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Biomedical subjects

D R Harder

Publications and source records attributed to D R Harder.

At least 91 records · Page 5Linked to original sources
PubMed1986

Electrophysiological mechanisms of arterial muscle activation: alterations associated with cerebral vasospasm and hypertension.

The active state of arterial muscle can be regulated by electrical events occurring at the plasma membrane. Factors which affect the level of the resting membrane potential can markedly alter resting tone, and sensitivity and contractility to agonists. The relative K+ conductance (gk) appears to be a principle factor in this regard. Reduction of gk induces generation of action potentials with concomitant mechanical activity. Cerebral arteries exposed to subarachnoid blood exhibit altered electrical and mechanical properties which predispose them to spasm; a phenomenon related to a reduced gk. Arterial muscle from hypertensive animals exhibit membrane electrical properties which may contribute to an elevated peripheral vascular resistance, namely, an elevated PNa/Pk ratio and altered electrogenic ion transport. Upon exposure to elevated transmural pressures, isolated cerebral arterial muscle cells depolarize and generate spontaneous "pacemaker-like" action potentials, processes which appear to be Ca2+ dependent. Cerebral arteries from spontaneously hypertensive rats depolarize more to elevated transmural pressures when compared to WKY. This increased membrane depolarization to pressure may be the result of an elevated Ca2+ permeability and/or an alteration in gk at the SHR arterial muscle cell membrane. Thus, abnormal activation of arterial muscle can be mediated by factors controlling transmembrane electrical gradients and ionic conductance systems.

Animals↗
PubMed1986

Vascular smooth muscle transmembrane potentials during hypotensive stress.

Although transmembrane potential (Em) appears to be an important regulator of vascular smooth muscle (VSM) contractile force in vivo, little is known of the electrophysiological changes in VSM during low flow states. In rats, VSM in small mesenteric veins depolarizes in the compensatory stage of hemorrhagic hypotension while the onset of peripheral vascular decompensation is associated with VSM hyperpolarization. Pretreatment with 30 mg/kg i.v. of methylprednisolone prevents the Em changes in mesenteric veins of hemorrhaged rats and reduces the depolarization of isolated vessels in response to norepinephrine, suggesting that some therapeutic agents may act by modifying the electrophysiological responses of VSM during the stress. Finally, adrenergic depolarization under resting conditions may contribute to a reduced ability of spontaneously hypertensive rats (SHR) to tolerate blood loss by reducing their compensatory venoconstrictor reserve relative to normotensive WKY controls. Although these observations suggest that vascular responses to hypotensive stress are related to the effects of the sympathetic nervous system upon VSM Em, further studies are required fully to elucidate the relative role of Em-dependent and Em-independent mechanisms in controlling active VSM tone during low flow states.

Animals↗
PubMed1985

Cellular mechanism of force development in cat middle cerebral artery by reduced PCO2.

These studies were undertaken to determine the effect of reducing a PCO2 below physiological levels on cat middle cerebral artery. Upon reduction of PCO2 from 37 to 14 torr (pH 7.4) we observed membrane depolarization and force development. Reducing PCO2 decreased the slope of the Em vs. log [K]o curve and increased the slope of the steady-state I/V relationship suggesting that the change in Em was due to reduction of outward K+ conductance (gk). Elevation of pH from 7.37 to 7.6 had a very similar effect on these cerebral arterial muscle cells, depolarizing the muscle membrane (reducing the Em vs. log [K]o curve) and increasing the slope of the I/V relationship to statistically equivalent values as reduction of PCO2. Returning PCO2 from 14 to 37 torr rapidly relaxed these preparations, but only transiently. This relaxation was followed by a rebound contraction within 3 min, demonstrating a transient nature for the action of elevating PCO2 in cerebral arteries. The response to changing pHo followed a slower time course but did not change with time. These studies demonstrate that both elevated pHo and reduced PCO2 activate cerebral arterial muscle by a mechanism which includes reduction in gk. However, it can not be determined if these similar responses and reduction of gk are mediated by changing pHi or mediated through different mechanisms. It is possible that pHo and PCO2 can modify cerebral arterial tone by direct mechanisms and not necessarily by their effect on pHi. It is clear, however, that reduction of PCO2 and elevation of pHo both activate cerebral arterial muscle by a mechanism which includes reduction of gk.

Animals↗
PubMed1985

A cellular mechanism for myogenic regulation of cat cerebral arteries.

