Biomedical subjects

J E Faber

Publications and source records attributed to J E Faber.

At least 37 records · Page 2Linked to original sources

PubMed1995

ATP-sensitive K+ channels mediate alpha 2D-adrenergic receptor contraction of arteriolar smooth muscle and reversal of contraction by hypoxia.

Evidence in rat skeletal muscle suggests that local metabolic control of blood flow is facilitated by the reliance on alpha 2D-adrenergic receptors (ARs) for constriction of arterioles, together with the strong sensitivity of this constriction to inhibition by hypoxia. The present study examined the role of ATP-sensitive K+ (KATP) channels in the selective interaction between alpha 2D-ARs and hypoxia. Arterioles from rat cremaster muscle that possess both alpha 1D (alpha 1A/D)- and alpha 2D-AR subtypes were microcannulated, pressurized, and isolated in a tissue bath for measurement of changes in lumen diameter. Three studies first examined whether stimulation of alpha 2D- and alpha 1D-ARs involves inhibition of the KATP channel. Concentration-dependent constriction by the KATP antagonists glibenclamide (GLB, 0.01 to 10 mumol/L) and disopyramide (0.001 to 1 mmol/L) were abolished during alpha 2D stimulation but unaffected during alpha 1D stimulation. Activation of the KATP channel by cromakalim inhibited alpha 2D constriction with greater potency than alpha 1D (EC50, 7.0 +/- 0.2 versus 6.3 +/- 0.1). Finally, GLB (0.5 mumol/L) abolished dose-dependent alpha 2D constriction, whereas alpha 1D was unaffected. These data suggest that alpha 2D but not alpha 1D stimulation is "coupled" with closure of the KATP channel, leading to depolarization and contraction of vascular smooth muscle. In a second series, hypoxic (PO2, 6 mm Hg) inhibition of intrinsic smooth muscle tone was completely reversed by 0.1 mumol/L GLB, concentration-dependent GLB constriction was enhanced during hypoxia, and hypoxia reversed GLB constriction. These data confirm reports by others that hypoxia potentiates the activation of KATP channels, leading to hyperpolarization and relaxation. Finally, GLB constriction, which was abolished by concomitant alpha 2D stimulation, was completely restored by simultaneous activation of KATP channels with hypoxia. These findings suggest that the sensitivity of alpha 2D-AR constriction to inhibition by hypoxia arises through "antagonistic coupling" between these two stimuli, by which the alpha 2D-AR inhibits and hypoxia activates KATP channels.

Adenosine Triphosphate↗

PubMed1993

Vasopressinase-altered vasopressin elevates arterial pressure in anesthetized rats.

Transient diabetes insipidus of pregnancy (TDIP) is associated with elevated activity of vasopressinase, a plasma enzyme that opens the vasopressin (AVP) ring to produce a linear peptide that we have named vasopressinase-altered vasopressin (VAV). VAV may play a role in the pathogenesis of the arterial hypertension associated with TDIP. We sought to determine if VAV elevates arterial pressure, the potency of VAV relative to that of AVP, and whether the peptide binds to the vascular AVP receptor. AVP was incubated with vasopressinase and VAV was separated from residual AVP by high-pressure liquid chromatography. Intravenous bolus administration of VAV or AVP to ganglionic blocked rats produced dose-dependent increases in arterial pressure, with VAV demonstrating approximately 6000-fold lower potency than AVP. Vasopressin receptor blockade abolished the response to both AVP and VAV. These results suggests that high levels of VAV may contribute to the hypertension seen in TDIP.

Animals↗

PubMed1993

Characterization of alpha-adrenoceptor gene expression in arterial and venous smooth muscle.

