Simulated microgravity impairs vascular contractility.
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Animals↗
Biomedical subjects
R E Purdy
Publications and source records attributed to R E Purdy.
Serotonin-induced vasoconstriction in rabbit femoral artery: mediation by both 5-HT2 serotonergic and alpha 1-adrenoceptors.
We determined the receptors mediating the contractile response of the rabbit femoral artery to serotonin in isolated vascular rings mounted in tissue baths for the measurement of isometric contraction. Serotonin elicited a biphasic concentration-response curve (CRC). The threshold and maximal concentrations of the first phase were 0.03 and 3 microM, respectively. The respective values for the second phase were 10 and 1,000 microM. Benextramine, a selective, irreversible alpha-adrenoceptor antagonist, eliminated the second phase. Similar results were obtained with benextramine in femoral arteries acutely denervated with 6-hydroxydopamine (6-OHDA). In contrast, the reversible, competitive 5-HT2 antagonist ketanserin shifted the first phase of the serotonin CRC to the right ina concentration-dependent manner but had little or no effect on the second phase. No evidence for functional alpha 2-adrenoceptors was found. We conclude that the first phase of the serotonin CRC in rabbit femoral artery was mediated predominantly by 5-HT2 receptors and that the second phase was mediated by alpha 1-adrenoceptors.
Adrenergic alpha-Antagonists↗
Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure.
We studied the mechanism of erythropoietin (EPO)-induced hypertension (HTN) in rats with chronic renal failure (CRF). After partial nephrectomy, rats were randomized into four groups. Group A received EPO, 150 U/kg, two times weekly for 6 wk to prevent anemia; group B received placebo injections and became anemic; group C received EPO but was kept anemic by dietary iron deficiency; and group D received placebo and regular transfusions to match hematocrit (Hct) in group A. Blood pressure (BP), Hct, platelet cytosolic calcium ([Ca2+]i) and magnesium concentration, and pressor and vasodilatory responses were determined. By design, Hct in groups A and D were comparable and significantly greater (P < 0.01) than in groups B and C. Despite divergent Hct values, the EPO-treated groups A and C showed a significant rise in BP compared with the placebo-treated groups B and D. HTN occurred whether EPO therapy was begun immediately or 4 wk after nephrectomy. EPO therapy augmented the elevation of basal [Ca2+]i and restored the defective thrombin-mediated rise of platelet [Ca2+]i in CRF animals. EPO therapy did not alter caudal artery contraction in response to either 68 mM K(+)-induced depolarization, angiotensin II or alpha 1-agonist, methoxamine in vitro, or the pressor response to angiotensin II in vivo. However, EPO therapy impaired the hypotensive response to nitric oxide (NO) donors, sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine, and reversed the CRF-induced upregulation of guanosine 3',5'-cyclic monophosphate production by thoracic aorta in vitro. Thus EPO-induced HTN in CRF rats is Hct independent and is associated with and perhaps causally related to increased basal and stimulated [Ca2+]i and impaired vasodilatory response to NO.
Angiotensin II↗
Relationship of Na-K-ATPase inhibitors to blood-pressure regulation in continuous ambulatory peritoneal dialysis and hemodialysis.
Inhibitors of sodium-potassium-activated adenosine triphosphatase (Na-K-ATPase) have been implicated in the pathogenesis of hypertension. In the study presented here, an attempt was made to determine whether differences in the plasma levels and the removal rates of high-molecular weight (HMW) and low-molecular weight (LMW) forms of Na-K-ATPase inhibitors might relate to blood-pressure control in hemodialysis (N = six ultrafiltered and N = six non-ultrafiltered) and CAPD (N = six long-term and N = five short-term) patients. The latter group was studied before the initiation of continuous ambulatory peritoneal dialysis (CAPD) and 2 wk after starting the treatment. The mean blood pressure was significantly reduced after dialysis in the nonultrafiltered hemodialysis group and in both CAPD groups. Plasma levels of both HMW and LMW inhibitors were found to be elevated before dialysis in all patients and were modified only slightly after dialysis. Irrespective of whether ultrafiltration was utilized in hemodialysis patients and despite significant losses of both HMW and LMW inhibitors into CAPD effluent. Because CAPD effluent was found to contain vasopressors that were not exclusively Na-K-ATPase inhibitors, losses of these other vasopressors may contribute to improved blood-pressure control in CAPD in contrast to hemodialysis.
