Vasomotor responses of cerebral arterioles in situ to putative dopamine receptor agonists.

The vasomotor responses of individual cerebral pial arterioles on the convexity of the cerebral cortex to subarachnoid perivascular micro-injections of dopamine and the putative dopamine receptor agonists, apomorphine, SKF 38393 and LY 141865, have been examined in 38 anaesthetized cats. The perivascular microapplication of dopamine (10(-9)-10(-3)M) effected dose-dependent reductions in pial arteriolar calibre, with the maximum reductions in calibre (22 +/- 2% from preinjection levels: mean +/- s.e.) being observed at 10(-3)M. The cerebrovascular constriction produced by dopamine (10(-5)M) could be significantly attenuated by the concomitant perivascular administration of phentolamine (10(-6)M) or methysergide (10(-6)M). The perivascular microapplication of apomorphine (10(-8)-10(-4)M) effected dose-dependent increases in arteriolar calibre, with the maximum increase (31 +/- 6%) being observed with apomorphine (10(-5)M). The perivascular administration of the putative dopamine D1-receptor agonist, SKF 38393 (10(-9)-10(-4)M) increased arteriolar calibre, with the maximum response (24 +/- 3%) being observed with injection of 10(-7)M. The putative dopamine D2-receptor agonist, LY 141865, also increased cerebral arteriolar calibre, but only at high concentrations (maximum calibre increase 25 +/- 6.1 with 10(-4)M). The cerebrovascular dilatations elicited by apomorphine and by SKF 38393 were markedly attenuated by the concomitant perivascular microapplication of the putative dopamine D1-receptor antagonist, SCH 23390 (10(-8)M). The perivascular administration of SCH 23390 (10(-9)-10(-5)M) per se did not alter arteriolar calibre nor the arteriolar dilatation provoked by microinjections of acidic cerebrospinal fluid. These results point to the presence on cat cerebral arterioles of dopamine receptors (probably of D1 subtype) mediating dilation.     

Biphasic responsiveness of rat pial arterioles to dopamine: direct observations on the microcirculation.

The effects of local perivascular application of dopamine to rat pial arterioles. (20-40 micrometer i.d.) were examined in situ, at the microcirculatory level, by use of a high-resolution closed circuit television microscope recording system. Local application of very low, physiological doses (1 to 10 pg) of dopamine to pial arterioles of the anaesthetized rat induces vasodilatation, whereas higher doses induce vasoconstriction. The magnitudes of these biphasic responses obtained in male rats were not significantly different from those obtained in female animals. Our findings support the theory that local release of this neurotransmitter amine from perivascular cells in the brain may promote local increases in cerebral blood flow.     

Second messenger systems: functional role in cerebrovascular smooth muscle regulation

The role of two second messenger systems in alterations of cerebrovascular smooth muscle tone was examined in feline cerebral arteries using an in vitro preparation of vessel segments and cortical pial vessels in situ. Forskolin, which is known to activate adenylate cyclase, elicited a concentration-dependent relaxation of arteries preconstricted with prostaglandin F2 alpha (PGF2 alpha) (EC50 was approximately 300 nM). Microapplication of forskolin around individual cortical arteries and arterioles in situ elicited a dose-dependent dilatation. The maximum increase in arteriolar calibre was 54 +/- 4% from pre-injection calibre and EC50 was approximately 100 nM. Phorbol 12,13 dibutyrate (PDBu), which activates protein kinase C, elicited strong contractions of cerebral vessels. In vitro, PDBu contracted vessel segments in a concentration-dependent manner (EC50 was approximately 100 nM). Similarly, PDBu elicited potent dose-dependent constriction of pial arterioles in situ. The maximum response to PDBu was a 37 +/- 5% reduction in arteriolar calibre and the concentration eliciting EC50 was approximately 100 nM. These data provide an assessment to capacity of feline cerebral arteries to dilate and contract in response to adenylate cyclase and protein kinase C activation respectively.     