Six genes coding for three unique alpha 1- (1A, 1B, 1C) and three unique alpha 2- (2A, 2B, 2C) adrenergic receptor (AR) subtypes have been cloned. Ligand binding and contractile studies have demonstrated that both alpha 1- and alpha 2-ARs can exist on vascular smooth muscle (VSM) cells, although less is known about the relative distribution and specific subtypes in different vascular segments. In the present study polymerase chain reaction (PCR) analysis was used to characterize the species of alpha-AR messenger RNA (mRNA) present in freshly isolated rat thoracic aortic media and vena cava and in cultured VSM cells (passage 2) derived from both sources. To prevent possible contamination of VSM mRNA, aortic media was separated from adventitia, and vessels were denuded of endothelial cells. Oligonucleotide primers specific for each of the six adrenergic genes were synthesized and used to probe for the presence of alpha-AR mRNA species after reverse transcription of total cellular RNA to cDNA. PCR-amplified AR transcripts were distinguished by the size of amplified DNA fragments and unique restriction endonuclease cleavage. Expression of alpha 1C- or alpha 2C-mRNA was not detected in vascular tissues or cultured VSM cells, although the alpha 2C-primers detected the expected alpha 2C expression in cerebral cortex. Only alpha 1A-mRNA was detected in aortic adventitia. VSM from aorta expressed alpha 1A-, alpha 1B-, and alpha 2A-mRNA, and this pattern was preserved in cultured aortic VSM. Vena cava also expressed both alpha 1A and alpha 1B; however only alpha 2B-mRNA was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

ANG II reverses selective inhibition of alpha 2-adrenoceptor sensitivity after in vitro isolation of arterioles.

To determine whether in vitro isolation attenuates alpha 2-reactivity, we examined postjunctional alpha-adrenoceptor sensitivity of isolated rat skeletal muscle first-order arterioles that we have previously characterized in vivo. Microdissected, pressurized arterioles (mean lumen diam +/- SE, 115 +/- 7 microns) were studied after cannulation with micropipettes. As expected, the alpha 1-antagonist, prazosin (10(-8) M), produced a parallel, 10-fold dextral displacement of the phenylephrine (alpha 1-agonist) concentration-response curve, whereas the alpha 2-antagonist, rauwolscine (10(-7) M) had no effect. However, prazosin inhibited UK-14,304 (full alpha 2- but partial alpha 1-agonist), which was opposite to our previous in vivo studies of these vessels; namely, prazosin shifted the UK-14,304 response curve by 21-fold, whereas rauwolscine induced only a twofold shift. These data suggest a loss of alpha 2-adrenoceptor responsiveness after in vitro isolation. In a second experiment, the presence of 10 pM angiotensin II, which was subthreshold for constriction, increased phenylephrine sensitivity 10-fold, UK-14,304 sensitivity 16-fold, and the UK-14,304 maximal response by 63%; the half maximum effective concentration response to UK-14,304 was now abolished by rauwolscine at a concentration that did not inhibit phenylephrine constriction. These data suggest that in vitro conditions selectively attenuate alpha 2-adrenoceptor sensitivity, and that subthreshold angiotensin II restores alpha 2-sensitivity to in vivo values.

Adrenergic alpha-Agonists↗

PubMed1992

Interaction between microvascular alpha 1- and alpha 2-adrenoceptors and endothelium-derived relaxing factor.

Intravital microscopy was used to study the effect of endothelium-derived relaxing factor (EDRF) on microvascular adrenoceptor sensitivity in rat cremaster skeletal muscle. NG-Monomethyl L-arginine (L-NMMA, 1-300 microM), an inhibitor of EDRF formation, produced concentration-dependent constriction of arterioles and venules. When an intermediate amount of alpha 1- versus alpha 2-adrenoceptor tone was first produced with bath-added norepinephrine (NE) in the presence of rauwolscine or prazosin, L-NMMA caused constriction with greater potency and efficacy during alpha 2 than during alpha 1 tone. During localized alpha 1 or alpha 2 constriction along an arteriole by perivascular micropipette suffusion of NE in the presence of rauwolscine or prazosin, again, bath-added L-NMMA produced constriction with greater potency during alpha 2 than during alpha 1 constriction. Like L-NMMA, disruption of EDRF release by microembolization caused baseline arteriole constriction and selectively increased alpha 2 sensitivity 75-fold. Although these findings support the hypothesis that endothelial cells possess alpha 2-adrenoceptors that promote EDRF release, a greater susceptibility of alpha 2 than alpha 1 constriction to EDRF inhibition could also account for the results. In support of this latter possibility, alpha 2 constriction was approximately 50-fold more susceptible than alpha 1 constriction to inhibition by the EDRF-like nitrodilator nitroprusside. The similarity in magnitude of this difference in sensitivity with the difference obtained in the embolization experiments does not support the hypothesis that microvascular endothelial cells in skeletal muscle possess EDRF-promoting alpha 2-adrenoceptors. However, these data do suggest that endogenous EDRF release modulates basal arteriole and venule tone and that alpha 2-adrenoceptor constriction is more sensitive than alpha 1 constriction to inhibition by EDRF.