Blood Pressure↗
In vivo and in vitro pressor effects of erythropoietin in rats.
Hypertension (HTN) is a common complication of recombinant erythropoietin (EPO) therapy, but the mechanism of the EPO-associated HTN is uncertain. In the present study we examined the effects of EPO and the vehicle alone on rat caudal artery contractile response and basal and thrombin-stimulated platelet cytosolic Ca2+ concentration ([Ca2+]i) in vitro and on blood pressure (BP) and heart rate in vivo. At high concentrations (200 U/ml) EPO caused a small but consistent contraction in the caudal artery rings (P < 0.01) without affecting the response to either angiotensin II (ANG II) or the alpha 1-agonist methoxamine. Incubation with EPO significantly increased basal platelet [Ca2+]i (P < 0.01) and augmented the thrombin-induced rise of [Ca2+]i in Ca(2+)-free medium (P < 0.05). Long-term EPO administration led to a significant elevation of BP within 2 wk regardless of whether the hematocrit was allowed to rise or was kept constant by dietary iron deficiency. In contrast, single intravenous administration of high-dose EPO (400 and 5,000 U/kg), estimated to yield plasma concentrations comparable with those employed in vitro, failed to either alter BP or modify the BP response to ANG II during a 60-min observation period. This was associated with a significant rise in plasma guanosine 3',5'-cyclic monophosphate but no discernible change in plasma atrial natriuretic peptide, suggesting enhanced nitric oxide (NO) release. Thus, at high concentrations, EPO appears to possess a fast-acting pressor effect in vitro but not in vivo. The observed discrepancy may be due to enhanced NO release with EPO administration in vivo. However, HTN does occur with repeated EPO administration in a time-dependent and hematocrit-independent manner. This suggest that expression of the hypertensive effect of EPO in vivo involves a gradual conditioning process.
Animals↗
Serotoninergic 5-HT1-like receptors of the rabbit ear artery: how silent are they?
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Adenylyl Cyclases↗
Effect of alpha adrenergic agonist on the rabbit ear artery contraction to serotonin: enhanced response mediated by serotonergic1-like receptors.
The effect of methoxamine or phenylephrine (PHE) on the contractile response of the rabbit ear artery to serotonin was assessed by using isolated arterial rings mounted in tissue baths for the measurement of isometric force development. A contractile threshold concentration of methoxamine or PHE (10-30 nM) shifted the serotonin concentration-response curve to the left by approximately 200-fold. Neither mechanical removal of the vascular endothelium nor chemical denervation had any effect on the alpha agonist-amplified response of ear artery to serotonin. Although the response to serotonin in the absence of the alpha agonist was mediated primarily by alpha-1 adrenergic receptors, prazosin did not block the amplified response to serotonin. Ketanserin (10 nM), ritanserin (50 nM) and MDL 72222 (1 microM) also had no effect on the amplified response, ruling out the involvement of serotonergic (5-HT)2 and 5-HT3 receptors. However, methiothepin (3 nM) and 1-(1-naphthyl)piperazine (10 and 100 nM) blocked the PHE-amplified contraction of ear artery to serotonin. When the contractile response of ear artery to 5-carboxamidotryptamine was measured in the presence of a threshold concentration of alpha agonist, the concentration-response curve was shifted 8300-fold to the left. The amplified response to 5-carboxyamidotryptamine was insensitive to 10 nM ketanserin, but was blocked by 3 nM methiothepin. Sumatriptan, a selective 5-HT1 agonist, failed to induce vasoconstriction in the absence of a threshold concentration of alpha agonist. However, in the presence of PHE, sumatriptan induced a concentration-dependent contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Characterization of a low molecular weight Na-K-ATPase inhibitor of urinary origin.