Autoregulation of cerebral blood flow is accomplished through integration of metabolic, neurogenic and myogenic mechanisms. Myogenic mechanisms involve activation of cerebral arterial muscle cells as transmural pressure increases, providing a means through which vessel caliber can be regulated to maintain blood flow constant. The cellular mechanisms involved in this myogenic response may involve changes in the electrical potential across the plasma membrane. When isolated cat middle cerebral arteries are cannulated and prepared in a manner allowing manipulation of transmural pressure, the muscle cell membrane depolarizes as pressure increases. The degree of membrane depolarization in response to an elevated pressure is dependent upon extracellular Ca2+ [( Ca]o), increasing as [Ca]o is elevated and markedly decreasing as [Ca]o is reduced to low levels. When these arterial preparations are maintained at a physiological pressure of around 100 mm Hg, spontaneous action potentials can be recorded which increase in frequency upon further elevation in pressure. Vessels exhibiting such electrical activity can be observed to decrease in diameter as pressure is increased. Such finding suggest a membrane electrical mechanism for myogenic autoregulation of cerebral arteries.

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PubMed1985

In vivo membrane potentials of smooth muscle cells in the caudal artery of the rat.

Membrane potentials measured in vivo may differ significantly from those measured in vitro in part due to humoral factors, innervation, and wall tension. These studies were initiated to determine whether it is feasible to record membrane potentials from vascular smooth muscle cells in vivo in the caudal artery of the pentobarbital-anesthetized male Wistar rat. Membrane potentials were measured using glass microelectrodes and correlated with systolic, diastolic, and mean blood pressures. For systolic blood pressures between 100 and 140 mmHg the average resting membrane potential was -38.4 +/- 0.48 mV. There was good correlation of systolic, diastolic, and mean blood pressures with membrane potential between 100 and 140 mmHg (r = 0.89, 0.75, and 0.89, respectively). Below 80 mmHg the arterial muscle cells became more depolarized than would be expected if the membrane potential were determined solely by transmural pressure. The depolarized membrane potential at low arterial pressures may be due to enhanced neural input. Spontaneous electrical activity was observed in some of the in vivo cells. When action potentials were present, they were generated at rates between 1-2/s and 6-7/min. These studies indicate that it is feasible to measure membrane potentials from arterial smooth muscle cells in vivo in the caudal artery of the rat.

Action Potentials↗
PubMed1985

Hypoxia-induced activation in small isolated pulmonary arteries from the cat.

Effects of hypoxia on force development and membrane potential were studied in isolated small (less than 300 microns diam) and large (greater than 500 microns diam) pulmonary arteries from cats. There was a consistent and reproducible hypoxic constrictor response in small pulmonary arteries that began at PO2 values between 350 and 300 Torr and reached a maximum at PO2 between 50 and 30 Torr. In the small artery smooth muscle cell the membrane potential, which was -51 +/- 1.4 mV at a PO2 of 400 Torr, was depolarized to -37 +/- 2 mV at a PO2 of 50 Torr. In contrast, larger arteries did not exhibit significant hypoxic constriction or depolarization upon exposure to low PO2. Constriction in small arteries was not blocked by phentolamine. Treatment with a low dose of indomethacin (10(-9) M) augmented the response; however, a larger dose of indomethacin (10(-3) M) blocked the constriction to hypoxia but not to 30 mM KCl. Depolarization during hypoxia was not blocked by ouabain. Results of this study suggest that the hypoxic response of these isolated small pulmonary vessels may be like that seen in the intact lung. Furthermore, these data suggest that hypoxic vasoconstriction may be mediated by electrical events occurring at the pulmonary arterial muscle cell membrane either directly or via mediators released from the vessel wall.

Animals↗
PubMed1985

Hypoxic induction of Ca2+-dependent action potentials in small pulmonary arteries of the cat.

Small pulmonary arteries (less than 300 micron) from cats were mounted in myographs to record mechanical and electrical responses to hypoxia. When these preparations were exposed to a PO2 of 30-50 Torr after equilibration at 300 Torr they consistently developed active force, which increased or decreased in amplitude as [Ca2+] was raised or lowered, respectively, and was blocked on addition of verapamil. Intracellular electrical recording with glass microelectrodes demonstrated membrane depolarization and action potential generation when PO2 was lowered. Steady-state voltage vs. applied current curves obtained before and during hypoxia showed a significant reduction in input resistance. The relationship between membrane potential and extracellular K+ was not different during hypoxia compared with control, suggesting that there were not marked changes in K+ permeability under this condition. In the presence of verapamil to block Ca2+ inward current the hypoxia-induced action potentials were abolished concomitant with partial membrane repolarization. The results of these studies suggest that in certain isolated pulmonary arteries hypoxia induces contraction by a mechanism involving an increased Ca2+ conductance. These data suggest that the sensor involved in hypoxic pulmonary vasoconstriction may lie within the vessel wall and somehow mediates changes in smooth muscle ionic conductances.

Action Potentials↗
PubMed1985

Enhanced myogenic depolarization in hypertensive cerebral arterial muscle.

