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PubMed2005

Enhanced role for RhoA-associated kinase in adrenergic-mediated vasoconstriction in gracilis arteries from obese Zucker rats.

Obesity, insulin resistance, dyslipidemia, and hypertension are components of the pathophysiological state known as metabolic syndrome. Adrenergic vasoconstriction is mediated through increases in cytosolic Ca2+ and the myofilaments' sensitivity to Ca2+. In many pathophysiological states, there is an enhanced role for Rho kinase (ROK)-mediated increases in Ca2+ sensitivity of the contractile apparatus. Thus we hypothesized that there is a greater role for ROK-mediated increases in Ca2+ sensitivity in alpha1-adrenergic vasoconstriction in arteries from obese Zucker (OZ) rats. Therefore, small gracilis muscle arteries from 11- to 12-wk-old and 16- to 18-wk-old lean and OZ rats were isolated, cannulated, and pressurized to 75 mmHg. For some experiments, vessels were loaded with fura 2-AM. Changes in luminal diameter and vessel wall Ca2+ concentration ([Ca2+]) were measured in response to phenylephrine (PE), the thromboxane mimetic U-46619, and KCl. alpha1-Adrenergic vasoconstriction was similar between 11- to 12-wk-old lean and obese animals and greater in older obese animals compared with controls. PE-induced increases in vascular smooth muscle cell [Ca2+] were blunted in OZ animals compared with lean controls in both age groups of animals. KCl and U-46619 elicited similar vasoconstriction and vascular smooth muscle cell [Ca2+] in both groups. ROK inhibition attenuated PE vasoconstriction to a greater degree in arteries from 11- to 12-wk-old OZ rats compared with lean animals; ROK inhibition in arteries from older rats right shifted both concentration-response curves to the same point. Total RhoA and ROKalpha protein expressions were similar between groups. These results suggest an enhanced role for the ROK pathway in alpha1-adrenergic vasoconstriction in metabolic syndrome.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Liposomal VIP attenuates phenylephrine- and ANG II-induced vasoconstriction in vivo.

The purpose of this study was to determine whether vasoactive intestinal peptide (VIP) modulates vasoconstriction elicited by phenylephrine and ANG II in vivo and, if so, to begin to elucidate the mechanisms underlying this phenomenon. Using intravital microscopy, we found that suffusion of phenylephrine and ANG II elicits significant vasoconstriction in the in situ hamster cheek pouch that is potentiated by VIP-(10-28), a VIP receptor antagonist, but not by VIP-(1-12) (P < 0.05). Aqueous VIP has no significant effects on phenylephrine- and ANG II-induced vasoconstriction. However, VIP on sterically stabilized liposomes (SSL), a formulation where VIP assumes a predominantly alpha-helix conformation, significantly attenuates this response. Maximal effect is observed within 30 min and is no longer seen after 60 min. Empty SSL are inactive. Indomethacin has no significant effects on responses induced by VIP on SSL. The vasodilators ACh, nitroglycerin, calcium ionophore A-23187, 8-bromo-cAMP, and isoproterenol have no significant effects on phenylephrine- and ANG II-induced vasoconstriction. Collectively, these data suggest that vasoconstriction modulates VIP release in the in situ hamster cheek pouch and that alpha-helix VIP opposes alpha-adrenergic- and ANG II-induced vasoconstriction in this organ in a reversible, prostaglandin-, NO-, cGMP-, and cAMP-independent fashion.

Acetylcholine↗
PubMed1987

Lipoxygenase and cyclooxygenase blockade by BW 755C enhances pulmonary hypoxic vasoconstriction.