It has been demonstrated that expansion of extracellular fluid volume induces the release of a low-molecular-weight natriuretic and sodium-potassium-activated adenosine triphosphatase inhibiting hormone (NKAI). In this study, we used a highly purified hormone extracted from pooled hypertensive urines (u-NKAI). Like ouabain, this compound was found to be a potent inhibitor of the sodium-potassium-activated adenosine-triphosphatase and potassium-stimulated paranitrophenyl phosphatase enzyme systems as well as a vasoconstrictor in vitro. In contrast to ouabain, which is a competitive inhibitor of both enzyme systems with respect to potassium, u-NKAI is noncompetitive. Furthermore, u-NKAI differs from ouabain by its lack of cross-reactivity with digoxin antibodies. In addition, whereas ouabain binds to both high-affinity and low-affinity binding sites on the sodium-potassium-activated adenosine-triphosphatase enzyme in the absence of potassium, u-NKAI binds only to the low-affinity binding sites. This study demonstrates that the highly purified u-NKAI, although ouabain-like in certain respects, is not an "endogenous ouabain."
4-Nitrophenylphosphatase↗
Lead-induced hypertension: possible role of endothelial factors.
The results of this study confirm that low lead (0.01%) but not high lead (0.5%) administration results in increased blood pressure in rats treated for up to 12 months. This effect appeared to be related to an imbalance of endothelially-derived vasoconstrictor and vasodilator compounds in low lead-treated animals but not in high lead-treated animals. In low lead-treated rats, measurement of plasma endothelins 1 and 3 (ET-1 and ET-3) revealed that ET-3 concentration increased significantly after both 3 months (Experimental, 92.1 +/- 9.7 v Control, 46.7 +/- 12.0 pmol/mL; P < .001) and 12 months (Experimental, 105.0 +/- 9.3 v Control, 94.1 +/- 5.0 pmol/mL; P < .01) while ET-1 was unaffected. Plasma and urinary cGMP concentrations (as a reflection of endothelium-derived relaxing factor (EDRF)) decreased significantly at 3 months (plasma, Experimental, 1.8 +/- 0.9 v Control, 4.2 +/- 1.6 pmol/mL; P < .001) and 12 months (plasma, Experimental, 2.2 +/- 0.7 v Control, 4.2 +/- 0.9 pmol/mL; P < .001). Thus, the path to development of hypertension in low lead rats may be through an increase in the concentration of the vasoconstrictor hormone, ET-3, and a decrease in the vasodilator hormone, EDRF. High levels of lead exposure did not result in hypertension, perhaps because plasma concentrations of ET-1, ET-3 and cGMP were unaltered at 3 months, while ET-1, ET-3 and cGMP concentrations were coordinately and significantly decreased at 12 months.
Animals↗
Comparison of low-molecular-weight plasma and urine Na-K-ATPase inhibitors/hypertensive factors.
Two highly purified low-molecular-weight (< 500 Da) Na-K-ATPase inhibitors, one originating from human plasma and the second from human urine, which both eluted in the identical locus from a C18 reversed-phase high-pressure liquid chromatography (HPLC) column, were compared with respect to (a) K effect on Na-K-ATPase inhibition; (b) displacement of [3H]ouabain from binding sites on purified hog brain Na-K-ATPase; (c) cross-reactivity with digoxin antibodies; and (d) vasoconstrictor effects in isolated rabbit femoral arteries. Inhibition of Na-K-ATPase by the plasma factor correlated inversely with K concentration, whereas inhibition by the urine factor correlated directly with K concentration. In the absence of K, the plasma factor displaced [3H]ouabain from both high- and low-affinity binding sites, whereas the urine factor displaced [3H]ouabain only from the low-affinity binding site. Neither factor possessed digoxin-like immunoreactivity. Both factors acted as direct vasoconstrictors, and potentiated the vasoconstrictor action of norepinephrine. The degree of vasoconstriction caused by the plasma factor diminished progressively with added K, indicating that the vasoconstrictor effect of this factor was mediated by the Na-K-ATPase pump. Thus, although both the plasma and urine Na-K-ATPase inhibitors are vasoconstrictors, their mechanisms of action are different.
