of P1075 and other ATP-sensitive K+ channel (KATP) openers. We tested this hypothesis by correlating the receptor binding of 3H-P1075 with its vasorelaxation effects in several isolated vascular preparations from three species: rat, rabbit and dog. In rat aorta and mesenteric artery, 3H-P1075 (1-5 nM) showed high amounts of specific binding (5-10 fmol/mg tissue), which was 48 to 79% of total binding. In contrast, little (< or = 17%) to no specific binding of 3H-P1075 (1-5 nM) was observed in dog coronary artery, dog mesenteric artery or rabbit mesenteric artery. However, all vascular preparations studied relaxed with P1075 (1-100 nM), showing maximal relaxations at 30 to 100 nM. The P1075 relaxation EC50 values in rat aorta, rabbit mesenteric artery and dog coronary artery ranged from 7.5 to 24.1 nM depending on the level of contractile activation. Thus, the pharmacological effect of P1075 could be correlated with the presence of specific receptor binding sites only in rat vascular preparations. These data show that there are significant differences in the characteristics of the proposed specific receptor site for 3H-P1075 in different vascular preparations from different species, and they raise questions regarding the pharmacological significance of this KATP opener binding site. Until such questions are resolved, it appears that the study of functional significance of this receptor site as well as further biochemical characterization of this receptor site may necessitate the use of only the rat vascular preparations.     

Heat acclimation does not alter rat mesenteric artery response to norepinephrine

Previous studies have shown that heat acclimation raises the temperature threshold for heat-induced splanchnic vasoconstriction in the rat (W. Haddad and M. Horowitz. Thermal Balance in Health and Disease, Advances in Pharmacological Sciences. Basel: Birkhauser, 1994, p. 203-208; M. Shochina, W. Haddad, U. Meiri, and M. Horo-witz. J. Therm. Biol. 21: 289-295, 1996). We tested the hypothesis that heat acclimation alters splanchnic resistance artery sensitivity to norepinephrine (NE). Male Sprague-Dawley rats (n = 5) were acclimated to 35 degreesC ambient temperature for 5-8 wk. Control rats (n = 5) were maintained at 22-23 degreesC ambient temperature for 5-7 wk. Small mesenteric artery segments (2- to 3-mm length, 100- to 340-micrometer ID) were isolated, cannulated at both ends, and pressurized to 50 mmHg. Artery luminal diameter was measured in response to cumulative doses of NE (10(-9) to 10(-5) M) by using video microscopy. NE dose response was measured at 37 and 43 degreesC bath temperatures. There were no differences in constriction responses to NE between acclimated and control rat arteries at either 37 or 43 degreesC. We conclude that acclimation does not alter rat mesenteric artery sensitivity to NE.     

Involvement of calcitonin gene-related peptide (CGRP) receptors in insulin-induced vasodilatation in mesenteric resistance blood vessels of rats

1. The vascular effect of insulin in the mesenteric resistance blood vessel and the role of calcitonin generelated peptide (CGRP)-receptor in insulin-induced vascular responsiveness were investigated in rats. 2. The mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer. In preparations contracted by perfusion with Krebs solution containing methoxamine in the presence of guanethidine, the perfusion of insulin (from 0.1 to 3000 nM) caused a concentration-dependent decrease in perfusion pressure due to vasodilatation. The pD2 value and maximum relaxation (%) were 6.94+/-0.22 and 43.9+/-5.2, respectively. 3. This vasodilator response to insulin was unaffected by 100 nM propranolol (beta-adrenoceptor antagonist) plus 100 nM atropine (muscarinic cholinoceptor antagonist), 100 microM L-NG-nitroarginine (nitric oxide synthase inhibitor), 1 microM ouabain (Na+-K+ ATPase inhibitor), or 1 microM glibenclamide (ATP sensitive K+-channel inhibitor). 4. In preparations without endothelium, perfusion of insulin produced a marked vasodilatation. The pD2 value and maximum relaxation (%) were 7.62+/-0.21 and 81.0+/-4.6, respectively, significantly greater than in preparations with intact endothelium. 5. The vasodilator responses to insulin in the preparations without endothelium were significantly inhibited by CGRP[8 37], a CGRP receptor antagonist, whereas pretreatment with capsaisin, a toxin for CGRP-containing nerves, did not affect insulin-induced vasodilatation. 6. These results suggest that insulin induces non-adrenergic, non-cholinergic and endothelium-independent vasodilatation, which is partially mediated by CGRP receptors.     