Lipoxygenase products (leukotrienes) have been proposed as the mediators of pulmonary hypoxic vasoconstriction. However, the supporting data are inconclusive because the lipoxygenase and leukotriene receptor blockers that reduce hypoxic vasoconstriction (such as diethylcarbamazine and the FPL's) have confounding effects. We investigated BW 755C, a potent inhibitor of both lipoxygenase and cyclooxygenase, in eight intact anesthetized dogs with acute left lower lobe atelectasis. We examined two manifestations of hypoxic vasoconstriction: shunt fraction, as an inverse indicator of regional constriction in response to local hypoxia, and the pulmonary pressor response to global alveolar hypoxia, as an index of general hypoxic vasoconstriction. During normoxia, shunt fraction, measured using a sulfur hexafluoride infusion, was 32.0 +/- 7.0%. The pulmonary pressor response to hypoxia, defined as the increase in pulmonary end-diastolic gradient produced by 10% O2 inhalation, averaged 4.5 +/- 1.8 mmHg. Then, during normoxia, BW 755C was administered. Shunt fraction fell in all eight dogs from the previous mean of 32% to 25.5 +/- 6.1% (t = 6.5, P less than 0.0005). The hypoxic pressor response rose in all dogs, from the previous 4.5 mmHg to 9.0 +/- 3.5 mmHg (t = 4.5, P less than 0.005). BW 755C enhances hypoxic vasoconstriction, an effect consistent with its activity as a cyclooxygenase inhibitor. These data do not support a substantive role for the lipoxygenase pathway in hypoxic vasoconstriction.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2007

Vasopressin-induced vasoconstriction: two concentration-dependent signaling pathways.

Current scientific literature generally attributes the vasoconstrictor effects of [Arg(8)]vasopressin (AVP) to the activation of phospholipase C (PLC) and consequent release of Ca(2+) from the sarcoplasmic reticulum. However, half-maximal activation of PLC requires nanomolar concentrations of AVP, whereas vasoconstriction occurs when circulating concentrations of AVP are orders of magnitude lower. Using cultured vascular smooth muscle cells, we previously identified a novel Ca(2+) signaling pathway activated by 10-100 pM AVP. This pathway is distinguished from the PLC pathway by its dependence on protein kinase C (PKC) and L-type voltage-sensitive Ca(2+) channels (VSCC). In the present study, we used isolated, pressurized rat mesenteric arteries to examine the contributions of these different Ca(2+) signaling mechanisms to AVP-induced vasoconstriction. AVP (10(-14)-10(-6) M) induced a concentration-dependent constriction of arteries that was reversible with a V(1a) vasopressin receptor antagonist. Half-maximal vasoconstriction at 30 pM AVP was prevented by blockade of VSCC with verapamil (10 microM) or by PKC inhibition with calphostin-C (250 nM) or Ro-31-8220 (1 microM). In contrast, acute vasoconstriction induced by 10 nM AVP (maximal) was insensitive to blockade of VSCC or PKC inhibition. However, after 30 min, the remaining vasoconstriction induced by 10 nM AVP was partially dependent on PKC activation and almost fully dependent on VSCC. These results suggest that different Ca(2+) signaling mechanisms contribute to AVP-induced vasoconstriction over different ranges of AVP concentration. Vasoconstrictor actions of AVP, at concentrations of AVP found within the systemic circulation, utilize a Ca(2+) signaling pathway that is dependent on PKC activation and can be inhibited by Ca(2+) channel blockers.

Animals↗
PubMed1992

Mechanisms of ciclosporin A-induced vasoconstriction in the isolated perfused rat kidney.

Hypertension is a well-known side effect of ciclosporin A (CsA). In the present study the mechanisms of vasoconstriction in renal vessels were examined in the isolated perfused rat kidney. Kidneys were perfused with constant flow at a temperature of 37 degrees C with Tyrode's solution equilibrated with 95% O2/5% CO2. CsA was dissolved in ethanol. 500 and 2000 ng/ml increased resistance of renal vessels by 0.97 +/- 0.55 x 10(5) and 2.29 +/- 1.33 x 10(5) dyn s cm-5, respectively (mean values +/- SD, n = 12). The vasoconstriction developed gradually over 4 min. The vasopressor effect of CsA was not changed by saralasin (10(-6) M), nifedipine (10(-6) M) and ketanserin (10(-6) M), but was completely blocked by phentolamine and prazosin (each 10(-6) M). CsA-induced vasoconstriction was not prevented by perfusion with Ca(2+)-free solution containing 2 mmol EGTA. Similarly, pretreatment with reserpine to deplete sympathetic nerve endings from catecholamines did not affect CsA-induced vasoconstriction. The findings suggest that CsA-induced vasoconstriction is mediated by stimulation of alpha 1-receptors. Ca2+ influx does not play a role for CsA-induced vasoconstriction. Prolonged perfusion of rat kidneys with the vehicle cremophor EL elicits an irreversible increase in perfusion pressure.