Animals↗
Possible novel action of ouabain: allosteric modulation of vascular serotonergic (5-HT2) and angiotensinergic (AT1) receptors.
Experiments were carried out to determine the effects of ouabain and dihydroouabain, both at 10 microM, on the vasoconstrictor responses of isolated rabbit blood vessel rings to both serotonin and angiotensin II. Ouabain plus dihydroouabain increased the sensitivity of central ear artery to serotonin and markedly reduced the antagonist potency of 0.1 microM prazosin against serotonin in this blood vessel; dihydroouabain alone had no effect. Ouabain, markedly reversed the reduction of maximal contractile response by both 2-brom-d-lysergic acid diethylamide against serotonin in aorta and 2-n-propyl-4-trifluoromethyl-1-[(2'-1H-tetrazol-5yl)biphenyl -4- yl)methyl]imidazole-5-carboxylic acid (EXP 3892) against angiotensin II in femoral artery; dihydroouabain had no effect. Whereas both 10 microM ouabain and dihydroouabain produced nearly maximal inhibition of Na+K+ATPase, dihydroouabain failed to modulate the vasoconstrictor responses to either serotonin or angiotensin II. Thus, it is concluded that the vasoconstrictor modulatory effects of ouabain are mediated by mechanisms unrelated to Na+K+ATPase inhibition. The present results are consistent with the hypothesis that both 5-hydroxytryptamine2 and angiotensinergic receptors can exist in high and low activity states. It is proposed that 5-hydroxytryptamine2 receptors exist in a low activity state in the ear artery, or are converted to the low activity state by 2-brom-d-lysergic acid diethylamide in the aorta. Hypothetically, 2-n-propyl-4-trifluoromethyl-1- [(2'-(1H-tetrazol-5yl)biphenyl-4-yl)methyl]imidazole-5-carbo xylic acid also converted the angiotensinergic receptor to the low activity state in femoral artery. In all three cases, ouabain enhanced vasoconstriction to serotonin and angiotensin II, respectively, possibly by allosterically modulating the respective receptors in these vessels to their high activity states.
Allosteric Regulation↗
Norepinephrine amplifies angiotensin II-induced vasoconstriction in rabbit femoral artery.
Several reports have focused on the ability of angiotensin II to amplify vascular contractile responses to norepinephrine, but none have determined whether norepinephrine enhances angiotensin II-induced vasoconstriction. Measuring isometric contraction in isolated rabbit femoral artery rings, we have found that the angiotensin II-induced contractile response was amplified in the presence of a threshold contraction to norepinephrine, as manifested by a 2.9-fold leftward shift of the midpoint of the concentration-response curve with no change in the maximal response. This amplification was attenuated markedly by nifedipine (0.1 microM), a calcium channel antagonist, implicating calcium channel activation in the amplification phenomenon. Precontracting the smooth muscle with a threshold concentration of angiotensin II had no enhancing effect on further angiotensin responses, indicating that the norepinephrine-induced amplification was due to a specific action of norepinephrine, rather than to a precontraction itself. In experiments in which the angiotensin II response was diminished by the presence of the noncompetitive angiotensin II antagonist [Sar1 Ala8]angiotensin II (0.3 microM), norepinephrine affected the angiotensin II response primarily by increasing the maximal response attainable. Prazosin (0.1 microM) both blocked the norepinephrine threshold contraction and abolished completely the amplification. However, when the norepinephrine concentration was increased until a threshold contraction was elicited in the presence of a fixed concentration of prazosin, amplification of the angiotensin II response was restored. These results indicate that norepinephrine exerts its amplifying effect on angiotensin II via activation of alpha-1 adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Dietary lipids modify receptor- and non-receptor-dependent components of alpha 1-adrenoceptor-mediated contraction.
