Gender differences in vascular reactivity to endothelin-1 in deoxycorticosterone-salt hypertensive rats.

In experimental models of hypertension, blood pressure reaches a higher level in male than in female rats. Because endothelin-1 (ET-1) seems to play a role in blood pressure elevation in deoxycorticosterone acetate (DOCA)-salt hypertension, we hypothesized that male DOCA-salt rats would display a greater vascular responsiveness to ET-1 than female DOCA-salt rats. Male and female Wistar rats were uninephrectomized, received DOCA injections (50 mg/kg/week) and water plus 1.0% NaCl/0.2% KCl. Control rats received vehicle and tap water. Responses to ET-1, norepinephrine (NE), serotonin (5-HT), IRL-1620, a selective endothelin-B- (ET(B)) receptor agonist, and acetylcholine (ACh) were evaluated in isolated aortic rings and also in vivo in the mesenteric microcirculation. Endothelium-intact aortas from male and female DOCA rats displayed increased sensitivity (p < 0.05) to NE and 5-HT, but decreased relaxation to ACh in comparison to aortas from respective control male and female rats. Endothelium-denuded, but not endothelium-intact, arteries from male DOCA rats displayed increased sensitivity (-log EC20) to ET-1, but no changes in ET-1 sensitivity were observed in female DOCA aortas. IRL-1620 induced contraction in male DOCA aortas, but not in female DOCA or control endothelium-denuded aortas. In the microcirculation, IRL-1620 induced vasodilation in male and female control rats, but marked vasoconstriction in male DOCA and minimal changes in vessels diameter in female DOCA rats. Bosentan, an ET(A)/ET(B)-receptor antagonist, induced a greater decrease in mean arterial blood pressure in male than in female DOCA-salt hypertensive rats. These data support the hypothesis that DOCA-salt rats exhibit gender differences in ET-1 vascular reactivity, which probably result from functional changes in ET(B)-receptors. The increased ET(B) responses in male DOCA-salt hypertensive rats may play a role in their higher blood pressure levels.

Influence of enalapril on the endothelial function of DOCA-salt hypertensive rats.

In the present study, we investigated whether the correction of endothelial dysfunction can be independent of the normalization of high blood pressure levels by enalapril in deoxycorticosterone (DOCA-salt) hypertensive rats. Aorta morphology and the response of aortas with (E+) and without (E-) endothelium to noradrenaline, acetylcholine, and sodium nitroprusside were studied. DOCA-salt hypertensive and normotensive (control) rats were or were not treated with enalapril (5 mg/day/rat in the drinking fluid) for 1, 7, or 15 days. Blood pressure was measured before and after 1, 3, 7, and 15 days of enalapril treatment. Enalapril normalized the high blood pressure levels in 50% (responders) of the hypertensive rats after 3 to as many as 15 days but not after 1 day of treatment. Initial blood pressure levels were not different between responders and nonresponders. Blood pressure levels of normotensive control rats were not altered by enalapril treatment. The tunica media of aortas of DOCA-salt hypertensive rats treated or not treated with enalapril for 15 days was thicker than aortas from normotensive rats. Enalapril corrected the reduced response to acetylcholine observed in aorta from hypertensive rats from the first day of treatment. This treatment rendered aortas from normotensive control rats more sensitive (lower EC(50)) to acetylcholine without a change in the maximal responses. The responses to sodium nitroprusside, a nitric oxide donor, were unaltered in aorta E+ or E- from control and hypertensive rats before and after enalapril treatment. Enalapril did not correct the increased responses to noradrenaline observed in aorta E+ of hypertensive rats. These results suggest that the high blood pressure in DOCA-salt hypertension is not correlated with the altered response to endothelium-dependent agents (either dilator or constrictors). The endothelium-dependent vasodilation by antihypertensive agents can be corrected independently of normalization of blood pressure levels or the vascular morphology.

Deoxycorticosterone acetate-salt hypertensive rats display gender-related differences in ET(B) receptor-mediated vascular responses.