Correct blue-light regulation of pea Lhcb genes in an Arabidopsis background

The phasic contraction of the isolated guinea pig vas deferens induced by adenosine 5'-triphosphate (ATP) 1mM was significantly augmented by acidification of bathing solution induced by administration of hydrochloric acid (HCL) 10mM (pH = 6.87 +/- 0.015 (n = 5); mean +/- S.E.), while the tonic contraction induced by norepinephrine (NE) 10microM was significantly depressed by HCl 10mM. The contractile response to ATP 1mM was markedly potentiated in the presence of NE 10 microM. The potentiated contractile response to ATP 1mM in the presence of NE 10microM was significantly augmented by HCl 1mM or 10mM. The potentiating ratio of the contraction induced by ATP 1mM in the presence of NE 10microM to that induced by ATP 1mM alone was almost unaffected by the administration of HCl. Electrical field stimulation (EFS) produced a biphasic contractile response of the isolated guinea pig vas deferens; viz. the first rapid phasic contractile response and the second slow maintained tonic contractile response. The phasic contractile response to EFS was significantly augmented by HCl 10mM. These results may indicate that acidification of the medium potentiates the neurochemical transmission between the nerve terminals and the smooth muscle of vas deferens via sensitization of P2X (presumably P2X1 or P2X2) receptors existing in the smooth muscle.     

Lipoteichoic acid from Staphylococcus aureus depresses contractile function of human arteries in vitro due to the induction of nitric oxide synthase

The aim of this study was to clarify the role of Gram-positive organisms in the genesis of sepsis. In the present study, we investigated the effect of lipoteichoic acid (LTA) from the cell wall of Staphylococcus aureus on contractions elicited by norepinephrine (NE) in rings cut from human gastroepiploic arteries. LTA diminished the contractile response to NE. This attenuation began after several hours of exposure, whether or not endothelium was present. The cyclic guanosine monophosphate content of LTA-treated rings was higher than that of control rings, whether there was a functional endothelium. These LTA-mediated responses were reduced significantly by inhibitors of nitric oxide (NO) synthase and guanylate cyclase. All of this indicates that the main underlying cause of the vascular hyporeactivity to NE was a massive generation of No. In addition, cycloheximide, an inhibitor of inducible NO synthase, prevented the attenuation of NE-induced contractions caused by LTA. Thus, our results offer strong supporting evidence that the important factor in the genesis by Gram-positive organisms of a diminished contractile response to pressor drugs is their induction of inducible NO synthase in smooth muscle.     

The isolated supported canine heart: a model for the evaluation of drug effects on regional myocardial blood flow

The present investigation was designed to determine the effect of propranolol on regional myocardial blood flow and oxygen consumption (MVO2) in the isolated supported dog heart preparation perfused at a constant coronary blood flow. The transmural distribution of blood flow, determined by the radioactive microsphere technique, was expressed as the epicardial/endocardial blood flow ratio (epi/endo). Propranolol (0.5 mg/kg i.v.) produced a significant decrease in heart rate and myocardial contractile force and an increase in coronary artery perfusion pressure due to an increase in coronary vascular resistance. These hemodynamic changes were accompanied by significant decreases in epi/endo (increased endocardial perfusion) and MVO2. Reduction of perfusion pressure to control by a decrease in total coronary blood flow produced no further change in epi/endo or MVO2. However, increasing heart rate to control increased epi/endo to predrug levels. Contractile force and MVO2 remained reduced below control. Norepinephrine infusion (1 mug/min intracoronary) produced a significant increase in heart rate and contractile force and decrease in perfusion pressure. These changes were accompanied by an increase in epi/endo and MVO2. Propranolol (0.5 mg/kg i.v.) abolished the response to norepinephrine. Propranolol may produce beneficial effects in angina pectoris by a decrease in epi/endo (via a reduction in heart rate) and MVO2 and by beta adrenergic blockade of the deleterious effects of catecholamines.     