Animals↗

PubMed1991

Occlusion of cremaster collateral circulation alters microvascular reactivity.

Surgical preparation of the rat cremaster skeletal muscle for microvascular study usually involves occlusion of the deferential artery and vein which supply a collateral circulation to the tissue. This allows removal of the testis and ductus deferens, and permits direct observation of the cremaster microvasculature. We examined with intravital microscopy the effect of this occlusion on alpha-adrenergic and nonreceptor-mediated (KCl) constriction of large arterioles (1A, 136 microns i.d.) and venules (1V, 193 microns i.d.). The acutely denervated cremaster was suspended in a tissue bath containing propranolol to block beta-adrenergic receptors. alpha 1-adrenergic (norepinephrine (NE) + rauwolscine), alpha 2-adrenergic (NE + prazosin), and KCl (+ phentolamine) concentration-response curves were obtained for bath-added agonists before vs after occlusion of the deferential circulation. Occlusion had no effect on baseline 1A diameter but increased 1V diameter slightly. Arteriolar alpha 1- and alpha 2-adrenergic sensitivities were unaffected by occlusion, but venular sensitivities were reduced by the same amount (approximately fourfold) for both receptor types. Occlusion increased arteriolar sensitivity to KCl but had no effect of venular KCl sensitivity. These data indicate that occlusion of the deferential collateral circulation can produce significant and varied effects on alpha-adrenoceptor and nonreceptor-mediated constriction of cremaster large arteriolar and venular smooth muscle, and underscore the need to avoid collateral occlusion for certain studies of the cremaster microcirculation.

Animals↗

PubMed1991

Adrenergic facilitation of myogenic response in skeletal muscle arterioles.

The myogenic response was studied in large skeletal muscle arterioles in the presence of varying degrees of constriction with norepinephrine (NE; 3 x 10(-8) to 1 x 10(-5) M) or potassium chloride (KCl, 40-120 mM). The cremaster muscle of anesthetized rats was exteriorized into a Krebs-filled tissue bath chamber for observation of the microvasculature using a video microscopy system. The body of the rats was enclosed in an airtight Plexiglas box that was pressurized from 0 to +30 mmHg to raise intravascular pressure and elicit the myogenic response. All experiments were performed in acutely denervated muscles with propranolol (1 x 10(-6) M) present to produce beta-receptor blockade. Diameter responses of the first-order arteriole (1A) were measured with a videoimage caliper and intravascular pressure with the servo-null micropipette technique. Under basal conditions, without NE, 1A diameter increased in a passivelike fashion from 122 +/- 5.4 to 130 +/- 5.1 microns as box pressure was elevated from 0 to +30 mmHg, respectively. Addition of NE to the cremaster bath produced a dose-dependent constriction of the 1A (EC50 2 x 10(-7) M). In the presence of this adrenergic tone the 1A exhibited myogenic constriction in response to increases in box pressure. For example, topical application of 3 X 10(-7) M NE caused the 1A to constrict from 122 +/- 5.4 to 70 +/- 5.3 microns. In the presence of this adrenergic tone elevating box pressure from 0 to +30 mmHg caused additional constriction to 55 +/- 6.6 microns.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Interactions between alpha-adrenoceptors and adenosine receptors on microvascular smooth muscle.