Effects of melatonin on rat pial arteriolar diameter in vivo.

1. Based on our finding that melatonin decreased the lower limit of cerebral blood flow autoregulation in rat, we previously suggested that melatonin constricts cerebral arterioles. The goal of this study was to demonstrate this vasoconstrictor action and investigate the mechanisms involved. 2. The effects of cumulative doses of melatonin (10-10 to 10-6 M) were examined in cerebral arterioles (30 - 50 microM) of male Wistar rats using an open skull preparation. Cerebral arterioles were exposed to two doses of melatonin (3x10-9 and 3x10-8 M) in the absence and presence of the mt1 and/or MT2 receptor antagonist, luzindole (2x10-6 M) and the Ca2+-activated K+ (BKCa) channel blocker, tetraethylammonium (TEA+, 10(-4) M). The effect of L-nitro arginine methyl ester (L-NAME, 10-8 M) was examined on arterioles after TEA+ superfusion. Cerebral arterioles were also exposed to the BKCa activator, NS1619 (10(-5) M), and to sodium nitroprusside (SNP, 10-8 M) in the absence and presence of melatonin (3x10-8 M). 3. Melatonin induced a dose-dependent constriction with an EC50 of 3.0+/-0.1 nM and a maximal constriction of -15+/(-1%). Luzindole abolished melatonin-induced vasoconstriction. TEA+ induced significant vasoconstriction (-10+/(-2%). No additional vasoconstriction was observed when melatonin was added to the aCSF in presence of TEA+, whereas L-NAME still induced vasoconstriction (-10+/(-1%). NS1619 induced vasodilatation (+11+/(-1%) which was 50% less in presence of melatonin. Vasodilatation induced by SNP (+12+/(-2%) was not diminished by melatonin. 4. Melatonin directly constricts small diameter cerebral arterioles in rats. This vasoconstrictor effect is mediated by inhibition of BKCa channels following activation of mt1 and/or MT2 receptors.     

Actions of vanadate on vascular tension and sodium pump activity in cat isolated cerebral and femoral arteries.

1. The mechanisms involved in the responses induced by sodium vanadate (Va3 VO4) on cat cerebral and femoral arteries were studied. The possibility that these responses were due to Na+, K+-ATPase inhibition was investigated by measuring the effect of vanadate on [3H]-ouabain binding to arterial membrane fractions, K+-induced vasodilatation and ouabain-sensitive 86Rb+ uptake. 2. The vanadium compounds (Na3VO4, VOSO4, VCl3 and O5V3) induced similar, concentration-dependent contractions in each kind of artery, the cerebral vessels being the most sensitive to these compounds. 3. Exposure of the arteries to a low-Na+ (25 mM) solution suppressed the contraction caused by vanadate in femoral but not in cerebral arteries. 4. Vanadate-induced contractions were reduced in Ca2+-free medium but remained unaffected by 3 x 10(-6) M phentolamine, reserpine pretreatment or 3 x 10(-6) M verapamil in both kinds of artery. 5. The addition of 7.5 mM K+ to the arteries immersed in a K+-free solution induced vasodilatation, which was not modified by 10(-3) M vanadate. 6. The consecutive administration of ouabain (10(-4) M) and vanadate (10(-3) M) (or vice versa), or the simultaneous administration of both agents (10(-8) to 10(-3) M) appeared to produce an additive contraction in both types of artery. 7. Vanadate (10(-7) to 10(-3) M) did not displace the [3H]-ouabain binding to arterial membrane fractions of these arteries, whereas 10(-4) M ouabain did. 8. In both kinds of artery, total 86Rb+ uptake was reduced by ouabain (10(-8) to 10(-3) M), in a concentration-dependent manner, whereas it was not modified by vanadate (10(-8)-10(-3) M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of the endothelium on histamine-induced relaxation of rat middle cerebral arteries in vitro.