Rat aorta and mesenteric artery respond differently to serotonin

The sensitivity (EC50) of the ring segment of the mesenteric artery to serotonin (4.84 +/- 0.53 x 10(-7) mol.l-1) was 17x greater than that of the aortic ring segment (5.29 +/- 0.46 x 10(-6) mol.l-1). Incubation of the ring segments in physiological salt solution (PSS) containing methylene blue greatly potentiated the sensitivity of both the aorta and mesenteric artery to serotonin. The degree of potentiation was higher in the aorta than mesenteric artery. L-NAME also increased the sensitivity of both the aorta and mesenteric artery to serotonin and there was no difference in the degree of potentiation of the responses between the aorta and the mesenteric artery. Indomethacin inhibited the contractile responses of the aorta and the mesenteric artery to serotonin. Phenoxybenzamine reduced the contractile responses of both the aorta and the mesenteric artery by the same magnitude. Captopril (10(-4) mol.l-1) significantly attenuated the responses of the mesenteric artery more than the aorta, while methysergide (10(-8) mol.l-1) completely abolished the difference in the responses (EC50 for aorta = 3.50 +/- 0.55 x 10(-5) mol.l-1 vs 5.00 +/- 0.49 x 10(-5) mol.l-1 for mesenteric artery). This study demonstrates that rat aorta and mesenteric artery respond differently to serotonin and the differential response is due to a methylene blue sensitive factor and differences in either the receptor population or sensitivity.     

Variability in PAH-DNA adduct measurements in peripheral mononuclear cells: implications for quantitative cancer risk assessment

We investigated the angiotensin II (Ang II)-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin J (Ang I), and tetradecapeptide (TDP) renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM). The angiotensin converting enzyme (ACE) inhibitor captopril (36 microM) completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 microM) significantly reduced (80-90%) the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95%) the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition.     

Coronary arterial hyperreactivity and mesenteric arterial hyporeactivity after myocardial infarction in the rat

After myocardial infarction, several neurohumoral systems become activated to maintain systemic perfusion pressure. We evaluated whether this leads to alterations of wall structure and contractile reactivity in the thoracic aorta, coronary septal artery, and mesenteric resistance arteries. In male Wistar rats, myocardial infarction (MI) was induced by permanent ligation of the left coronary artery. At 5 weeks after MI or sham operation, vessel segments were isolated, chemically sympathectomized, and mounted in a myograph for recording of isometric force development. Contractile reactivity to high potassium, norepinephrine, phenylephrine, serotonin, and Arg-vasopressin was determined. At the end of the experiments, vessels were fixed for morphometric analysis (cross-sectional area, media thickness, radius, and wall-to-lumen ratio). At 5 weeks after myocardial infarction, no alterations of contractile reactivity or wall structure were observed in the thoracic aorta of MI rats. In mesenteric resistance arteries, a nonselective reduction of maximal active wall tension and of active wall stress in response to vasoconstrictors was observed, whereas vessel wall structure and sensitivity to stimuli were not modified. On the other hand, coronary septal arteries displayed hyperreactivity to all strong contractile stimuli. These observations demonstrate a heterogeneity of arterial reactivity changes at 5 weeks after MI in the rat: (a) no alterations in thoracic aorta, (b) hyporeactivity of mesenteric resistance arteries despite maintenance of media mass, and (c) hyperreactivity of coronary vessels obtained from the hypertrophic remnant myocardium. This could result from the complex regional hemodynamic and neurohumoral changes associated with heart failure and may contribute to the further deterioration of cardiovascular function in this setting.     

Comparison of responses to T-kinin and bradykinin in the mesenteric vascular bed of the cat

Responses to T-kinin and bradykinin were compared in the mesenteric vascular bed of the cat. Under constant-flow conditions, injection of T-kinin and bradykinin into the perfusion circuit induced similar dose-related decreases in perfusion pressure. Responses to T-kinin and bradykinin were inhibited by the kinin B2 receptor antagonist Hoe-140, but were not altered by the B1 receptor antagonist des-Arg9-[Leu8]-BK, the histamine H1 antagonist pyrilamine, the histamine H2 receptor antagonist cimetidine, or the H3 receptor antagonist thioperamide. Vasodilator responses to T-kinin and bradykinin were attenuated by the nitric oxide synthase inhibitor, N omega Nitro-L-arginine methyl ester (L-NAME), but were not altered by the cyclooxygenase inhibitor, sodium meclofenamate, or the K+ ATP channel antagonist, U37883A. These data suggest that vasodilator responses to T-kinin and bradykinin are mediated by kinin B2 receptor stimulated release of nitric oxide from the endothelium, but that the activation of kinin B1 receptors, the release of vasodilator prostaglandins, or the opening of K+ ATP channels are not involved in the response to T-kinin in the mesenteric vascular bed of the cat.     