alpha 2-Adrenoceptor but not alpha 1-adrenoceptor constriction of arterioles is selectively inhibited by tissue acidosis, ischemia, and increased metabolic rate. To further examine neural-local interactions, we studied the effect of adenosine receptor stimulation on alpha 1- or alpha 2-adrenoceptor constriction. Intravital microscopy was used to study large arterioles (133 +/- 3 microns diam; mean +/- SE), small arterioles (16 +/- 1 microns), and large venules (178 +/- 3 microns) of rat cremaster skeletal muscle. Concentration-response (diameter change) curves were obtained for bath-added norepinephrine in the presence of either rauwolscine or prazosin to provide selective alpha 1- and alpha 2-constriction, respectively. The adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (2.24 x 10(-8) M) significantly attenuated both alpha 1- and alpha 2-constriction by 5- to 20-fold; alpha 1-constriction was three- to fourfold more sensitive than alpha 2-constriction. Similar inhibitory effects were obtained with adenosine (2.24 x 10(-6) M). The adenosine receptor antagonist 8-[4-[N(2-aminoethyl)carbamoylmethoxy]phenyl]-1,3-dipropylxanthine (0.7 microM) reversed the inhibitory effect of adenosine, which implicates extracellular A2 adenosine receptors. Intrinsic tone in large vessels was unaffected by adenosine receptor stimulation but was completely inhibited in small arterioles. These findings suggest that both alpha 2- and especially alpha 1-adrenoceptor constriction and intrinsic tone (of small but not large arterioles) are inhibited by physiologically relevant concentrations of adenosine.

Adenosine↗

PubMed1991

Differential activation of alpha 1- and alpha 2-adrenoceptors on microvascular smooth muscle during sympathetic nerve stimulation.

The relative contribution of postjunctional alpha 1- and alpha 2-adrenoceptors to constriction of microvessels was examined during sympathetic nerve stimulation and sympathetic escape (difference between peak and steady-state constriction). Large arterioles (120 +/- 4 microns control diameter) and venules (174 +/- 6 microns) and small arterioles (13 +/- 4 microns) were examined in rat cremaster skeletal muscle during stimulation of the cremaster efferent innervation (decentralized lumbar sympathetic chain, 0.5-16 Hz, 2-minute train). The muscle was suspended in a tissue bath, and diameter was measured with intravital microscopy. Frequency-response curves were obtained after vehicle (prazosin or rauwolscine) was added to the bath. In large arterioles, prazosin (10(-7) M) significantly attenuated constriction by 60-80%; a fivefold higher concentration had no additional effect. In contrast, rauwolscine (1 to 5 x 10(-7) M) had no effect. Venules evidenced minimal response to nerve stimulation. In small arterioles, rauwolscine (5 x 10(-7) M) significantly attenuated constriction by 50-60%, while prazosin (10(-7) M) had no effect. These data suggest that for large arterioles, which are known to possess both receptors, alpha 1-adrenoceptors are preferentially stimulated by nerve-released norepinephrine. In contrast, sympathetic constriction of small arterioles is mediated by alpha 2-adrenoceptors. Compared with large arterioles, small arterioles exhibited greater peak and steady-state constriction at all frequencies, with maximal responses achieved over the 0.5-4 Hz range. Large arterioles exhibit graded constriction over the entire frequency range. Sympathetic escape exhibited a small, negatively correlated frequency dependence for large arterioles, tended to be greater for small arterioles, and was more evident in large arterioles during alpha 2-adrenoceptor constriction at low-frequency stimulation. This distinct neural control of large resistance vessels by alpha 1-adrenoceptors and small terminal arterioles by alpha 2-adrenoceptors may allow neurogenic regulation of these vessel segments to be differentially susceptible to modulation by other extrinsic and intrinsic vasoactive controls that preferentially interact with alpha 1- and alpha 2-adrenergic contractile mechanisms.