Dietary lipid modulation of alpha-adrenoceptor (adrenergic receptor)- and non-adrenoceptor-mediated contractile properties of isolated rat abdominal aortic segments were assessed during the early developmental period. Rats were raised from conception to 90 days of age on semisynthetic diets containing various types and amounts of lipids. Aortic segments from three groups of rats fed high-fat diets (15% wt/wt) consisting of olive oil, corn oil, or lard as the sole lipid sources were compared with those from rats fed a low-fat control diet containing corn oil (5% wt/wt). alpha-Adrenoceptor activities were assessed by measuring the norepinephrine dose response of the tissue rings with and without partial inactivation of alpha-receptors by benextramine. alpha-Adrenoceptor sensitivity to norepinephrine increased, whereas receptor affinity decreased significantly in rats raised on high-fat diets. Qualitative features of dietary lipids influenced non-adrenoceptor-dependent aspects of vascular contractility. Diets rich in polyunsaturated fatty acids (high- and low-fat corn oil) raised the maximum response to norepinephrine and the contractile response to 60 mM potassium compared with more-saturated diets (olive oil and lard). These results demonstrate an effect of chronic feeding of high dietary fat on alpha-adrenoceptor-mediated contractility of abdominal aortic rings from young Sprague-Dawley rats. Qualitative features of dietary lipids also appear to modify receptor-independent parameters of the contractile response of the arterial tissue rings in these animals.
Animals↗
Evidence against serotonin-induced endothelium-dependent relaxation in bovine coronary artery.
Bovine coronary artery rings were mounted in tissue baths for the measurement of isometric contraction in order to test for serotonin-induced endothelium-dependent relaxation. A23187 caused a concentration-dependent relaxation in precontracted artery rings when the endothelium was intact, but not when it was removed. Endothelium removal had no effect on serotonin concentration contractile response curves (CRC) in normal Krebs' solution, but enhanced the response to serotonin in artery rings precontracted with 25 mM K+ Krebs' solution. In endothelium-intact, precontracted artery rings, ketanserin shifted the serotonin CRC to the right, but did not convert the contraction to relaxation. 5-Carboxamidotryptamine caused a weak contraction that was blocked by ketanserin, but not converted to relaxation. Inactivation of monoamine oxidase enhanced the contractile response to serotonin in precontracted artery rings in a manner identical to that caused by endothelium removal. Inactivation of monoamine oxidase had no effect in endothelium-denuded artery rings. De-endothelialized rabbit aorta strips pretreated with phenoxybenzamine were placed in close apposition to endothelium-intact coronary artery strips. Superoxide dismutase, acetylcholine and A23187 caused the precontracted rabbit aorta strip to relax, whereas serotonin had no effect. These results support the conclusion that the endothelium of the bovine coronary artery releases a relaxing factor both spontaneously and in response to acetylcholine and A23187. Serotonin appears to be incapable of releasing endothelium-derived relaxing factor or causing an endothelium-dependent relaxation. However, bovine coronary artery endothelium appears to be able to take up and metabolize serotonin.
Animals↗
Modulation of serotonin-induced vasospasm by endothelium and monoamine oxidase.
Endothelial modulation of flow induced by intraluminal serotonin (5-HT) in isolated and perfused bovine coronary artery segments was studied. A constant-pressure continuous perfusion apparatus was utilized. Control coronary arteries were perfused with a fixed volume of serotonin-containing solution followed by a serotonin-free solution, and flow-rate changes during onset and relaxation of vasospasm were measured. Both monoamine oxidase inhibition by iproniazide and endothelium disruption by collagenase increased the rate of onset and magnitude of vasospasm. When the endothelium was intact the vasospasm continued to increase, reaching maximum well after the end of the serotonin perfusion, followed by slow relaxation toward baseline. This contrasted with de-endothelialized vessels in which the increase in contractile response terminated abruptly at the end of the serotonin perfusion and returned rapidly to baseline. Coronary arteries stimulated with prostaglandin F2 alpha responded similarly to de-endothelialized vessels stimulated by 5-HT, although further de-endothelialization of F2 alpha-stimulated vessels showed increased rates of onset and relaxation of vasospasm, suggesting a physical barrier role for the endothelium towards unmetabolized agents. These observations are consistent with the hypothesis that endothelial cells are capable of taking up, storing and subsequently releasing serotonin. The results suggest a protective role of the endothelium as a metabolic and physical barrier. This may represent an anatomical substrate favouring the development of localized vasospasm at sites where the endothelium is injured.