Age-associated changes in beta-adrenergic modulation on rat cardiac excitation-contraction coupling

Previous studies have demonstrated that the ability of beta-adrenergic receptor (beta AR) stimulation to increase cardiac contractility declines with aging. In the present study, the control mechanisms of excitation-contraction (EC) coupling, including calcium current (ICa), cytosolic Ca2+ (Cai2+) transient and contraction in response to beta AR stimulation were investigated in ventricular myocytes isolated from rat hearts of a broad age range (2, 6-8, and 24 mo). While the baseline contractile performance and the Cai2+ transient did not differ markedly among cells from hearts of all age groups, the responses of the Cai2+ transient and contraction to beta-adrenergic stimulation by norepinephrine (NE) diminished with aging: the threshold concentration and the ED50 increased in rank order with aging; the maximum responses of contraction and Cai2+ transient decreased with aging. Furthermore, the efficacy of beta AR stimulation to increase ICa was significantly reduced with aging, and the diminished responses of the contraction and Cai2+ transient amplitudes to NE were proportional to the reductions in the ICa response. These findings suggest that the observed age-associated reduction in beta AR modulation of the cardiac contraction is, in part at least, due to a deficit in modulation of Cai2+, particularly the activity of L-type calcium channels.     

Effects of diabetes and uremia on mesenteric vascular reactivity

BACKGROUND: Diabetes and uremia are comorbid conditions that have significant effects on cardiovascular physiology. These studies were designed to examine the effects of diabetes and uremia on vascular reactivity. METHODS: Sprague-Dawley rats were divided into control (C), diabetic (D), uremic (U), and diabetic/uremic (D + U) groups. Diabetes (D, D + U groups) was induced with an injection of streptozotocin. Uremic (U, D + U groups) was produced by seven-eighths nephrectomy. Serum glucose, blood urea nitrogen, creatinine, creatinine clearance, and protein excretion were measured at baseline and before microvascular studies at 4 or 8 weeks after injection. Vascular reactivity was studied in isolated, pressurized, and superfused segments of mesenteric arterioles (300 microns). Changes in internal vessel diameter were measured in response to phenylephrine (10(-8) to 10(-4) mol/L), acetylcholine (10(-9) to 10(-5) mol/L), and nitroprusside (10(-9) to 10(-2) mol/L). RESULTS: Results at 4 and 8 weeks were similar in all groups. Vasoconstrictor responses to phenylephrine and endothelium-independent vasodilator responses to nitroprusside were not altered in any experimental group. Endothelium-dependent vasodilator responses to acetylcholine were significantly depressed in both diabetic groups (D and D + U, p < 0.01 versus control), and there were no differences between the two diabetic groups. CONCLUSIONS: Streptozotocin-induced diabetes results in impairment of endothelial-dependent (nitric oxide mediated) vasodilator responses in mesenteric resistance vessels, which are unaffected by coexisting uremia. Uremia has little effect on mesenteric vascular reactivity in this model.     

The lived experience of women military nurses in Vietnam during the Vietnam War

Excitation-contraction coupling is achieved by translocation of calcium from the extracellular space as well as by the release of calcium from intracellular stores. Thapsigargin has been shown to selectively block the sarcoplasmic Ca-ATPase, thereby preventing the reuptake of calcium into intracellular stores and the participation of these calcium storage sites in the contractile response to stimulation. The current study determined the effect of thapsigargin on the contractile response to field stimulation, bethanechol, and KCl in control rabbit bladders and bladders obtained from rabbits subjected to partial outlet obstruction. Partial bladder outlet obstruction resulted in a marked increase in bladder mass and in significant decreases in the contractile response to field stimulation, bethanechol, and KCl. Thapsigargin (5-40 microM) had no effect on the contractile responses of bladder strips isolated from control rabbits to field stimulation, bethanechol, or KCl. However, bladder strips isolated from obstructed rabbits showed a significant concentration-dependent decrease in the contractile response to field stimulation in the presence of thapsigargin. Thapsigargin had no effect on the contractile responses of bladder strips isolated from obstructed rabbits to either bethanechol or KCl. In general, the data described in this study support our current hypothesis: as smooth muscle cells enlarge (hypertrophy) and the cell volume increases, there is an increased dependence on the release of intracellular calcium from the sarcoplasmic reticulum to mediate the contractile response to field stimulation.