Animals↗

PubMed1991

Effect of reduced blood flow on alpha 1- and alpha 2-adrenoceptor constriction of rat skeletal muscle microvessels.

Adrenergic constriction of skeletal muscle arterioles, particularly small terminal arterioles, is opposed by decreased blood flow or increased metabolic rate. Our previous studies indicate that neural constriction of large arterioles, which have both postjunctional alpha 1- and alpha 2-adrenoceptors, is mediated by alpha 1-receptors; small arterioles depend on alpha 2-receptors. Also, alpha 2, but not alpha 1, constriction is reduced by acidosis. Differential sensitivity of alpha 1 versus alpha 2 constriction to metabolic signals such as H+ may underlie the sensitivity of arteriolar adrenergic constriction to metabolic inhibition. To examine this hypothesis, we studied the effect of reduced perfusion on alpha 1- versus alpha 2-mediated constriction of large arterioles and venules. Intravital microscopy of rat cremaster skeletal muscle was used to obtain concentration-response curves for phenylephrine (alpha 1-agonist) and UK-14,304 (alpha 2-agonist). Thirty percent reduction in cremasteric artery flow by venous outflow obstruction had no effect on baseline diameter, indicating no effect on "intrinsic tone." Reduced perfusion also had no effect on arteriolar or venular sensitivity to phenylephrine or venular sensitivity to UK-14,304 but significantly attenuated arteriolar response to UK-14,304. To examine a possible mechanism for the selective inhibition of alpha 2 constriction by acidosis, we determined the effect of acidosis on the partial alpha 1-agonist St587. Like alpha 2 constriction, St587-mediated constriction of arterioles was reduced during acidosis and was attenuated by nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗

PubMed1991

Differential sensitivity of arteriolar alpha 1- and alpha 2-adrenoceptor constriction to metabolic inhibition during rat skeletal muscle contraction.

Our previous studies in rat skeletal muscle have determined that neural constriction of large arterioles, which regulate blood flow and peripheral resistance, is mediated by alpha 1-adrenoceptors, whereas small arterioles, which determine effective capillary density, depend on alpha 2-receptors. During physical exercise, metabolic vasodilators from contracting skeletal muscle oppose neural vasoconstriction. By mechanisms that are not understood, adrenergic constriction of small arterioles is particularly sensitive to metabolic inhibition during imbalances in oxygen supply versus demand. This sensitivity may result from the reliance of small arterioles on alpha 2-receptors and a greater sensitivity of alpha 2 constriction to metabolic dilators. We previously demonstrated selective attenuation of arteriolar alpha 2 constriction during a reduction in the oxygen supply/demand ratio subsequent to decreased skeletal muscle perfusion. In the present study, intravital microscopy of rat cremaster skeletal muscle was used to examine the effect of increased oxygen demand on adrenergic constriction of arterioles. The effect of multiple frequencies of skeletal muscle contraction (via genitofemoral nerve stimulation) on alpha 1 (norepinephrine + rauwolscine) and alpha 2 (norepinephrine + prazosin) constriction was used to evaluate neural-metabolic interactions over a wide range of metabolic conditions. Low-frequency (less than or equal to 2 Hz) skeletal muscle contraction attenuated only alpha 2 constriction; contractions greater than or equal to 4 Hz attenuated alpha 1 constriction and further reduced alpha 2 constriction. Comparison of the frequency of contraction necessary to produce inhibition of 20% of maximal dilation indicated that alpha 2 constriction was approximately 10-fold more sensitive than alpha 1 constriction to "metabolic" inhibition. High-frequency, but not low-frequency, contraction also inhibited intrinsic tone. These data suggest that release of dilator substances during moderate exercise may preferentially attenuate alpha 2 constriction to produce small arteriolar dilation and increased capillary density. In contrast, metabolic signals associated with higher frequency muscle contraction may inhibit both intrinsic tone and large arteriolar alpha 1 tone so that blood flow and oxygen delivery increase to match the elevated oxygen demand of more heavily exercising muscle.

