Search PubMed⌕ Search

Biomedical subjects

I G Joshua

Publications and source records attributed to I G Joshua.

At least 37 records · Page 2Linked to original sources
PubMed1993

Neural release of substance P causes dilation of arterioles in rat striated muscle.

Substance P, which is present in small nerve terminals and proximal to microvessels in rat strated muscle, may have a vasodilator role if released into the microcirculation. Male, Sprague-Dawley rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and the cremaster muscle, with intact blood supply and innervation, was suspended in a bath containing a physiological salt solution. The major autonomic innervation to the cremaster (genito-femoral nerve) was isolated and its cut, distal end was stimulated (3-5 Hz, 2 ms, 10-20 V). Diameters of third order arterioles (14-23 microns) were measured by television microscopy. Stimulation after a 20-min pretreatment with the alpha-adrenergic receptor antagonist phentolamine (2.10(-5) M) unmasked a moderate vasodilation, which was attenuated by treatment with the substance P receptor antagonist [D-Arg1,D-Pro2, D-Trp7,9,Leu11]-substance P (1.10(-6) M). This neurogenic vasodilation was not sensitive to muscarinic receptor blockade by atropine (1.10(-4) M), but was partially blocked by the beta-adrenergic receptor antagonist propranolol (1.10(-5) M). These data suggest that the rat striated muscle microvasculature is innervated with nerves containing substance P, and the release of substance P from the nerve terminals causes arteriolar dilation.

Animals↗
PubMed1993

Cadmium-induced arteriolar constriction in skeletal muscle microcirculation.

Cadmium, an environmental pollutant, is known to induce hypertension in animal models, in part via an increase in peripheral vascular resistance. Since prior studies have investigated the vascular effects of cadmium using large, nonresistance arteries, we directly assessed cadmium's action on resistance size arterioles in skeletal muscle using the intact rat cremaster muscle preparation. Cadmium evoked a concentration-dependent constriction of the large arterioles (120 to 50 microns in diameter) but elicited no change in the diameter of smaller arterioles (30 to 15 microns). Blockade of alpha-adrenergic receptors did not diminish the constrictor response of the larger arterioles to cadmium, but bathing the cremaster muscles with a solution containing low calcium attenuated the arteriolar constriction to cadmium. Calcium repletion caused the arterioles to constrict further. These observations provide the first direct evidence that cadmium constricts resistance arterioles in skeletal muscle. The cadmium constriction: (1) is selective for the large arterioles, (2) is not mediated by alpha-adrenergic receptors, and (3) is influenced by the extracellular level of calcium. We conclude that arteriolar constriction in skeletal muscle tissue may play a role in the hypertensive actions of cadmium.

Animals↗
PubMed1993

Arteriolar dilation mediated by capsaicin and calcitonin gene-related peptide in rats.

In addition to altering vascular tone by stimulating primary afferent nerves and acting through reflex pathways, capsaicin acts locally. We examined effects of topically applied capsaicin on arteriolar diameter in striated muscle and tested the hypothesis that capsaicin can alter microvascular tone by releasing substance P (SP) or calcitonin gene-related peptide (CGRP). In anesthetized rats, the right cremaster muscle was exposed and suspended in a tissue bath filled with a physiological salt solution. Diameters of third-order arterioles were displayed and measured using in vivo video microscopy. In 17 of 20 rats, addition of capsaicin (3 x 10(-7) M) to the bath dilated arterioles (85 +/- 14% above control). Failure of a second administration of capsaicin to produce a sustained dilation in 6 of 7 arterioles that had previously dilated to capsaicin is consistent with the hypothesis that this agent causes depletion of an endogenous vasodilator. Pretreatment with an SP inhibitor did not alter capsaicin-induced dilation. CGRP (1 x 10(-10) to 2 x 10(-8) M) caused dilation similar to that caused by capsaicin. Pretreatment with a CGRP inhibitor to the bath prevented capsaicin-induced dilation, but not constriction. These results suggest that capsaicin can dilate microvessels by releasing CGRP, which can modulate tone.

Animals↗
PubMed1993

Decreased arteriolar endothelium-derived relaxing factor production during the development of genetic hypertension.