Animals↗
PubMed1983

Pathophysiology of hydronephrotic atrophy: the cause and role of active preglomerular vasoconstriction.

Unilateral complete ureteral occlusion is followed by a decreased blood flow in the ipsilateral kidney, which is established within 1 week, after which a steady state of whole renal blood flow is observed. Active preglomerular vasoconstriction is assumed to be the main factor causing renal flow reduction in the hydronephrotic kidney, resulting in rapid decrease of the initial elevated pelvic pressure within 24 h. The assumption of active preglomerular vasoconstriction also explains the observation that blood flow reduction clearly precedes renal atrophy after ureteral ligation. Neither alpha-receptor blocking agents nor angiotensin II blockage, nor denervation, reversed flow reduction in the first hours or weeks after ureteral ligation. A thromboxane synthesis inhibitor (imidazole) did reverse flow reduction completely without affecting the contralateral renal blood flow, indicating that active vasoconstrictive is present. In respect to renal hydronephrotic atrophy, compartment analysis of the blood flow of the obstructed kidney demonstrates that vasoconstriction contributes to ischemic atrophy at least in the cortex of the hydronephrotic kidney. Vasoconstriction cannot be reversed by prostaglandin synthesis inhibition after renal atrophy is established, although the renal blood flow is still sensitive to other vasodilating drugs like dopamine. From our data we conclude that prostaglandin-mediated active preglomerular vasoconstriction is a main factor causing renal atrophy by ischemia.

Animals↗
PubMed1988

Platelets, vasoconstriction, and nitroglycerin during arterial wall injury. A new antithrombotic role for an old drug.

Endothelial injury in vivo is associated with platelet deposition and a localized platelet-dependent vasoconstrictive response. To assess the influence of nitroglycerin on platelets and vasoconstriction, quantitative 111In-labeled platelet deposition (no platelets x 10(6)/cm2) of the injured segment and the degree of angiographic vasoconstriction (percent diameter narrowing proximal and distal to the dilated segment) produced during injury by balloon angioplasty of the common carotid arteries were studied in heparinized normal pigs that were sacrificed immediately after the procedure. In deeply injured (injury extending through the internal elastic lamina) compared with mildly injured (deendothelialization only) arteries, there was both greater platelet deposition (63.8 vs. 6.9, p = 0.04) and more vasoconstriction (30% vs. 19%, p = 0.02). In the presence of deep arterial wall injury, nitroglycerin given intravenously at a dose sufficient to lower mean arterial pressure by 9 +/- 2% significantly decreased both platelet deposition (16.2 vs. 63.8, p less than 0.008) and the vasoconstrictive response (20 vs. 30%, p less than 0.02) relative to control. However, in the presence of mild arterial wall injury, nitroglycerin decreased vasoconstriction relative to control (10% vs. 19%, p less than 0.01) without causing a significant decrease in the already low level of platelet deposition (5.6 vs. 6.9, respectively; p = NS), suggesting a direct smooth muscle relaxant effect of nitroglycerin. This is the first reported in vivo effectiveness of nitroglycerin in the reduction of platelet deposition after deep arterial injury.

Angioplasty, Balloon↗
PubMed1988

Coronary artery vasoconstriction routinely occurs after percutaneous transluminal coronary angioplasty. A quantitative arteriographic analysis.