Animals↗
Effect of ouabain on the rabbit ear artery contraction to serotonin: enhanced response mediated by serotonergic rather than alpha adrenergic receptors.
The effect of ouabain on the rabbit ear artery response to serotonin was assessed in isolated vascular rings mounted in tissue baths for the measurement of isometric contractions and denervated with 6-hydroxydopamine in vitro. Ouabain, 1 and 10 microM, caused 5- and 6-fold shifts to the left of the serotonin concentration-response curve (CRC). However, 10 microM ouabain caused only a 1.6-fold shift to the left of the norepinephrine CRC. In the absence of ouabain, 0.01 microM ketanserin had little effect, whereas 0.1 microM prazosin caused a marked shift to the right of the serotonin CRC. In the presence of ouabain, prazosin exhibited little or no antagonism below 3 microM serotonin. Antagonism by ketanserin was increased by 1 and 10 microM ouabain, yielding 6.5- and 10.5-fold shifts to the right of the serotonin CRC, respectively. Benextramine pretreatment to inactivate alpha adrenoceptors nearly abolished the rabbit ear artery response to serotonin. However, in the presence of 10 microM ouabain, there was a substantial recovery of the response to serotonin, and this response was antagonized by ketanserin. These results are consistent with our hypothesis that serotonergic receptors are present in the smooth muscle cell membranes of the rabbit ear artery but are either uncoupled to the contractile mechanism or in a low efficacy state. In the presence of ouabain, these receptors either become coupled or convert to a high efficacy state and thereby contribute to the serotonin-induced contraction. Because the serotonin CRC was shifted to the left in the presence of ouabain, it is likely that most of the CRC was below the threshold concentration at which serotonin activates alpha adrenoceptors. Thus antagonism by prazosin was lost.
Animals↗
Effects of a human-derived sodium transport inhibitor on in vitro vascular reactivity.
Concentrations of sodium-transport inhibitors (STI) which block the sodium-potassium-ATPase pump are increased in the plasma and urine of volume-expanded and low-renin hypertensive humans and animals. To evaluate the physiologic relevance of STI to blood-pressure-raising mechanisms, we have examined the in vitro properties of STI extracted from the urine of human subjects. STI produced a significant (by ANOVA: P less than .01) dose-contraction response in the isolated rabbit femoral artery. Moreover, small noncontractile doses of STI in this in vitro preparation produced a fivefold leftward shift in the contraction dose-response curve of norepinephrine (P less than .01) and a threefold shift for angiotensin II (P less than .01); at lower, physiologic, concentrations of these vasoconstrictor hormones the amplifications in contraction caused by STI ranged from 100% to 500%. In studies in calcium-free tissue bath solutions, the direct contractile action of STI was abolished; however, its amplification of responses to norepinephrine remained, suggesting that this latter effect of STI is not entirely dependent upon calcium influx into vascular smooth muscle cells. The glycoside ouabain produced effects identical to those of STI in arteries, but its actions on a rabbit atrium preparation were different: ouabain stimulated powerful inotropic effects, whereas human STI failed to cause myocardial contractions even though the amounts of STI administered had the same sodium-transport inhibitory capacity as the ouabain. Thus, the actions of human STI are primarily in the peripheral circulation, where they directly produce arterial contractions and also enhance contractile responses to other pressor hormones, suggesting that they may have a role in regulating systemic blood pressure.
Angiotensin II↗
The degree of atrial natriuretic peptide (ANP)-induced contraction inhibition is dependent on spare receptors.
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Animals↗