In the present study, basal and stimulated production of endothelium-derived relaxing factor (EDRF) were examined in young (4-5 week-old) and mature (10-12 week-old) spontaneously hypertensive rats (SHR) and were compared with those of age-matched Wistar Kyoto (WKY) normotensive rats. Nw-nitro-L-arginine methyl ester (L-NAME) was used as a probe for basal EDRF production in vivo. We also determined the dose-response effects of acetylcholine (Ach, 10(-9)-10(-5) M), sodium nitroprusside (NP, 10(-9)-10(-5) M), and norepinephrine (NE, 3 x 10(-10)-10(-6) M), on third-order arterioles (3A) in the two age groups. Relaxation of 3A vessels in response to Ach was significantly lower (p < 0.01) in mature SHR than in WKY rats. No significant differences were observed in responses to Ach in young animals or in responses to NP in either age groups. Preincubation with L-NAME (2 x 10(-4) M) shifted the dose-response curves of NE to the left in mature WKY rats (n = 6), but not in mature SHR (n = 6). These data indicate that both basal and stimulated production of EDRF are decreased in small arterioles in the striated muscle microcirculation at an established stage of genetic hypertension. These data suggest that a diminished EDRF response by arterioles may be in part responsible for the elevated microvascular reactivity observed in genetic hypertension.

Acetylcholine↗
PubMed1991

Substance P mechanisms in the regulation of striated muscle microcirculation.

The effects of substance P (SP) on microvessels in the cremaster of sodium pentobarbital-anesthetized male, Sprague-Dawley rats were investigated using closed-circuit television microscopy. Topically added SP (bath concentrations of 10(-13) to 10(-8) M) caused significant dilation of small arterioles. SP vasodilation was sensitive to pretreatment of the muscle tissue with SP analogues, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (APTL-SP) and [D-Pro2, D-Trp7,9]-substance P (PT-SP). Attenuation of the responses by pyrilamine suggests that part of the SP-induced dilation involves the release of histamine. The vasodilation was abolished by hydroquinone, suggesting an intermediate role for endothelium-derived relaxing factor in the response to SP.

Animals↗
PubMed1990

Endothelin-1-induced constriction in the coronary resistance vessels and abdominal aorta of the guinea pig.

The purpose of this study was to examine contractile properties of endothelin-1, a newly discovered vasoactive peptide, in guinea pig coronary resistance vessels and abdominal aorta. Changes in perfusion pressure after injections of endothelin-1 were measured using a constant-flow modified Langendorff preparation. The ED10 values of coronary perfusion pressure were about 100-fold less for endothelin-1 than for prostaglandin F2 alpha. After the endothelium was damaged by exposure to free radicals, maximal coronary constriction in response to endothelin-1 (10(-9) moles) was not altered, whereas dilator responses to low doses of endothelin-1 were converted to constrictor responses. Removal of the endothelium from aortic rings significantly increased responsiveness to endothelin-1 and the maximal response to the peptide. In calcium-free medium, endothelin-1 induced small increases both in perfusion pressure in coronary vessels and in tension in the aorta. Reintroduction of calcium in the coronary and aortic preparations produced a rapid increase in perfusion pressure and tension, respectively. Further, endothelin-1-induced coronary constriction was inhibited 59% +/- 7% by nifedipine (10(-7) moles). We conclude that endothelin-1 is a more potent constrictor than prostaglandin F2 alpha in the coronary vasculature. Endothelin-1-induced constriction in the coronary vasculature of the guinea pig is not mediated through an endogenous constricting factor released from the endothelium or a constrictor prostaglandin. Further, endothelin-1-induced dilation in the coronary vasculature and attenuation of endothelin-1-induced contraction in the abdominal aorta of the guinea pig are mediated through the release of a factor from the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Endothelin-induced vasoconstriction of small resistance vessels in the microcirculation of the rat cremaster muscle.

Recently, a peptide (endothelin) which has been shown to have potent vasoconstrictor properties has been isolated from the vascular endothelium. In the present study, we assessed the responsiveness of small arterioles and venules in the rat cremaster muscle to topical application of endothelin using closed-circuit television microscopy. Exposure to increasing concentrations of endothelin (10(-15)-10(-7) M) produced a dose-dependent constriction in large (90 +/- 8 microns), intermediate (50 +/- 6 microns), and small (21 +/- 4) arterioles. Large (144 +/- 17 microns) and intermediate (79 +/- 18 microns) venules also constricted to the peptide, but the responses were inconsistent and smaller in magnitude. The constriction to endothelin was long lasting and resistant to washout. Arteriolar reactivity to endothelin was similar for all vessel levels with ED50 values ranging from 10(-9) to 10-s;1(0) M. Exposure to the calcium entry blocker, verapamil, attenuated the endothelin-induced constriction in 3A arterioles, suggesting that the constriction in skeletal muscle arterioles is at least partially due to the increased entry of extracellular calcium.