Histamine relaxed PGF2 alpha-precontracted rat isolated middle cerebral arteries (ID approximately 230 microns) concentration dependently with a pD2 of 5.31 (EC50: 5 x 10(-6) M). Cimetidine induced a concentration-dependent rightward shift of the histamine concentration-response curve of endothelium-intact arteries. The slope of the Schild plot was indistinguishable from unity, and the estimated pA2 for cimetidine was 6.14. The selective H2-receptor agonist dimaprit induced a concentration dependent relaxation of the cerebral arteries similar to that induced by histamine. This indicates that the histamine receptor mediating the relaxation in rat middle cerebral arteries belongs to the H2-receptor subtype. 2-Pyridylethylamine, a selective H1-receptor agonist, induced a small concentration-dependent contraction of the arteries with a pD2 of 4.16. Mepyramine, a selective H1-receptor antagonist had no potentiating effect on the relaxation induced by histamine, suggesting either that the contractile effect of 2-pyridylethylamine is nonselective or that H1 receptors mediating contraction are of minor importance for the overall histamine response. The selective H3-receptor agonist, (R)-alpha-methylhistamine, was without effect in a specific concentration range (10(-7)-10(-5) M) excluding participation of H3 receptors in the histamine-induced relaxation of these vessels. Indomethacin did not affect the vessel response to histamine, but removal of the endothelium and treatment of endothelium-intact arteries with 3 x 10(-6) M methylene blue induced a similar 0.5 log rightward shift of the histamine concentration-response curve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anandamide induces endothelium-dependent vasoconstriction and CGRPergic nerve-mediated vasodilatation in the rat mesenteric vascular bed

An endogenous cannabinoid anandamide (N-arachidonoylethanolamide) has been shown to cause vasodilatation in vitro and a brief vasoconstriction followed by prolonged depressor response in vivo. This study investigated the vascular effects of anandamide and underlying mechanisms in rat mesenteric vascular beds. In preparations with an intact endothelium and active tone, anandamide at low concentrations (0.1 - 1 nM) caused a concentration-dependent decrease in perfusion pressure due to vasodilatation, but at high concentrations (10 nM - 1 μM) elicited an initial and sharp increase in perfusion pressure due to vasoconstriction followed by long-lasting vasodilatation in a concentration-dependent manner. Treatment with SR141716A [cannabinoid-1 (CB(1))-receptor antagonist] blunted both the vasoconstrictor and vasodilator responses. Also, removal of the endothelium and indomethacin (cyclooxygenase inhibitor), but not adrenergic denervation with 6-hydoxydopamine (adrenergic neurotoxin), markedly inhibited the vasoconstrictor response to anandamide, while these treatments did not affect vasodilatation. The vasodilatation, but not vasoconstriction, in response to anandamide was markedly attenuated by capsazepine [selective antagonist for transient receptor potential vanilloid-1 (TRPV1)], pretreatment with capsaicin [calcitonin gene-related peptide (CGRP)ergic-nerve depletor], or cold-storage denervation. These results suggest that in rat mesenteric vascular beds, anandamide causes CB(1)-receptor- and prostanoid-mediated endothelium-dependent vasoconstriction and perivascular capsaicin-sensitive CGRPergic nerve-mediated vasodilatation.     

Noradrenergic component in the vasoconstriction induced by 5-hydroxytryptamine in goat cerebral arteries