To determine whether percutaneous transluminal coronary angioplasty (PTCA) increases coronary artery luminal dimensions by stretching and injuring ("paralyzing") the smooth muscle of the arterial wall, we prospectively analyzed spontaneous changes and then intracoronary nitroglycerin-induced changes in segmental coronary artery diameters during the first 30 minutes after uncomplicated single-vessel PTCA in 10 patients. Five additional patients received intravenous nitroglycerin throughout the procedure to determine whether nitroglycerin could prevent vasoconstriction after PTCA. All of the patients were maintained on oral doses of diltiazem and aspirin at the time of the study. Coronary arteriography was performed at 2, 5, 15, and 30 minutes after PTCA and then 3 minutes after 300 micrograms i.c. nitroglycerin. Quantitative measurements (computerized edge-detection) were performed at each time, in coronary segments centered in the dilated segment, distal to the dilated segment, and in a control vessel not manipulated with the balloon catheter or guidewire. Progressive vasoconstriction (defined as a loss of diameter that was reversed by intracoronary nitroglycerin) was observed after PTCA in the dilated and distal segments (10 of 10 patients) but not in the control segment. The vasoconstriction in the dilated segment at 30 minutes (mean, 30 +/- 4%) was highly statistically significant compared with vasoconstriction at 2 and 5 minutes after PTCA (p less than 0.001) and compared with the control segment at 30 minutes (p less than 0.005). There was no significant loss of diameter after PTCA in the dilated segment in the five patients who received intravenous nitroglycerin. In conclusion, 1) spontaneous coronary artery vasoconstriction after PTCA occurs routinely at and distal to the site of balloon dilatation despite pretreatment with aspirin and calcium channel blockers; 2) coronary artery vasoconstriction after PTCA is rapidly reversed by intracoronary nitroglycerin and can be prevented by the continuous administration of intravenous nitroglycerin during and after the procedure; 3) these results are incompatible with the hypothesis that PTCA improves coronary luminal dimensions by arterial "paralysis"; and 4) these findings have implications concerning the etiology and prophylaxis of abrupt vessel closure after PTCA.

Aged↗
PubMed1995

Endothelin ETA and ETB receptors cause vasoconstriction of human resistance and capacitance vessels in vivo.

BACKGROUND: The role of endothelin ETB receptors in mediating vasoconstriction in humans is unclear. As yet, there have been no in vivo studies in resistance vessels, and in vitro data have been contradictory. We therefore investigated the function of ETB receptors in vivo in human forearm resistance and hand capacitance vessels using endothelin-1 as a nonselective agonist at ETA and ETB receptors and endothelin-3 and sarafotoxin S6c as selective agonists at the ETB receptor. METHODS AND RESULTS: A series of single-blind studies were performed, each in six healthy men. Brachial artery infusion of endothelin-1 and endothelin-3 caused slow-onset dose-dependent forearm vasoconstriction. Although endothelin-3 caused significantly less forearm vasoconstriction than endothelin-1 at low doses, vasoconstriction was similar to the two isopeptides at the highest dose (60 pmol/min). Endothelin-3 caused transient forearm vasodilatation at this dose, whereas endothelin-1 showed only a nonsignificant trend toward causing early vasodilatation. Intra-arterial sarafotoxin S6c caused a progressive reduction in forearm blood flow, although less than that to endothelin-1 (P = .04). Dorsal hand vein infusion of sarafotoxin S6c caused local venoconstriction that was also less than that to endothelin-1 (P = .002). CONCLUSIONS: Selective ETB receptor agonists cause constriction of forearm resistance and hand capacitance vessels in vivo in humans, suggesting that both ETA and ETB receptors mediate vasoconstriction. Hence, antagonists at both ETA and ETB receptors, or inhibitors of the generation of endothelin-1, may be necessary to completely prevent vasoconstriction to endogenously generated endothelin-1.

Adult↗
PubMed1998

Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo.