We have previously demonstrated pressure-dependent membrane depolarization and action potential generation in cat cerebral arteries. It was the purpose of this study to examine and compare the membrane electrical responses to increasing transmural pressure in spontaneously hypertensive rats with those of their normotensive Wistar-Kyoto controls. It was found that at transmural pressures from 40-160 mm Hg, spontaneously hypertensive rat cerebral arterial muscle depolarized more than normotensive counterparts. Pressure-induced action potentials could be recorded from arterial segments from both animal strains; however, the amplitude and upstroke velocity was significantly greater in spontaneously hypertensive rat cerebral arterial muscle. These data suggest that there are altered ionic permeabilities in spontaneously hypertensive rat cerebral arterial muscle which result in enhanced response to increasing transmural pressure. The implications of these findings are discussed.

Action Potentials↗
PubMed1985

A membrane electrical mechanism for hypoxic vasoconstriction of small pulmonary arteries from cat.

Using specially fabricated muscle myographs, we examined electrical and mechanical responses to reduction of PO2 in small (less than 300 micron) pulmonary arteries excised from cat lungs. Upon lowering PO2 from 400 to 50 mm Hg, these preparations consistently developed contractile responses concomitant with membrane depolarization and action potential generation. The largest changes in electromechanical responses to reduction of PO2 occurred between 150 and 50 mm Hg. These data strongly suggest that hypoxic activation of small pulmonary arteries is mediated by direct effects of reduced PO2 on muscle cell membrane ionic conductance systems.

Animals↗
PubMed1985

Vascular smooth muscle membrane potentials in rats with one-kidney, one clip and reduced renal mass-saline hypertension: the influence of a humoral sodium pump inhibitor.

Ninety to 120 min after removal of the caudal arteries, vascular smooth muscle cells from one-kidney, one clip (1-K, 1C) hypertensive animals were depolarized relative to those in appropriate control animals but cells from reduced renal mass-saline (RRM-S) hypertensive animals were not. However, supernatants of boiled plasma from both of the hypertensive models depolarized vascular smooth muscle cells in arteries taken from normotensive animals. These studies suggest that an agent in the plasma of these animals depolarizes vascular smooth muscle cells. This could help to explain the vasoconstriction in these hypertensive animals.

Animals↗
PubMed1984

Cellular mechanisms of opiate receptor stimulation in cat middle cerebral artery.

To determine some of the cellular mechanisms of opiate receptor stimulation in cat middle cerebral arterial muscle, intracellular electrical measurements and force development were monitored before and after addition of morphine. Addition of morphine resulted in a dose-dependent hyperpolarization of the muscle cells in the middle cerebral artery with a concomitant relaxation, indicating a high degree of electromechanical coupling in this preparation. The curve relating membrane potential vs. morphine was shifted to the right and downward by naloxone, demonstrating competitive inhibition at receptor sites. When middle cerebral arteries were studied from animals which had been injected with morphine prior to sacrifice, a significant hyperpolarization of the membrane was recorded when studied in an organ bath. This hyperpolarization was abolished if the animal had been pretreated with naloxone prior to morphine injection, suggesting that morphine may act in vivo as we have observed it to act in vitro. Morphine-induced hyperpolarization could be blocked in the organ bath when potassium conductance (gk) was inhibited. Similarly, the reduction in the slope of the voltage/current curve induced by morphine was blocked by agents which reduced gk. These data suggest the presence of opiate receptors on cat cerebral artery and suggest that morphine relaxes these vessels through a mechanism involving increased gk. These findings suggest a role for opiate-mediated systems in cerebral vascular control.

Animals↗
PubMed1984

Pressure-dependent membrane depolarization in cat middle cerebral artery.

This study was undertaken to examine the effect of increasing transmural pressure on membrane electrical properties of cat middle cerebral arterial muscle. Middle cerebral arteries were removed from the cat brain, cannulated, and prepared so that transmural pressure within a segment could be manipulated. Intracellular membrane potential was recorded with glass microelectrodes at various transmural pressures. There was a positive slope relating changes in intracellular membrane potential as a function of transmural pressure with a correlation coefficient of 0.79. Blockade of nerve excitation with tetrodotoxin and inhibition of alpha-adrenergic receptors with phentolamine not only did not block the pressure-induced depolarization, but increased the slope of the intracellular membrane potential vs. pressure relationship. This slope was increased upon elevation of extracellular calcium concentration from 2.5 to 4.0 mM and was significantly reduced upon reduction of extracellular calcium concentration to 0.5 mM. When arterial preparations were equilibrated at 0 mm Hg prior to pressurization, action potentials were recorded only when pressure was initially elevated, while a sustained depolarization was recorded during the pressure plateau. However, when arteries were equilibrated at a transmural pressure of 100 mm Hg for 90 minutes, spontaneous action potentials were recorded which increased in frequency as a function of pressure until they were inactivated when intracellular membrane potential approached -30 mV at high transmural pressures. Photomicrographs demonstrated that these vessels either maintained or decreased diameter upon pressurization. These findings provide a cellular mechanism for myogenic regulation of cerebral arterial diameter.