Animals↗
PubMed1990

Lung inflation evokes reflex dilation of microvessels in rat skeletal muscle.

Lung inflation can reflexively decrease peripheral resistance, but effects on the microcirculation have not been determined. In this study, we examined the effects of lung inflation on microvessels in skeletal muscle. In anesthetized spontaneously breathing rats, the right cremaster muscle with intact circulation and innervation was exposed and suspended in a tissue bath filled with a physiological salt solution. Diameters of third-order arterioles (3As) were displayed by television microscopy and measured as an index of microcirculatory resistance. In other experiments, sympathetic activity (in the genital femoral nerve) to the cremaster was recorded. Lung inflation decreased systemic blood pressure by 32 +/- 3 mmHg and increased 3A diameter by approximately 23% (P less than 0.05, n = 17). The increase was abolished by cutting the cervical vagus nerves or the right genital femoral nerve. Furthermore, inflation decreased sympathetic nerve activity by 47.6 +/- 11.3% (P less than 0.05, n = 5) before vagotomy but not after. Dilation in response to inflation was also abolished by phentolamine or guanethidine. These results suggest that stimulation of vagal afferents by inflation reflexively decreases microvascular resistance by withdrawal of sympathetic tone.

Animals↗
PubMed1989

Dilator actions of endothelin in coronary resistance vessels and the abdominal aorta of the guinea pig.

Endothelin has been characterized as a potent constricting factor. The purpose of this study was to investigate possible dilator effects of this peptide and to examine whether dilator responses occur through an endothelium-mediated mechanism in guinea pig coronary resistance vessels and isolated aortic rings. Changes in perfusion pressure after bolus injections of endothelin were measured using a constant-flow modified Langendorff preparation with a transducer between the flow pump and the heart. An immediate fall in perfusion pressure, averaging 6 mmHg, was observed after injection of endothelin (10(-14)-10(-12) moles). This effect was maximal at 1 minute and tended to return toward baseline levels within 4 minutes. In response to endothelin (10(-9) M), isolated aortic rings relaxed 35% after being contracted with prostaglandin F2 alpha (10(-7) M). In both preparations, dilation was converted to constriction after endothelium damage by oxygen radicals or endothelium removal (mechanical rubbing). Dilator responses to endothelin were blocked by pretreatment for 30 minutes with indomethacin (14 microM) in the presence of an intact endothelium in coronary resistance vessels, whereas in the abdominal aorta they were not. We conclude that endothelin has significant dilator properties and that this effect is opposed by its constrictor action at higher doses. In addition, dilator responses to endothelin require an intact endothelium in both coronary vessels and abdominal aorta. Finally, endothelin-induced dilation in coronary resistance vessels appears to occur through a cyclooxygenase product-mediated mechanism.

Acetylcholine↗
PubMed1989

Lanthanum potentiation of the vascular response to a protein kinase C activator in genetically hypertensive rats.

The effects of lanthanum on the contraction induced by the protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate (TPA) were studied in femoral artery rings from stroke-prone, spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). When exposed to a calcium-free buffer containing 1 mmol/l EGTA, the femoral artery rings from SHRSP and WKY, pre-contracted with TPA (10(-6) mol/l), relaxed by 52 and 24%, respectively. Treatment of the rings in this calcium-free buffer with 2.6 mmol/l lanthanum significantly potentiated the TPA-induced contractions in vascular rings from WKY (49%) and SHRSP (136%). Potentiation by lanthanum of the TPA-induced contraction in the absence of extracellular calcium suggests that this cation is acting intracellularly to increase protein kinase C activity. The increased vascular responsiveness of SHRSP to lanthanum may reflect an abnormality in protein kinase C activation in vascular smooth muscle of genetically hypertensive rats.

Animals↗
PubMed1988

Predisposition to hypertension in rat pups from renal hypertensive dams.