BACKGROUND: Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone. METHODS AND RESULTS: Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12+/-2%; P=0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (P=0.6) after pretreatment with both placebo (13+/-1%, P=0.006) and enalapril (17+/-6%, P=0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ETA antagonist BQ-123 (100 nmol/min), and both combined. Thiorphan caused local forearm vasoconstriction (13+/-1%, P=0.0001); BQ-123 caused local vasodilatation (33+/-3%, P=0.0001). Combined thiorphan and BQ-123 caused vasodilatation (32+/-1%, P=0.0001) similar to BQ-123 alone (P=0.98). In a fourth study, 6 hypertensive patients (blood pressure >160/100 mm Hg) received intra-arterial thiorphan (30 nmol/min). Thiorphan caused a slowly progressive forearm vasoconstriction (10+/-2%, P=0.0001). CONCLUSIONS: Inhibition of local NEP causes vasoconstriction in forearm resistance vessels of both healthy volunteers and patients with hypertension. The lack of effect of ACE inhibition on the vasoconstriction produced by thiorphan and its absence during concomitant ETA receptor blockade suggest that it is mediated by endothelin-1 and not angiotensin II. These findings may help to explain the failure of systemic NEP inhibition to lower blood pressure.

Adult↗
PubMed2005

Pancreatic polypeptide-fold peptide receptors and angiotensin II-induced renal vasoconstriction.

The Gi pathway augments renal vasoconstriction induced by angiotensin II in spontaneously hypertensive but not normotensive Wistar-Kyoto rats. Because the Gi-coupled pancreatic polypeptide (PP)-fold peptide receptors Y1 and Y2 are expressed in kidneys and are activated by endogenous PP-fold peptides, we tested the hypothesis that these receptors regulate angiotensin II-induced renal vasoconstriction in kidneys from hypertensive but not normotensive rats. A selective Y1-receptor agonist [(Leu31,Pro34)-neuropeptide Y; 6 to 10 nmol/L] greatly potentiated angiotensin II-induced changes in perfusion pressure in isolated, perfused kidneys from hypertensive but not normotensive rats. A selective Y2-receptor agonist (peptide YY(3-36); 6 nM) only slightly potentiated angiotensin II-induced renal vasoconstriction and only in kidneys from hypertensive rats. Neither the Y1-receptor nor the Y2-receptor agonist increased basal perfusion pressure. BIBP3226 (1 micromol/L, highly selective Y1-receptor antagonist) and BIIE0246 (1 micromol/L, highly selective Y2-receptor antagonist) completely abolished potentiation by (Leu31,Pro34)-neuropeptide Y and peptide YY(3-36), respectively. Y1-receptor and Y2-receptor mRNA and protein levels were expressed in renal microvessels and whole kidneys, but the abundance was similar in kidneys from hypertensive and normotensive rats. Both Y1-receptor-induced and Y2-receptor-induced potentiation of angiotensin II-mediated renal vasoconstriction was completely abolished by pretreatment with pertussis toxin (30 microg/kg IV, blocks Gi proteins). These data indicate that, in kidneys from genetically hypertensive but not normotensive rats, Y1-receptor activation markedly enhances angiotensin II-mediated renal vasoconstriction by a mechanism involving Gi. Although Y2 receptors can also potentiate angiotensin II-mediated renal vasoconstriction via Gi, the effect is modest compared with Y1 receptors. These findings may have important implications for the etiology of genetic hypertension.

Angiotensin II↗
PubMed1994

Insulin blunts sympathetic vasoconstriction through the alpha 2-adrenergic pathway in humans.