5-Hydroxytryptamine (5-HT) elicited dose-dependent increases in tension in the middle cerebral artery of the goat, which were significantly antagonized by lysergic acid diethylamide (LSD, 10(-8) M) and methysergide (10(-7) M). In the presence of phentolamine (10(-6) M), the dose-response curve to 5-HT was shifted to the right, the pA2 value for this antagonism was 6.52. Pretreatment of goats with reserpine (0.02 mg kg-1 day-1 for three days) or removal of both superior cervical ganglia 15 days before the experiment brought about a significant decrease in the vasoconstriction induced by doses of 5-HT higher than 10(-7) M. The remaining contraction produced by 5-HT in arterial segments from reserpinized or gangliectomized goats was further reduced in the presence of LSD. In addition, high concentrations of 5-HT induced tritium release from goat pial arteries preloaded with (-)-[3H]noradrenaline, 2 X 10(-7) M) which was significantly decreased in vessels from gangliectomized or reserpinized goats. These results in goat cerebral arteries indicate that in the contraction evoked by 5-HT there are two components. The first appears with low concentrations (up to 10(-7) M) in which 5-HT acts directly on 5-HT receptors. The second occurs at high doses (greater than 10(-7) M) in which 5-HT also acts indirectly on alpha-adrenoceptors by release of noradrenaline from noradrenergic nerve endings.     

Dexfenfluramine-induced contraction of human and rat isolated pulmonary arteries

Mechanisms of dexfenfluramine-induced vasoconstriction were studied in isolated pulmonary arteries suspended in organ baths for isometric tension recording. Dexfenfluramine (10(-7)-10(-4) M) caused concentration-dependent contractions in rat and human pulmonary arteries with and without endothelium. In pulmonary arteries of the rat, the response to dexfenfluramine was nearly abolished by treatment with the alpha-adrenoceptor antagonists, phentolamine (10(-6) M) or prazosin (10(-7) M). In human pulmonary arteries, the concentration-response curve to dexfenfluramine was unaltered by the presence of phentolamine (10(-6) M), prazosin (10(-7) M), ketanserin (10(-6) M), or indomethacin (3x10(-6) M). The results suggest that dexfenfluramine causes contraction of pulmonary vascular smooth muscle by multiple mechanisms, one of which involves activation of alpha-adrenoceptors within the blood vessel wall. The mechanisms by which dexfenfluramine causes pulmonary vasoconstriction may differ between rat and human pulmonary arteries.     

Rho-kinase inhibitor and nicotinamide adenine dinucleotide phosphate oxidase inhibitor prevent impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats.

INTRODUCTION: We previously reported that acute cigarette smoking can cause a dysfunction of endothelium-dependent vasodilation in cerebral vessels, and that blocking the angiotensin II (Ang II) type 1 (AT1) receptor with valsartan prevented this impairment. Our aim was to investigate the effects of a Rho-kinase inhibitor (fasudil) and a Nicotinamide Adenine Dinucleotide PHosphate (NADPH) oxidase inhibitor (apocynin) on smoking-induced endothelial dysfunction in cerebral arterioles. METHOD: In Sprague-Dawley rats, we used a closed cranial window preparation to measure changes in pial vessel diameters following topical acetylcholine (ACh) before smoking. After one-minute smoking, we again examined the arteriolar responses to ACh. Finally, after intravenous fasudil or apocynin pre-treatment we re-examined the vasodilator responses to topical ACh (before and after cigarette smoking). RESULTS: Under control conditions, cerebral arterioles were dose-dependently dilated by topical ACh (10(-6) M and 10(-5) M). One hour after a one-minute smoking (1 mg-nicotine cigarette), 10(-5) M ACh constricted cerebral arterioles. However, one hour after a one-minute smoking, 10(-5) M ACh dilated cerebral pial arteries both in the fasudil pre-treatment and the apocynin pre-treatment groups, responses that were significantly different from those obtained without fasudil or apocynin pre-treatment. CONCLUSION: Thus, inhibition of Rho-kinase and NADPH oxidase activities may prevent the above smoking-induced impairment of endothelium-dependent vasodilation.     