1. Male DOCA-salt rats exhibit vasoconstriction upon ET(B) activation. Because hypertension is less severe in female than male DOCA rats, we hypothesized that female DOCA rats would display attenuated ET(B) vasoconstrictor responses. 2. Uninephrectomized Wistar rats received DOCA and drinking water containing NaCl/KCl. Control rats received vehicle and tap water. Systolic blood pressure was higher in male vs female DOCA rats. Responses to endothelin-1 (ET-1), IRL-1620, an ET(B) agonist, and acetylcholine were evaluated in isolated aortas and in vivo in the mesenteric microcirculation. 3. Endothelium-denuded aortas from male, but not female, DOCA rats displayed increased sensitivity to ET-1. IRL-1620 contracted aortas from male DOCA rats, but not control or female DOCA aortas. Noradrenaline-constricted and endothelium-intact aortas from male, but not female, DOCA rats displayed increased relaxation to IRL-1620 compared to control aortas. 4. In vivo, increased vasoconstriction to ET-1 was observed in male and female DOCA rats. IRL-1620 induced vasodilation in control rats, but vasoconstriction in male DOCA rats. There were minimal changes in diameter in vessels from female DOCA rats. 5. The initial fall in blood pressure induced by ET-1 and IRL-1620 was attenuated in male DOCA rats. Bosentan, a mixed ET(A)/ET(B) receptor antagonist, lowered blood pressure in male and female DOCA rats, but a greater and marked decrease occurred in the male DOCA group. 6. The gender-related differences in ET-1/ET(B)-mediated effects both in the vasculature and blood pressure suggest that sex-related functional up-regulation of ET(B) receptors may play a role in the more severe hypertension in male DOCA hypertensive rats.

Sexual dimorphism in the response of thoracic aorta from SHRs to losartan.

1. We compared the endothelium-dependent responses of thoracic aortic rings obtained from male and female spontaneously hypertensive rats (SHR) in order to explore gender differences in the normalization of the high blood pressure by antihypertensive drug therapy and in the correction of the endothelial dysfunction found in these animals. 2. Concentration-effect curves to acetylcholine (ACh) and sodium nitroprusside (SNP) were obtained using aortic rings isolated from male and female rats pretreated or not with losartan for 24 h or 15 d. The responses achieved and the EC50s were determined. 3. Losartan, AT(1) receptor antagonist, normalized (around 125 mmHg) the high blood pressure levels in 100% of the females and in 53.3% of males SHR within 24 h of initiating the treatment and remained normal during the remainder of the treatment period (15 d). 4. Losartan (15 d) corrected the decreased response to ACh in male and female SHR, independently of the normalization of blood pressure in male SHR. 5. An increased sensitivity to SNP was observed after chronic treatment with losartan in aortic rings from female SHR. 6. Ridogrel, a TXA(2)/PGH(2) receptor antagonist, restored the decreased response to ACh in aortic rings from male and female SHR. 7. These results suggest that there are gender-related differences in the normalization of the high blood pressure levels by losartan in SHR. The decreased response to ACh observed in male and female is corrected after sustained (15 d) reduction of high blood pressure. In female but not in male SHR, correction seems to involve an increased sensitivity of the smooth muscle to nitric oxide.

Influence of female sex hormones on endothelium-derived vasoconstrictor prostanoid generation in microvessels of spontaneously hypertensive rats.

Although female sex hormones may attenuate endothelial dysfunction in spontaneously hypertensive rats (SHR) by increasing endothelium-derived relaxing factors (EDRFs), the influence of ovarian hormones on the generation of endothelium-derived contracting factors (EDCFs) remains unknown. The aim of this study was to evaluate the effect of estrogen and progesterone on the generation of vasoconstrictor prostanoids and superoxide anion (O2(-)) by microvessels from SHR. Vascular reactivity to norepinephrine (NE), acetylcholine (ACh), and sodium nitroprusside (SNP) were evaluated in the mesenteric arteriolar bed from estrous (OE) and ovariectomized (OVX) SHR. OVX-SHR were treated for 24 hours or 15 days with estradiol and for 15 days with estradiol+progesterone. The vascular reactivity was evaluated in the absence or presence of indomethacin (INDO, 10 micromol/L) and sodium diclofenac (DIC, 10 micromol/L), ridogrel (RID, 50 micromol/L), dazoxiben (DAZ, 10 micromol/L), or superoxide dismutase (SOD, 100 U/mL). Prostanoid levels in the arteriolar perfusate of mesenteries with or without endothelium were measured by enzyme immunoassay. An increased reactivity to NE and reduced sensitivity to ACh were observed in microvessels from OVX-SHR compared with OE-SHR. There were no differences in the responses to SNP. Treatments with estradiol and estradiol+progesterone similarly restored these altered responses. INDO, DIC, RID, and SOD also restored the NE and ACh responses in OVX-SHR. DAZ had no effect on the vascular reactivities. The release of PGF(2alpha), but not of TXB(2) and 6-keto-PGF(1alpha), was greater in OVX-SHR than in OE-SHR microvessels with endothelium when stimulated by NE. This response was normalized by hormonal treatments. Neither NE nor ACh stimulated prostanoid production by microvessels without endothelium. These results suggest that estrogen may protect female SHR against severe hypertension partly by decreasing the synthesis of EDCFs such as PGH(2)/PGF(2alpha) and O2(-).