We investigated the mechanisms underlying the insulin-induced attenuation of sympathetic forearm vasoconstriction in healthy humans. In 5 subjects, we applied 20 mm Hg lower body negative pressure for 30 minutes in control conditions and during a 60-minute infusion of insulin (0.05 mU/kg per minute) in the brachial artery and measured forearm norepinephrine kinetics and hemodynamics. In 11 subjects, we applied graded lower body negative pressure at 5, 10, 15, and 20 mm Hg for 5 minutes each in control conditions and during the simultaneous intrabrachial administration of insulin (0.05 mU/kg per minute) (5 subjects) or insulin plus ouabain (3.5 micrograms/min per liter) (6 subjects) to investigate whether insulin acts through a potentiation of the vascular smooth muscle Na+,K(+)-ATPase. To assess a possible effect of insulin on a specific adrenergic receptor pathway, in a further study group we evaluated (1) the forearm vascular response to intrabrachial infusion of the alpha 1-adrenergic receptor agonist phenylephrine (0.5, 1, and 2 micrograms/kg per minute; n = 7) and of the alpha 2-adrenergic receptor agonist BHT-933 (0.5, 1, 2, and 4 micrograms/kg per minute; n = 9), and (2) the effects of intra-arterial infusion of prazosin (0.5 microgram/100 mL per minute) alone or combined with insulin on the forearm vascular response to graded lower body negative pressure (7 subjects). Insulin blunted the peak increase in forearm vascular resistance (from 13 +/- 2 to 6 +/- 2 U, P < .05) but not the rise in forearm norepinephrine spillover induced by 20 mm Hg lower body negative pressure (from 8.3 +/- 1.8 to 11.1 +/- 3.5 pmol/min per liter, P = NS). Ouabain administration did not prevent the insulin-induced attenuation of the forearm vasoconstrictive response to graded lower body negative pressure. Insulin infusion in the brachial artery did not modify the forearm vasoconstriction induced by intra-arterial infusion of phenylephrine but significantly reduced the increase in forearm vascular resistance induced by BHT-933 (F = 6.111, P < .001). Finally, intra-arterial infusion of prazosin significantly attenuated the forearm vasoconstriction induced by graded lower body negative pressure. The residual vasoconstrictive response was abolished by insulin infusion. Taken together, these findings suggest that insulin interacts with the sympathetic nervous system at the vascular level predominantly through the alpha 2-adrenergic vasoconstrictive pathway.

Adrenergic alpha-Agonists↗
PubMed1990

Oxidized low density lipoproteins potentiate vasoconstrictions to various agonists by direct interaction with vascular smooth muscle.

In hypercholesterolemia, low density lipoproteins (LDLs) may be oxidized by monocytes/macrophages in the arterial wall. Therefore, we investigated the effect of LDL and its oxidative derivatives (ox-LDL) on vascular tone in isolated perfused rabbit femoral arteries. Perfusion of endothelium-intact and endothelium-denuded segments with ox-LDL (80 micrograms protein/ml) caused no or only weak vasoconstrictions in the absence of contractile agonists. However, in the presence of ox-LDL, vasoconstrictions to threshold concentrations of norepinephrine, serotonin, phenylephrine, or potassium were significantly enhanced. This enhancement correlated with the degree of oxidation. When ox-LDL was administered at higher concentrations (greater than 200 micrograms protein/ml), it evoked moderate vasoconstrictions even in the absence of contractile agonists. Native LDL had no effect on vascular tone. Preincubation with verapamil, diltiazem, and nitrendipine inhibited vasoconstrictions evoked by ox-LDL, both in the presence and in the absence of a contractile agonist. The contractile responses to ox-LDL were significantly greater in endothelium-denuded segments than in endothelium-intact segments. At the above concentrations, ox-LDL had no influence on endothelium-derived relaxing factor-mediated vasodilations. These data indicate that ox-LDL enhances agonist-induced vasoconstrictions by a direct effect on the vascular smooth muscle. We therefore suggest that ox-LDL is an important factor that may increase the risk of inappropriate vasoconstriction in hypercholesterolemia, independent of its putative cytotoxic effect on the endothelium.

Animals↗
PubMed2001

Impaired modulation of sympathetic vasoconstriction in contracting skeletal muscle of rats with chronic myocardial infarctions: role of oxidative stress.