Vasodilator effects of KRN2391, levcromakalim and 3-morpholino-sydnonimin in human pial and omental arteries

The vasodilator action of KRN2391 (10 nM-10 microM), a combined ATP-sensitive potassium channel (KATP) opener and organic nitrate, was investigated in human pial and omental arteries. Previous animal studies have suggested that opening of KATP and activation of guanylate cyclase may contribute to varying extents to the vasodilator action of KRN2391, depending on the origin and size of the vascular preparation. Vasodilator responses were studied in isolated vascular segments (diameter 0.4-0.8 mm) pre-contracted with endothelin-1 in the presence or absence of glibenclamide (inhibitor of KATP), LY83583 (inhibitor of guanylate cyclase), zaprinast (inhibitor of cyclic GMP phosphodiesterase V) and NG-nitro-L-arginine (inhibitor of nitric oxide synthase). KRN2391 induced concentration-dependent vasodilator responses of similar potency in arteries from the two vascular regions. While glibenclamide (1 microM) had no effect in omental arteries, this compound produced a tenfold rightwards shift of the concentration-response curve for KRN2391 in pial arteries without affecting the maximal response (Emax). LY83583 (10 microM), zaprinast (10 microM) and NG-nitro-L-arginine (0.1 mM) all failed to affect the vasodilator responses to KRN2391 significantly in either artery. However, in ring segments of rat aorta LY83583 displaced the concentration-response curve for the nitric oxide donor 3-morpholino-sydnonimin (10 nM-0.1 mM) to the right, while zaprinast produced a leftwards shift. The prototype KATP opener levcromakalim (0.01-10 microM) elicited a larger relaxation in pial (Emax 80+/-6%) than in omental (Emax 47+/-13%) arteries, whereas 3-morpholino-sydnonimin produced a smaller relaxation in pial (Emax 50+/-18%) than in omental (Emax 90+/-4%) arteries. These results suggest that the vasodilator response to KRN2391 is mediated by KATP in human cerebral arteries, but dependent on neither KATP nor guanylate cyclase in human omental arteries. The results with levcromakalim and 3-morpholino-sydnonimin indicate that opening of KATP may be a more effective mechanism of vasodilatation in pial than in omental arteries from man, whereas the reverse appears to be true for guanylate cyclase activation.     

Introduction of the closed cranial window technique in gerbils and verification by observation of the effects of specific drugs.

The exact mechanisms of cerebral arterial hypoxia are not perfectly defined. Our purpose is to adapt and validate, with drugs well known in rats and rabbits, a closed cranial window technique in gerbils. The method was used with seventeen gerbils to measure diameter changes of the pial arterioles under normoxia (after the topical application of agonists and antagonists of ATP-sensitive and Ca2+-dependent potassium channels), as well as under hypoxia. In normoxia, aprikalim (10(-6) M), a direct activator of ATP-sensitive potassium channels, increases the diameter of pial arterioles by 10+/-2% (N = 17). This effect is inhibited by glibenclamide (10(-6) M), but not affected by iberiotoxin (10(-6) M), a specific inhibitor of Ca2+-dependent potassium channels. The adenosine-induced dilation by 19+/-5% (N = 17) is reduced by 59+/-16% with iberiotoxin, by 33+/-23% with glibenclamide and inhibited by theophylline (10(-5) M). In hypoxia (15% O2), pial arteriole diameters are increased by 24+/-5% (N = 17) and partially decreased by the application of glibenclamide and iberiotoxin to 59+/-11% and 54+/-5%, respectively. These data are similar to those obtained in other species and validate the closed cranial window technique on gerbils. They indicate that, as for rats and rabbits, both ATP-sensitive and Ca2+-dependent potassium channels are present in gerbil pial vessels and play a role in hypoxia.     

Mechanism of hypoxia-induced alteration in cerebral arteriolar tone in rats.