We determined that a predisposition to hypertension could be transmitted by a nongenetic, renal hypertensive (HT) mother to her pups. The pups of one-kidney: one clip Goldblatt (1K:1C) hypertensive female rats and of sham operated normotensive female rats were subjected to the 1K:1C procedure at 28 days of age and tail cuff blood pressures (BP) were determined. After surgical induction of hypertension, HT male pups of HT dams had a significantly greater (p less than .05) BP by 14 days after surgery (194 +/- 8 mm Hg) than did HT male pups of normotensive (NT) dams (169 +/- 6 mm Hg). A similar trend (p less than .08) was observed for the HT female pups of HT dams (185 +/- 7 mm Hg) compared to HT females from NT dams (163 +/- 4 mm Hg). Thus, in utero exposure of pups to a chronic HT state alters the response of the pups to the surgical induction of hypertension. Furthermore, the results suggest that transfer of a predisposition to hypertension from mother to offspring occurred during the pregnancy/lactation period.

Animals↗
PubMed1988

The influence of extracellular calcium on microvascular tone in the rat cremaster muscle.

In vivo responses of arterioles and venules to changes in bath calcium concentrations were observed in the cremaster muscle of male Sprague-Dawley rats. Small arterioles (2A, 3A) initially exposed to a solution containing calcium (2.55 mM) significantly dilated in response to a 0-calcium bath. Reexposure to calcium (greater than 0.65 mM) caused 2A and 3A arterioles to constrict to diameters similar to the initial control values. In contrast, large arterioles (1A) and all venules (1V, 2V, 3V) were unresponsive to exposure to a 0-calcium solution or to reexposure to calcium (0.65-5.10 mM). Treatment with mefenamic acid (10 micrograms/ml), a prostaglandin synthesis inhibitor, produced marked constriction of arterioles but not of venules, suggesting the involvement of endogenous vasodilator prostaglandins in the regulation of resting diameters of arterioles. In the presence of mefenamic acid, 1A arterioles dilated when exposed to a 0-calcium solution and constricted back to control diameters following reintroduction of calcium into the bath. These data demonstrate heterogeneity in the responsiveness of cremasteric microvessels to changes in extracellular calcium. The small arterioles were most responsive to calcium. The lack of response by the largest arterioles appears to be due to the dilator influences of endogenous prostaglandins.

Animals↗
PubMed1987

Endogenous prostaglandins selectively mask large arteriole constriction to angiotensin II.

Television microscopy was used to observe the responses of in vivo arterioles and venules of the rat cremaster muscle to the topical application of angiotensin II (10(-8) and 10(-6) M). Neither the first- (A1) or second-order arterioles (A2) nor the first- (V1) or second-order venules (V2) constricted significantly to angiotensin II. However, after the inhibition of local prostaglandin synthesis with either mefenamic acid or indomethacin, both A1 and A2, but not the venules, gave a significant constrictor response to angiotensin II (10(-6) M). Arterioles and venules, which were preconstricted with norepinephrine, dilated to their initial baseline diameters after angiotensin II (10(-6) M), a response not observed when the microvessels were pretreated with either an angiotensin antagonist or a prostaglandin synthesis inhibitor. These observations indicate that endogenous prostaglandins exert a significant dilator influence on the larger arterioles, that this dilator influence appears to oppose the constrictor effect of angiotensin II, and that angiotensin II acts on specific receptors to induce synthesis and/or release of dilator prostaglandins in large arterioles. However, prostaglandins cannot account for the absence of a venular constriction to angiotensin.

Angiotensin II↗
PubMed1987

In vivo arteriolar reactivity to norepinephrine and calcium in one-kidney, one-clip Goldblatt hypertensive rats.

The in vivo reactivity of small arterioles to norepinephrine and to changes in external calcium was investigated in normotensive (NT) and one-kidney, one-clip Goldblatt hypertensive rats (1K1C). Rats were anesthetized with sodium pentobarbital (50 mg/kg) and arterioles in the cremaster muscle were exposed to increasing concentrations of either norepinephrine (10(-10) to 10(-5) M) or of bath calcium (0 to 5.1 mM). Third-order arterioles of 1K1C showed almost a ten-fold increased reactivity to NE compared to arterioles of NT rats (pD2 values of 7.88 +/- .43 vs 6.92 +/- .30). Arterioles of 1K1C rats showed an increased reactivity to re-exposure to calcium (0.65 to 5.10 mM). Following exposure to phentolamine this hyper-reactivity was abolished and arterioles of 1K1C and NT exhibited similar responses to changes in bath calcium concentrations, suggesting that the increased reactivity in the 1K1C was due to stimulation of endogenous norepinephrine release. When arterioles were exposed to increasing bath concentrations of the calcium entry blockers, verapamil and diltiazem, dilator responses were similar for 1K1C and NT groups. Collectively, these data suggest that during the development of renovascular hypertension, observed increases in arteriolar reactivity involve an increase in the receptor mediated entry of extracellular calcium into vascular smooth muscle and no change in non-receptor-mediated entry of calcium.