Skeletal muscle perfusion during exercise is impaired in heart failure, but the underlying mechanisms are poorly understood. One possibility is that sympathetic vasoconstriction is enhanced in exercising muscle in heart failure as a result of impaired counterregulatory mechanisms that normally act to attenuate vasoconstrictor responses. In healthy animals, sympathetic vasoconstriction in contracting skeletal muscle is attenuated by endogenously produced nitric oxide (NO). Because the NO pathway may be dysfunctional in heart failure, we hypothesized that reduced NO in contracting muscle would result in enhanced sympathetic vasoconstriction. In sham rats and rats with chronic myocardial infarctions (MIs) produced by coronary artery ligation, we measured arterial pressure and femoral artery blood flow responses to sympathetic nerve stimulation (1, 2.5, and 5 Hz) in resting and contracting hindlimb. In resting hindlimb, sympathetic stimulation decreased femoral vascular conductance similarly in sham and MI rats. In contracting hindlimb, these vasoconstrictor responses were attenuated to a greater extent in sham than in MI rats. NO synthase inhibition enhanced sympathetic vasoconstriction in contracting hindlimb of sham, but not MI, rats. Conversely, infusion of L-arginine or a superoxide scavenger, tempol or tiron, attenuated sympathetic vasoconstriction in contracting hindlimb of MI rats. NO synthase expression was similar, but malondialdehyde (a marker of free radical damage) was greater in skeletal muscle from MI than from sham rats. These data suggest that impaired metabolic modulation of sympathetic vasoconstriction in contracting skeletal muscle of MI rats is a consequence of superoxide-mediated disruption of the NO pathway.

Animals↗
PubMed1990

Evidence for altered epicardial coronary artery autoregulation as a cause of distal coronary vasoconstriction after successful percutaneous transluminal coronary angioplasty.

To determine whether vasoconstriction distal to the site of successful percutaneous transluminal coronary angioplasty (PTCA) is a result of altered autoregulation in a hypoperfused coronary artery, we examined the association of this distal vasoconstriction with lesion severity in 20 patients. Lesion severity was classified as moderate, severe or critical (greater than 1.0, 0.5-1.0, and less than 0.5 mm, respectively). Quantitative coronary measurements were made at 3, 15, and 30 min after PTCA, and then after intracoronary (IC) nitroglycerin, in coronary segments distal to the dilated lesion (distal) and in a nonmanipulated vessel (control). Coronary vasoconstriction in the Distal segment after PTCA correlated with lesion severity, with 14 +/- 4%, 28 +/- 2%, and 41 +/- 5% vasoconstriction (vs. IC nitroglycerin, 30 min after PTCA) in the moderate, severe and critical lesion severity subgroups, respectively (P less than 0.01 for critical or severe vs. moderate). This vasoconstriction was significantly greater than that observed in the corresponding control segment for patients with severe (P less than 0.01), and critical (P less than 0.001) lesions. These findings suggest that hypoperfused human epicardial coronary arteries "reset" their autoregulatory responsiveness and that distal vasoconstriction after PTCA is the result of this altered autoregulation. These findings have clinical implications concerning the etiology, prophylaxis and treatment of coronary spams after PTCA and coronary bypass surgery.

Angiography↗
PubMed1989

The effect of alkalosis on hypoxia-induced pulmonary vasoconstriction in lungs of newborn rabbits.

The purpose of this study was to determine whether metabolic and respiratory alkalosis reduce hypoxia-induced pulmonary vasoconstriction in lungs of newborn rabbits. To accomplish this, we isolated and perfused with blood the lungs from 33 newborn rabbits, 3-14 d old. In all pairs of lungs, we first measured the magnitude of hypoxia-induced pulmonary vasoconstriction at a pH of 7.30-7.42. We then measured the effect of alkalosis on the magnitude of hypoxic pulmonary vasoconstruction by following one of two different sequences of exposure to hypoxia and alkalosis. For the first sequence, we exposed 13 lungs to hypoxia, and during the hypoxic exposure we either decreased the inspired PCO2 (respiratory alkalosis, n = 8) or infused NaHCO3 (metabolic alkalosis, n = 5) to achieve a pH of 7.50-7.65. For the second sequence, we first decreased the inspired PCO2 (n = 9) or infused NaHCO3 (n = 11) to achieve a pH of 7.50-7.65 and then exposed the lungs to hypoxia. We found that hypoxic pulmonary vasoconstriction was reduced by either respiratory or metabolic alkalosis, when alkalosis was induced during hypoxia. When respiratory or metabolic alkalosis was induced before hypoxia, the magnitude of hypoxia-induced pulmonary vasoconstriction was the same as at the normal pH. We conclude that both metabolic and respiratory alkalosis reduce ongoing hypoxic pulmonary vasoconstriction in lungs of newborn rabbits. However, neither mode of alkalosis blunts pulmonary vasoconstriction in response to subsequent exposures to hypoxia.