We studied the changes in pial arteriolar diameter during hypoxia and 60 and 120 min after restoration of normoxia, using the closed cranial window technique in artificially ventilated and normocapnic rats. Pial arteriolar diameter increased 16 +/- 4% during hypoxia (PaO2 less than 25 mm Hg, lasting 10 min). Although blood pressure (BP), heart rate (HR), and blood gases returned to prehypoxic level when measured at 60 and 120 min after hypoxia, pial arterial diameter decreased significantly (13 +/- 5 and 16 +/- 6% below control levels, respectively). This posthypoxic vasoconstriction was reversed by treatment of the brain surface with L-660,711 (10(-5) M), a specific leukotriene D4 receptor antagonist. These data suggest that leukotrienes may be involved in delayed cerebral vasoconstriction that follows a brief period of hypoxia.     

Red wine polyphenols improve endothelium-dependent dilation in rat cerebral arterioles

Moderate consumption of red wine is associated with a lower incidence of cardiovascular disease. Red wine polyphenols (RWP) have been proposed to be beneficial, but there is lack of evidence concerning the cerebrovascular effects of RWP. We studied the effect of local administration of a RWP extract (10(-2) mg/mL) on the diameter of rat cerebral arterioles using an open cranial window technique in vivo. We measured cerebral arteriolar diameter and systemic blood pressure. Cerebral arterioles reacted concentration-dependently to adenosine diphosphate [ADP, dilatation EC50 5.3 x 10(-5) M (95% confidence interval: 3.1 to 9.0 x 10 M(-5))], NG-nitro-L-arginine methyl ester [L-NAME, constriction EC50 5.8 x 10(-9) M (95% CI: 2.5 x 10(-9) to 1.4 x 10(-8) M)]. and sodium nitroprusside [SNP, dilatation EC50 1.0 x 10(-6) M (95% CI: 9.2 x 10(-7) to 1.1 x 10(-6) M)]. RWP enhanced vasodilation induced by ADP (10(-4) M) from 17 +/- 2% to 29 +/- 4% and reversed L-NAME-induced vasoconstriction but did not affect SNP-induced vasodilation. Systemic hypotension induced by hemorrhage caused myogenic arteriolar dilation. RWP further dilated cerebral arterioles (from -1 +/- 2% to 8 +/- 3%) with 1 mL of blood withdrawn. In summary, RWP improved endothelium-dependent and pressure-induced vasodilation in rat cerebral arterioles. This could be beneficial in improving cerebral blood flow under ischemic condition.     

Regional differences in the arterial response to vasopressin: role of endothelial nitric oxide.

1. The isometric response to arginine-vasopressin (10(-10)-10(-7)M) was studied in 2 mm long rabbit arterial segments isolated from several vascular beds (cutaneous, pial, renal, coronary, muscular, mesenteric and pulmonary). 2. Vasopressin induced contraction in central ear (cutaneous), basilar (pial), renal, coronary and saphenous (muscular) arteries, but had no effect in mesenteric and pulmonary arteries; the order of potency for the contraction was: ear > basilar > renal > coronary > saphenous arteries. 3. Treatment with the blocker of nitric oxide synthesis NG-nitro-L-arginine methyl ester (L-NAME; 10(-6)-10(-4) M) increased significantly (P < 0.05) the contraction to vasopressin in ear (148% of control), basilar (150% of control), renal (304% of control), coronary (437% of control) and saphenous (235% of control) arteries. Removal of the endothelium increased significantly (P < 0.05) the contraction to vasopressin in basilar (138% of control), renal (253% of control), coronary (637% of control) and saphenous (662% of control) arteries, but not in ear artery. Mesenteric and pulmonary arteries in the presence of L-NAME or after endothelium removal did not respond to vasopressin, as occurred in control conditions. 4. The specific antagonist for V1 vasopressin receptors d(CH2)5Tyr(Me)AVP (3 x 10(-9)-10(-7) M) was more potent (pA2 = 9.3-10.1) than the antagonist for both V1 and V2 vasopressin receptors desGly-d(CH2)5-D-Tyr(Et)ValAVP (10(-7)-10(-6) M) (pA2 = 7.4-8.4) to block the contraction to vasopressin of ear, basilar, renal and coronary arteries. 5. The specific V2 vasopressin agonist [deamino-Cys1, D-Arg8]-vasopressin (desmopressin) (10(-10)-10(-7) M) did not produce any effect in any effect in any of the arteries studied, with or without endothelium. 6. In arteries precontracted with endothelin-1, vasopressin or desmopressin did not produce relaxation. 7. These results suggest: (a) most arterial beds studied (5 of 7) exhibit contraction to vasopressin with different intensity; (b) the vasoconstriction to this peptide is mediated mainly by stimulation of V1 vasopressin receptors, and (c) endothelial nitric oxide may inhibit the vasoconstriction to this peptide, especially in coronary and renal vasculatures.     