Animals↗

PubMed1991

Preservation of venular but not arteriolar smooth muscle alpha-adrenoceptor sensitivity during reduced blood flow.

To compare arteriolar versus venular smooth muscle sensitivity to myogenic and metabolic inhibition during reduced blood pressure and flow, we measured the diameter of first-order venules (diameter, 230 microns) and arterioles (diameter, 156 microns) of the denervated, blood-perfused rat cremaster skeletal muscle that was suspended in a tissue bath. Sensitivity was determined for bath-added norepinephrine in the presence of yohimbine or prazosin to produce alpha 1- and alpha 2-adrenoceptor constriction, respectively, and for KCl to examine non-receptor-mediated sensitivity. To reduce venular pressure and flow, vasopressin, which constricts cremaster arterioles but not venules, was applied locally at a maximally effective concentration. This arteriolar constriction had no effect on venular sensitivity to alpha 1-adrenoceptor and KCl-mediated constriction. Venular sensitivity (-log M EC50) to alpha 1 and to KCl activation was 6.20 +/- 0.10 and 1.20 +/- 0.04 in the absence and 6.34 +/- 0.09 and 1.30 +/- 0.03 in the presence of arteriolar constriction, respectively. Venular sensitivity to alpha 2 activation was actually greater during arteriolar constriction (6.25 +/- 0.11 in the absence of constriction versus 7.06 +/- 0.13 in the presence of constriction, p less than 0.001). In a second series, the effect of reduced cremaster perfusion pressure and flow on both arteriolar and venular sensitivity was examined by mechanically lowering cremaster inflow. Reduction of first-order arteriolar and venular flow by 82-85% attenuated arteriolar alpha 1 and abolished alpha 2 sensitivity but had no effect on venular adrenergic sensitivity; KCl sensitivity was increased. These data indicate that, in contrast to arteriolar smooth muscle, venular smooth muscle alpha-adrenoceptor sensitivity is preserved during reduced pressure and flow and, thus, is little affected by metabolic and myogenic regulation. The selective depressant effect on arteriolar adrenergic but not KCl constriction suggests that myogenic/metabolic inhibition of arterioles is receptor specific.

Animals↗

PubMed1990

Cochlear microcirculation. Effect of adrenergic agonists on arteriole diameter.

We used intravital fluorescent microscopy coupled with computerized video image processing to examine the cochlear microvasculature. In Mongolian gerbils the bulla was opened ventrally and a small window was made in the second turn of the cochlea. After fluorescein isothiocyanate-dextran administration, the radiating arterioles were video-recorded under X675 magnification. Computer determinations of arteriolar response to norepinephrine bitartrate (mixed alpha 1/alpha 2 agonist), phenylephrine hydrochloride (alpha 1 agonist), and UK 14,304 tartrate (alpha 2 agonist) were made at multiple dose levels over time. Findings were consistent with arteriolar constriction in response to alpha-adrenergic stimulation. The presence of alpha 1 and alpha 2 receptors was established, and a predominance of alpha 2 receptors in the cochlea was suggested.

Adrenergic alpha-Agonists↗

PubMed1990

Lack of an effect of atrial natriuretic peptide on myogenic contraction of microvascular smooth muscle.