Alkalosis↗
PubMed2004

Different prostanoids are involved in bradykinin-induced endothelium-dependent and -independent vasoconstriction in rat mesenteric resistance arteries.

Mechanisms underlying bradykinin-induced vasoconstriction were investigated in rat perfused mesenteric vascular beds with active tone. In preparations with intact endothelium, bolus injections of bradykinin (1 to 1,000 pmol) dose-dependently produced three-phase vascular effects, which consisted of a first-phase vasodilation followed by a second-phase vasoconstriction and a subsequent third-phase vasodilation; these effects were abolished by FR172357 (bradykinin B(2)-receptor antagonist), but not by des-Arg(9)-[Leu(8)]-bradykinin (bradykinin B(1)-receptor antagonist). In preparations with intact endothelium, indomethacin (cyclooxygenase inhibitor), seratrodast (thromboxane A(2) (TXA(2))-receptor antagonist), ONO-3708 (TXA(2)/prostaglandin H(2) (PGH(2))-receptor antagonist) or ozagrel (TXA(2) synthesis inhibitor) markedly inhibited the bradykinin-induced vasoconstriction. In preparations without endothelium, the bradykinin-induced vasoconstriction was abolished by indomethacin and ONO-3708, while seratrodast and ozagrel had no effect. These results suggest that the endothelium-dependent vasoconstriction of bradykinin is mainly mediated by TXA(2) and that prostanoids other than TXA(2), probably PGH(2), in mesenteric vascular smooth muscle are responsible for bradykinin-induced endothelium-independent vasoconstriction.

Animals↗
PubMed2000

Signaling mechanisms for muscarinic receptor-mediated coronary vasoconstriction in isolated rat hearts.

Signaling mechanisms for muscarinic receptor-mediated vasoconstriction in coronary resistance arteries were studied in potassium-arrested isolated rat hearts perfused at a constant flow rate. The cholinergic agonist bethanechol was given by bolus injection or constant infusion. Perfusion pressure was monitored as an indicator of coronary vascular resistance. Bolus injection of bethanechol evoked a phasic vasoconstriction in a dose-dependent manner, whereas infusion of bethanechol evoked a tonic vasoconstriction without producing tachyphylaxis. Bethanechol-induced phasic vasoconstriction was eliminated by perfusion with a Ca(2+)-free buffer. The L-type voltage-operated Ca(2+) channel blocker nifedipine decreased the maximal constrictor response to bethanechol by 59 +/- 2% (n = 4, P <.001), whereas the putative receptor-operated Ca(2+) channel blocker SK&F 96365 converted this vasoconstriction into vasodilation that was not mediated by nitric oxide. The protein kinase C inhibitor chelerythrine reduced the maximal phasic vasoconstrictor response to bethanechol by 78 +/- 2% (n = 6, P <.001) Bethanechol-induced tonic vasoconstriction was rapidly converted to a sustained vasodilation during infusion of SK&F 96365 or nifedipine, whereas infusion of chelerythrine gradually attenuated the tonic response to bethanechol. Results from other experiments do not support a role for phospholipase A(2)-dependent mediators in generating coronary vasoconstrictor responses to bethanechol. It is concluded that voltage-independent receptor-operated Ca(2+) channels, voltage-operated Ca(2+) channels, and protein kinase C are major signaling components for muscarinic receptor-mediated contraction of rat coronary resistance arteries.

Animals↗