Response of canine cerebral arteries to endothelin-1.

The effects of endothelin-1 (10(-10)-10(-7) M) were isometrically recorded in 4 mm cylindrical segments from the middle cerebral artery of dogs. Cumulative application of endothelin-1 produced marked, sustained contraction of arteries in a concentration-dependent-manner, the maximal response being about 2.6 times higher than that achieved with KCl (50 mM). The contraction by endothelin-1 was unaffected either by endothelium removal or by the cyclo-oxygenase inhibitors indomethacin (10(-6) M) and meclofenamate (10(-6) M). In a Ca(2+)-low (25 microM) solution the endothelin-1-induced arterial contraction was decreased. Therefore, the cerebral vasoconstriction induced by endothelin-1 could be caused by activation of specific receptors located on smooth muscle cells which would lead to the influx of extracellular calcium and vascular musculature contraction.     

Effects of felodipine on microvascular resting tone and responses to nerve stimulation and perfusion pressure reduction in rabbit skeletal muscle.

The effects of felodipine, a vasoselective dihydropyridine calcium antagonist, on microvascular dynamics were investigated in skeletal muscle. The diameters of the transverse (10-28 microns) and terminal (4-8 microns) arterioles, located at the immediate precapillary level in the rabbit tenuissimus muscle, were registrated by intravital microscopy. Topical application of felodipine (10(-7)-10(-5) M) induced a concentration-dependent vasodilation of both arteriolar generations. The steady state response at 10(-7) M revealed a relatively more pronounced dilatation of transverse (92 +/- 30% increase in diameter) than of terminal arterioles (44 +/- 12%). This is in contrast to muscle exercise, which elicits a more pronounced dilatation of terminal (260 +/- 39% increase) than of transverse arterioles (103 +/- 15%). Vasomotor nerve stimulation evoked a frequency-dependent constriction both in the absence and presence of felodipine (10(-6) M). However, the vasodilatory response elicited by graded perfusion pressure reductions was eliminated in the presence of felodipine (10(-7) M). Thus, the vasomotor nerve response was better preserved than the autoregulatory response in the presence of the calcium antagonist. The results indicate that felodipine dilates arterioles via an inhibition of myogenic vascular reactivity, which supports previous results obtained both in vivo and in vitro.     

Differential effects of nebivolol on adrenoceptors in the heart and in resistance arterioles in the rat. Quantitative intravital microscopic analysis