The role of thromboxane A2 in the altered microvascular reactivity in two-kidney, one-clip hypertension.

To investigate the nature of the arachidonic acid metabolite involved in the altered reactivity of microvessels of two-kidney, one-clip hypertensive rats and the possible contribution of this product to the elevated blood pressure levels found in two-kidney, one-clip hypertension, mesenteric arterioles either perfused in vitro or studied in vivo were used along with blood pressure determinations. The decreased response to acetylcholine observed was normalized by ridogrel, a thromboxane A2 receptor antagonist, and dazoxiben, a thromboxane A2 synthase inhibitor. The smooth muscle response to nitric oxide, tested with sodium nitroprusside, was unaltered in two-kidney, one-clip hypertensive microvessels. Neither ridogrel nor dazoxiben modified the response to this vasodilator. In contrast, the potentiated response to noradrenaline was corrected by ridogrel and dazoxiben in vitro but not in vivo. Noradrenaline and acetylcholine increased the release of thromboxane A2 from the mesenteric microvessels of two-kidney, one-clip hypertensive rats. Ridogrel and dazoxiben decreased but did not normalize the elevated blood pressure of hypertensive rats. Based on these results, we concluded that: 1) the decreased responsiveness of smooth muscle to acetylcholine resulted from an increase in thromboxane A2 formation rather than a decrease in sensitivity to nitric oxide; 2) thromboxane A2 contributes to the increased noradrenaline response in mesenteric microvessels perfused in vitro while in in vivo other blood borne vasoactive agents may also be involved since the potentiated noradrenaline response was not corrected by inhibiting thromboxane A2 synthesis or receptors; 3) in addition to thromboxane A2, another as yet unidentified factor, may contribute to the elevated blood pressure in two-kidney, one-clip hypertension.

Sex-related differences in the response of spontaneously hypertensive rats to angiotensin-converting enzyme inhibitor.

We have compared the endothelium-dependent responses of thoracic aortic rings obtained from age-matched male and female SHR in order to explore gender differences in the effectiveness of antihypertensive drug therapy in correcting the endothelial dysfunction found in these animals. For this, concentration-effect curves to acetylcholine and sodium nitroprusside were obtained using aortic rings with and without endothelium isolated from male and female rats which had or had not been pre-treated with enalapril for 72 h (acute) or 15 d (chronic). The maximal responses achieved and the EC50s were determined. The blood pressure of male and female spontaneously hypertensive rats (SHR) decreased to normal levels within 72 h of initiating treatment with enalapril and remained normal during the remainder of the treatment period (15 d). However, enalapril was not effective in restoring a normal blood pressure in all of the male and female SHR. Female SHR were more responsive to enalapril after both acute and chronic treatment (70% of the females and 45% of the males became normotensive). Enalapril corrected the decreased response to acetylcholine in male but not in female SHR. An increased sensitivity to sodium nitroprusside, an endothelium-independent vasodilator, was observed after acute or chronic treatment with enalapril in aortic rings with endothelium from male SHR. Indomethacin restored the decreased response to acetylcholine in aortic rings from enalapril-treated females and potentiated the response to acetylcholine in aortic rings from treated male SHR. We conclude that: a) there are significant differences in the responses of male and female SHR to enalapril, b) the imbalance in endothelium-dependent relaxing and contracting factors in SHR is corrected by enalapril in male but not in female SHR, c) correction of the endothelial dysfunction probably occurs independently of the normalization of blood pressure levels and appears to be gender-dependent.

Influence of aldose reductase inhibition on the microvascular reactivity in experimental diabetes.