In previous studies we demonstrated that constriction of cremaster microvessels by occupation of alpha 1- but not alpha 2-adrenoceptors is inhibited by atrial natriuretic factor (ANF) at physiological concentrations (10(-11) to 10(-9) M). The present study examined the effect of ANF on "myogenic" constriction of arterioles induced by elevation of intravascular pressure. The cremaster skeletal muscle of anesthetized rats was denervated and extended with intact circulation into a tissue bath. Intravital microscopy was used to measure diameters of first- and second-order arterioles (80-150 microns diam). In group 1, propranolol and phentolamine (both at 10(-6) M) were added to the cremaster bath to block beta- and alpha-adrenoceptors, respectively. Norepinephrine was infused (3.51 micrograms.kg-1.min-1 iv) to raise arterial pressure by 30-35 mmHg. This induced a 30 +/- 3% (means +/- SE) decrease in arteriolar diameter (myogenic constriction). Thereafter, cumulative addition of ANF (10(-11) to 10(-7) M) to the tissue bath had no effect on microvessel diameter, except at the highest concentration wherein the myogenic constriction was reduced by approximately 40%. In a second study the rat's body, excluding the cremaster, was enclosed in an airtight Plexiglas box. Cremaster intravascular pressure was increased by elevating box (ambient) pressure by 10 and 20 mmHg, which caused arteriolar diameter to decrease to 81 +/- 5 and 73 +/- 8% control diameter, respectively, in the absence, and similar amounts 72 +/- 4 and 69 +/- 5%, in the presence of 10(-8) M ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Selective interaction of alpha-adrenoceptors with myogenic regulation of microvascular smooth muscle.

The interaction of alpha 1- and alpha 2-adrenoceptor constriction of arterioles with the myogenic mechanism was examined in rat cremaster skeletal muscle using intravital microscopy. Intravascular pressure was increased or decreased by changing pressure from 0 to +30 and 0 to -20 mmHg in a chamber that surrounded the animal but not the cremaster. Arterioles of 110 microns in diameter were constricted by approximately 30% with the alpha 1-agonist, phenylephrine, or the alpha 2-agonist, UK-14304. Increases in microvascular (box) pressure caused stepwise constrictions of similar magnitude (10-30%) regardless of the prevailing type of alpha-adrenergic tone. In contrast, during alpha 2 tone, decreases in pressure caused a three- to fourfold greater dilation (myogenic inhibition) than during alpha 1 tone. Thus myogenic constriction, normally minimal in these large arterioles, was amplified similarly during either alpha 1 or alpha 2 tone; however, alpha 2 tone was much more susceptible than alpha 1 tone to myogenic inhibition. Similar results were obtained with tone produced by thromboxane A2 vs. the Ca2+ channel agonist, BAY K 8644. Thus the particular sensitivity of alpha 2 constriction to myogenic inhibition may relate to interactions between these stimuli at the postreceptor level. The degree and type of alpha-adrenoceptor tone at different microvasculature levels may be important in myogenic autoregulatory blood flow adjustments during changes in perfusion pressure.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Effect of acidosis on contraction of microvascular smooth muscle by alpha 1- and alpha 2-adrenoceptors. Implications for neural and metabolic regulation.

Our previous studies have identified that adrenergic regulation of large arterioles and venules in skeletal muscle uses both postjunctional alpha 1- and alpha 2-adrenoceptors, whereas terminal arterioles appear to be subserved primarily by alpha 2-receptors. Adrenergic constriction of terminal arterioles is known to be particularly susceptible to inhibition by increased tissue metabolic rate. The purpose of this study was to examine the influence of tissue acidosis on alpha 1- and alpha 2-adrenoceptor constriction of skeletal muscle microvessels to determine if this differential receptor distribution might have significance in neural-metabolic interactions. Intravital microscopy of rat cremaster skeletal muscle was used to obtain concentration-response curves (diameter changes) of large distributing arterioles (mean diameter, 100 microns), small precapillary arterioles (20 microns), and capacitance venules (150 microns) for addition to the tissue bath of alpha-adrenergic agonists during normal pH (7.4) and during tissue bath acidosis (pH 7.1) produced by increasing bath PCO2. The following alpha-agonists were used: phenylephrine (alpha 1), B-HT 933 (alpha 2), and norepinephrine (mixed alpha 1/alpha 2). Acidosis had no effect on baseline diameter of the three vessel types, indicating a lack of effect on "intrinsic tone." Acidosis also had no effect on large microvessel sensitivity to phenylephrine but markedly reduced responses to B-HT 933. Acidosis had no effect on large arteriolar and venular sensitivity to norepinephrine but markedly decreased (x300) small precapillary arteriolar sensitivity. These data suggest that 1) alpha 2- but not alpha 1-adrenoceptor-mediated constriction of microvessels may be selectively sensitive to modest reductions in tissue pH, and 2) the prevalence of alpha 2-receptors on terminal arterioles and the marked sensitivity of alpha 2 constriction to tissue acidosis may contribute to the particular susceptibility of neural constriction at this level of the microcirculation to metabolic inhibition.