The effects of adrenoceptor antagonists on heart rate and on arteriolar reactions to epinephrine, terbutaline, vasopressin, angiotensin II or dopamine in the rat cremaster muscle were compared using ECG analysis and quantitative intravital microscopy. Phentolamine (0.5 mg/kg i.v.) significantly reduced the vasoconstriction of arterioles elicited by topically applied epinephrine (10(-8) to 3.3 x 10(-6) M) while propranolol (0.63 mg/kg i.v.) significantly attenuated the arteriolar vasodilatation elicited by topically applied terbutaline (10(-6) to 10(-4) M). Nebivolol (0.63 mg/kg i.v.) at a dose producing a reduction of resting heart rate equivalent to that caused by propranolol modified neither the epinephrine-induced constriction nor the terbutaline-induced vasodilatation of arterioles. The arteriolar vasoconstriction induced by topically applied vasopressin (9.3 x 10(-9) M), angiotensin II (9.4 x 10(-7) M) or dopamine (5.2 x 10(-5) M) was not modified by nebivolol either. While propranolol reduced the tachycardia and hypotension induced by isoprenaline (0.025, 0.1 microgram/kg i.v.), nebivolol reduced the cardiac rhythm increase but not the blood pressure drop in response to the catecholamine (0.025, 0.1, 0.4 micrograms/kg i.v.). The present intravital microscopic study in the rat demonstrated that, at a dose exerting cardiac beta 1-adrenoceptor blockade, nebivolol is devoid of significant activity on alpha 1-, alpha 2-, beta-2-adrenoceptors and on receptors for vasopressin, angiotensin II or dopamine in resistance arterioles.     

Effects of dobutamine on isolated canine cerebral, coronary, mesenteric, and renal arteries

The effects of dobutamine on helical strips of isolated canine cerebral, coronary, mesenteric, and renal arteries was investigated. Dobutamine contracted only renal arterial strips under resting condition. When renal and mesenteric arterial strips were partially contracted with prostaglandin F2 alpha (PGF2 alpha), dobutamine caused further concentration-related contraction, while coronary arterial strips were relaxed. Cerebral arterial strips, on the other hand, did not significantly respond to dobutamine. After treatment with 10(-5) M dl-phenoxybenzamine hydrochloride (POB) for 1 h, dobutamine-induced contractions of partially precontracted mesenteric and renal arterial strips were converted to relaxations. Relaxations of coronary arteries were not potentiated by the alpha-antagonist, but were attenuated by treatment with 10(-6) M propranolol and 10(-6) M metoprolol to a similar extent. On the other hand, relaxations of mesenteric and renal arterial strips were not inhibited by metoprolol but by propranolol. Droperidol (3 X 10(-5) M) failed to significantly alter the concentration-response curve for dobutamine. These results suggest that dobutamine causes vasoconstriction mediated by apha-adrenergic receptor and vasodilatation mediated by beta 1- and beta 2-adrenoceptors. Dobutamine does not appear to act on dopamine receptors.     

Role of K(+) channels in the coronary and renal vascular reactivity to vasopressin in diabetic rats

To study the role of K(+) channels in the coronary and renal vascular response to vasopressin during diabetes mellitus, and whether there are gender differences in this role, we have examined the isometric response to this peptide of 2-mm-long arterial segments from male and female, normoglycemic and streptozotocin-induced diabetic rats. Vasopressin (10(-12)-3 x 10(-8) M) produced arterial concentration-dependent contraction, and during normoglycemia, this contraction was lower in coronary arteries from female than from male rats, and it was similar in renal arteries from both genders. This contraction was reduced by diabetes in coronary arteries, and increased in renal arteries, from both genders. The blocker of Ca(2+)-sensitive K(+) channels charybdotoxin (10(-7) M) increased the contraction to vasopressin in coronary arteries of diabetic females, but not in the other cases (diabetic males and normoglycemic females or males). This blocker also increased the contraction to vasopressin in renal arteries from diabetic, but not in those from normoglycemic female rats, and also increased it in a higher magnitude in arteries from diabetic than in those from normoglycemic male rats. The blocker of ATP-sensitive K(+) channels glybenclamide (10(-5) M) or the scavenger of superoxide radicals superoxide dismutase (100 U/ml) did not modify the contraction to vasopressin in any experimental group. These results suggest that diabetes activates the modulatory role of K(+) channels in the coronary and renal vasoconstriction to vasopressin, but it alters in a different way the vasoconstriction to vasopressin in these two types of arteries. The effects of diabetes on this vasoconstriction are not related to increased release of superoxide radicals.