Action Potentials↗
PubMed1983

Electromechanical coupling in feline basilar artery in response to serotonin.

This study was undertaken to define some of the cellular mechanisms of action of serotonin on cerebral vascular muscle. Application of serotonin to cat basilar artery resulted in a dose dependent depolarization and contraction beginning at 10(-8) M. The correlation coefficient relating the degree of force development with the change in membrane potential (Em) was 0.98. Excess K+ depolarized these vascular muscle cells with a slope (between 10 and 100 mM [K]0) of 54 mV/decade. When the muscle cells within this artery were depolarized by only 7 mV by addition of excess K+ there was a significant reduction in force development in response to serotonin. When the membrane was depolarized from -63 to -40 mV the mechanical response to serotonin was reduced by around 50%. Steady state current/voltage curves demonstrated a reduction in input resistance suggesting that serotonin's mechanism of depolarization is not due to a reduction in gk. These data demonstrate that serotonin contracts cat basilar artery through mechanisms involving vascular muscle cell depolarization and that factors which influence the level of Em will markedly effect the contractile response to serotonin.

Animals↗
PubMed1983

Altered membrane electrical properties of smooth muscle cells from small cerebral arteries of hypertensive rats.

Certain electrophysiological properties of smooth muscle cells within middle cerebral arteries of spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls were recorded with glass microelectrodes. Under control conditions the smooth muscle cells of arteries from SHR rats exhibited fast and slow oscillations of the resting membrane potential (Em). In marked contrast the smooth muscle cells of WKY cerebral arteries were electrically quiescent. The Em vs. log [K]o relationship was similar for arteries from both SHR and WKY rats and extrapolated to similar [K]i values of 150-155 microM when determined under control conditions. When Em vs. log [K]o curves were obtained in the presence of ouabain to block electrogenic Na-K transport, the smooth muscle cells of SHR cerebral arteries exhibited a lower mean slope per decade change in [K]o (i.e., depolarized more at various concentrations of [K]o in the presence of ouabain) when compared to WKY. Arterial smooth muscle cells from SHR also depolarized to a greater extent when exposed to zero K+ solutions. The results of this study indicate that smooth muscle cells of cerebral arteries from SHR rats have a greater electrogenic Em component as well as altered ionic conductances for K+ and possibly Na+ both of which may contribute to their spontaneous electrical activity.

Animals↗
PubMed1983

Electromechanical coupling in rat basilar artery in response to morphine.

Force development, intracellular membrane potential (Em), and voltage vs. current curves were measured in rat basilar artery to help elucidate the mechanism of action of morphine sulfate and a synthetic narcotic, meperidine hydrochloride, on this preparation. Morphine sulfate caused a dose-dependent contraction of these vessels, which was reversible with naloxone. Electrical studies show that morphine may act upon this vascular smooth muscle preparation by decreasing potassium conductance (gk). This hypothesis is supported by the findings that morphine sulfate depolarized these cells and increased the input resistance (rin) determined by the application of rectangular hyperpolarizing and depolarizing current pulses through the microelectrode during impalement and recording of the associated voltage changes (delta V). Meperidine hydrochloride had significantly less effect on this preparation than morphine sulfate. Further studies show that the vehicular medium used for the commercially available preparation of naloxone (viz. the methyl and propyl esters of p-hydroxybenzoic acid in a ratio of 9:1) is, in vitro, a vasodilator of cerebral vascular smooth muscle.

Animals↗
PubMed1983

Heterogeneity of membrane properties in vascular muscle cells from various vascular beds.

It is becoming increasingly more apparent that vascular smooth muscle cannot be treated as a homogeneous group and cannot be compared to other types of smooth muscle at least in terms of responsiveness to vasoactive agents. This heterogeneity may have as part of its basis differences in the molecular structure at the level of the plasma membrane. Such differences manifest themselves in terms of resting membrane potential (Em), response to cardiac glycosides, ionic conductances, and membrane responses to neurotransmitters. Results show that the middle cerebral artery of the cat has a higher Em and depolarizes to excess K+ with a steeper slope than other peripheral arteries of the same animal. Furthermore, cerebral arteries from different areas of the brain exhibit distinctly different resting membrane properties as well as different responses to norepinephrine. In addition, cerebral arteries exhibit a high degree of electromechanical coupling not always observed in other peripheral arteries.

Action Potentials↗