Acidosis↗

PubMed1989

Effects of althesin and urethan-chloralose on neurohumoral cardiovascular regulation.

The cardiovascular effects of althesin (ALT) and urethan-chloralose (UC) anesthesia were compared in conscious, chronically instrumented rats. Althesin had no effect on arterial pressure or base-line resistance in the renal, superior mesenteric, and hindquarters vasculatures but increased heart rate. In contrast, UC decreased arterial pressure, heart rate, and mesenteric resistance. Although UC attenuated depressor responses to nitroglycerin, neither anesthetic significantly altered regional vascular reactivity to intravenous phenylephrine and nitroglycerin. The cardiac chronotropic baroreflex was examined by comparing the slope of the curves relating maximal changes (delta) in heart rate (pulse interval) that occurred at the point coinciding in time with the maximal changes in mean arterial pressure produced by phenylephrine and nitroglycerin. Neither anesthetic significantly altered the baroreflex slope (delta pulse interval/delta mean arterial pressure) for pressor and depressor stimuli. Both anesthetics attenuated the sympathoexcitatory response to cerebroventricular angiotensin II, although ALT had less of a depressive effect (pressor response during ALT and UC = 65 and 30%, respectively, of conscious). Plasma renin activity (PRA) and the hemodynamic response to peripheral angiotensin-receptor antagonism were significantly increased (PRA by almost 6-fold) during UC, whereas ALT was without effect. Similarly, UC but not ALT induced vasopressin-dependent vascular tone. Ganglionic blockade indicated that peripheral neurogenic tone was not altered by ALT anesthesia. These data suggest that althesin produces fewer hemodynamic disturbances than urethan-chloralose and largely maintains cardiovascular regulation intact.

Alfaxalone Alfadolone Mixture↗

PubMed1988

Effect of local tissue cooling on microvascular smooth muscle and postjunctional alpha 2-adrenoceptors.

The effect of local tissue cooling on microvascular smooth muscle contractile behavior and sensitivity to adrenergic constriction was examined in rat cremaster skeletal muscle. Intravital microscopy was used to measure the diameter of first- and second-order arterioles (control diam = 101 +/- 7 microns) and venules (diam = 142 +/- 9 microns), and third-order terminal arterioles (diam = 19 +/- 4 microns). Norepinephrine (NE) was added to the cremaster bath to produce a 20-35% reduction in control diameter obtained at 34 degrees C bath temperature (in situ cremaster temperature). In the presence of NE, cooling the bath to 26 degrees C caused additional constriction of large arterioles and venules. Terminal arterioles exhibited a more pronounced cooling-induced constriction. Spontaneous vasomotion, evident only in this vessel type, was abolished by cooling. Cooling-induced constriction and inhibition of vasomotion were readily reversible with rewarming to 34 degrees C. Blockade of postjunctional alpha 2-adrenoceptors with yohimbine (1-5 X 10(-7) M) completely abolished cooling-induced constriction, as did the alpha 1- and alpha 2-adrenoceptor antagonist phentolamine (10(-6) M); blockade of alpha 1-adrenoceptors with prazosin (10(-8) M) had no effect on the response. After inhibition of the noradrenergic constriction with yohimbine or phentolamine, local cooling dilated terminal arterioles; however, the dilation was transient. These data suggest that modest tissue cooling has a direct, although transient, depressant effect on microvascular smooth muscle tone. However, in the presence of adrenergic constriction, the inhibitory effect of local tissue cooling is overcome by a selective increase in alpha 2- but not alpha 1-mediated vasoconstriction.

Animals↗