Animals↗
PubMed1986

Histamine-induced protein leakage in hypertensive rats: inhibition by verapamil.

Hypertension has been associated with an enhanced transport of macromolecules from the vasculature to the interstitium. The first objective of this study was to determine if, under control conditions, there is an enhanced leakage of macromolecules from the cremaster vasculature of the hypertensive rat. The second objective was to determine if the response to a mediator of macromolecular leakage (histamine) was altered in the renovascular hypertensive rat. A third objective was to determine if a calcium entry blocker, verapamil, could inhibit histamine-induced leakage and, if so, was the sensitivity to verapamil different in the renovascular hypertensive rat. Rats were anesthetized with pentobarbital, and the cremaster preparation was used for in vivo television microscopy studies. Fluorescein isothiocyanate was tagged to rat serum albumin (FITC-RSA), and the leakage of this albumin from the vasculature to the interstitium was quantitated by the use of fluorescent microscopy techniques. There was no difference during control conditions in macromolecular leakage between the normotensive and hypertensive rats. However, histamine induced a greater leakage in the renovascular hypertensive rat than in the normotensive controls. In addition, verapamil, in the presence of normal calcium levels, inhibited the histamine-induced leakage in the hypertensive rats but not in the normotensive controls. These data suggest that enhanced macromolecular leakage during hypertension may be due to an increased sensitivity to mediators of protein leakage. These agents may produce protein leakage by enhancing entry of extracellular calcium into endothelial cells.

Animals↗
PubMed1986

In vivo venular changes with the development of one-kidney, one-clip hypertension in the rat.

Television microscopy was used to quantify in vivo resting venular diameters and the responses to topically applied norepinephrine in the cremaster muscle of two groups of urethanchloralose anesthetized rats: normotensive rats (NT) and one-kidney, one-clip Goldblatt hypertensive rats (1K1C). Observations were made two weeks after the surgery which was used to induce renovascular hypertension. At this stage, we have previously observed an increase in arteriolar reactivity (1). In the current study, mean arterial blood pressures for 1K1C (149 +/- 5 mmHg) were significantly higher than pressures for NT (102 +/- 3 mmHg). Venules were categorized by branching order and venular diameters were measured at three different levels of the microcirculation: first (1V), second (2V), and third order (3V) venules. Reactivity to norepinephrine at all venular levels in the 1K1C group was similar to that recorded for the NT group. Resting venular luminal diameters, however, were significantly smaller (20%) for large (1V) venules of the HT group (137 +/- 9 micron) compared to those for the NT group (171 +/- 10 micron). Thus, in contrast to previously reported data for arterioles, a structural venoconstriction and not an increase in venular reactivity appears to characterize the early vascular changes associated with this form of renovascular hypertension.

Abdominal Muscles↗
PubMed1984

Mechanism of the biphasic arteriolar response to angiotensin II.

Male Sprague-Dawley rats (140-180 g) were anesthetized with alpha-chloralose and urethan. The cremaster muscle with intact blood supply and neural innervation was suspended in a tissue bath containing a modified Krebs solution. With the use of television microscopy the luminal diameters of third-order arterioles (14-32 micron) were measured before and after adding angiotensin II (ANG II, bath concn 10(-6) M). The arterioles responded to ANG II with an initial, transient constriction followed by a more prolonged dilation to a diameter larger than the control diameter. Pretreating the muscle with [Sar1, Ile8]ANG II significantly attenuated both the arteriolar constriction and subsequent dilation induced by ANG II. Treatment of the cremaster muscle with mefenamic acid or indomethacin, inhibitors of prostaglandin synthesis, produced a significant reduction in the diameter of the arterioles and abolished the dilator phase of the arteriolar response to ANG II without preventing the ANG II-induced constriction. These results demonstrate that within the intact microcirculation, ANG II produces both an arteriolar constriction and a dilation that are mediated by specific ANG II receptors. The ANG II-induced dilation of the arterioles appears to be caused by increased prostaglandin synthesis and release.

Angiotensin II↗