1. To verify if tolrestat, an aldose reductase inhibitor, corrects the impaired responses of microvessels to histamine and bradykinin in alloxan-diabetic rats, the mesenteric microcirculation was studied in vivo in anaesthetised animals. 2. The impaired responses were corrected by tolrestat 5 mg/kg/day for 7 days p.o. Similar responses to acetylcholine and sodium nitroprusside were obtained in preparations of diabetic and control rats and were not altered by tolrestat treatment. 3. As in diabetes, galctosemia induced impaired responses to histamine and bradykinin; these altered responses were corrected by tolrestat treatment. 4. These data allow us to suggest that the polyol pathway activity might be involved in the altered responses of microvessels observed in diabetic rats. It is possible that polyol activation may play an important role in the development of vascular dysfunction in diabetes mellitus.

Spontaneously hypertensive versus control rat aorta response to neutrophil-derived factors.

We designed experiments to study the interaction of activated rat peritoneal neutrophils with aortas from spontaneously hypertensive rats (SHR) compared with those from normotensive rats. In aortic rings precontracted with phenylephrine, neutrophils obtained from normotensive rats caused a cell number-dependent relaxation of normotensive rat aorta with or without endothelium, whereas relaxation (at lower concentrations) followed by contraction (at higher concentrations) was observed in SHR aorta with endothelium. In SHR aortic rings denuded of endothelium, neutrophils did not induce contraction. The relaxation might be due to a factor indistinguishable from nitric oxide. The contraction might be due to prostaglandin H2 because it was blocked by indomethacin, a cyclooxygenase inhibitor, and ridogrel, a thromboxane A2 synthetase inhibitor/thromboxane A2-prostaglandin H2 antagonist, but not by superoxide dismutase, a superoxide anion scavenger, or dazoxiben, a thromboxane A2 synthetase inhibitor. SHR neutrophils caused a cell number-dependent relaxation of normotensive rat aorta with or without endothelium, whereas relaxation followed by contraction was observed in SHR aorta with endothelium. In SHR aortic rings denuded of endothelium, neutrophils did not induce contraction. The relaxation might be due to a factor indistinguishable from nitric oxide. The contraction seems to be due to superoxide anion because it was inhibitable by indomethacin and superoxide dismutase but not by dazoxiben and ridogrel. Equivalent amounts of superoxide anion were produced by unstimulated and phorbol myristate acetate-stimulated neutrophils obtained from either SHR or normotensive rats. Therefore, increased production of this anion could not explain the contraction observed in hypertensive aortas.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium inactivation in in vitro perfused vascular beds. Comparison of methods.

In order to choose the best procedure to inactive the endothelium from vascular beds perfused in vitro, we compared four methods: perfusion with sodium deoxycholate 0.3% for 30 sec; 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulfonate 0.3% (CHAPS) for 2.5 min; collagenase 0.2% for 15 min, and distilled water for 10 min, using the mesenteric arterial bed (MAB) of the rat. The effectiveness of the treatments used to inactivate the endothelium was assessed functionally by using acetylcholine and sodium nitroprusside and histologically using light microscopy. Phenylephrine was used to test the contractile properties of the preparations after each treatment. After collagenase, distilled water, and CHAPS treatment, a potentiated response to phenylephrine was observed, whereas sodium deoxycholate treatment did not modify phenylephrine-induced responses. Acetylcholine-induced responses were reduced by collagenase (60% reduction), CHAPS (30% reduction), and distilled water (52% reduction) treatment, and sodium deoxycholate completely abolished acetylcholine-induced responses. Except after collagenase treatment, smooth muscle relaxant responses were not altered. Medial smooth muscle cells displayed an unchanged morphology, appearing similar to those in control mesenteric arterial beds, except for collagenase and distilled water. Despite the fact that sodium deoxycholate treatment completely abolished acetylcholine-induced response, endothelial cells were still found. No treatment totally removed endothelial cells. In conclusion, we suggest that sodium deoxycholate treatment is the best procedure to inactivate endothelial cells from vascular beds perfused in vitro since it completely abolished endothelium-dependent relaxation and did not interfere with smooth muscle vasodilating and contracting properties.

Effect of indomethacin on the microvessel reactivity of two-kidney, one-clip hypertensive rats.

Endothelial cells modulate vascular tone by releasing endothelium-derived relaxing and contracting factors. An imbalance of these factors in hypertension could contribute to increased peripheral vascular resistance. To investigate whether an endothelium-derived contracting factor is involved in the altered reactivity of microvessels of two-kidney, one-clip hypertensive rats, mesenteric arterioles either perfused in vitro or studied in vivo were used. In two-kidney, one-clip hypertensive rats, a potentiation to noradrenaline was observed in preparations tested either in vitro or in vivo. Indomethacin treatment did not correct the increased response to noradrenaline in microvessel preparations. Thus the involvement of an endothelium-derived contracting factor which is sensitive to indomethacin blockade, could be discarded. A decreased response to acetylcholine, an endothelium-dependent vasodilator, was observed in in vitro and in vivo preparations. The responses to sodium nitroprusside, an endothelium-independent vasodilator, were not altered in microvessel preparations of hypertensive rats. In two-kidney, one-clip hypertensive preparations, indomethacin normalized the endothelium-dependent relaxations. Relaxations to sodium nitroprusside were not altered by indomethacin. It is suggested that endothelium-dependent relaxations are impaired in two-kidney, one-clip hypertension because of a cyclooxygenase-dependent substance interfering with the release and/or action of endothelium-dependent relaxing factor.

Influence of sex on the reactivity to endothelin-1 and noradrenaline in spontaneously hypertensive rats.

The response to endothelin-1 and noradrenaline in isolated aortas in vitro and mesenteric arterioles in situ was studied in male and female spontaneously hypertensive rats (SHR). Greater sensitivity to endothelin-1 and noradrenaline and decreased reactivity to endothelin-1 but not to noradrenaline were found in aortas of male SHR. Mesenteric arterioles of male SHR were more sensitive to endothelin-1 and noradrenaline. Aortas and mesenteric arterioles of female SHR exhibited similar sensitivity to endothelin-1 as compared to controls, whereas a greater reactivity to this agent was only observed in microvessels. It is suggested that sex-linked alterations of vascular reactivity exist in SHR. These alterations seemed not to affect all vascular territories and were not due to differences in blood pressure levels of male and female SHR.

Enhancement of aorta tonus evoked by hypertonic solutions is endothelium-dependent.

1. The effect of NaCl hypertonic solutions on the contractions induced by noradrenaline or prostaglandin F2 alpha and on the relaxant effect of acetylcholine and sodium nitroprusside was investigated in aortae with or without endothelium isolated from rats. 2. Hypertonic solutions enhanced the contractions elicited by the vasoconstrictor agents in preparations with endothelium and this phenomenon was not altered by previous treatment of the animals with reserpine or the preparations with methylene blue or indomethacin. 3. In hypertonic medium acetylcholine but not sodium nitroprusside vasodilator effect was inhibited. 4. We suggest that NaCl hypertonic solutions modify vascular reactivity probably through: (i) the release of an endothelium-derived contracting factor not sensitive to cyclooxygenase inhibitors; (ii) a diminished release of an endothelium-derived relaxing factor not related to the cGMP system.

Indirect evidence for an endothelium-derived contracting factor released in arterioles of deoxycorticosterone acetate salt hypertensive rats.

In order to investigate if endothelium-derived contracting factor (EDCF) is involved in the altered reactivity of microvessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, mesenteric arterioles, either perfused in vitro or studied in vivo in situ, were used. The responses to norepinephrine, acetylcholine, sodium nitroprusside and papaverine were studied in animals treated with indomethacin. Norepinephrine was equally effective in evoking a constrictor response in the in vitro perfused arteriolar bed of DOCA-salt hypertensive and control rats. A potentiation to this agent was, however, observed in preparations tested in vivo in situ. A decreased response to acetylcholine, an endothelium-dependent vasodilator, was observed in perfused in vitro and in vivo in situ preparations. The responses to sodium nitroprusside, an endothelium-independent agent, in microvessel preparations of hypertensive rats, and the response to papaverine, an agent partially dependent on endothelium, were unaltered. Indomethacin treatment did not correct the altered response to norepinephrine in mesenteric preparations studied in vivo in situ. Thus, the involvement of an EDCF which is sensitive to indomethacin blockade could be discarded. Since indomethacin treatment corrected the decreased response to acetylcholine observed in both mesenteric arterioles perfused in vitro or tested in vivo in situ, it is suggested that in arterioles of DOCA-salt hypertensive rats, an EDCF is involved in the decreased response to acetylcholine. Smooth muscle vasodilating capability appears to be unaltered.

Nitric oxide release may be involved in the microcirculatory response to acetylcholine.

An image-splitter television microscope for measurement of microvascular dimension changes in the rat exteriorized mesentery was used to investigate the role of endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) in the microcirculation. This was done by studying the effect of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO formation, on the responses induced by acetylcholine (an endothelium-dependent vasodilator agent) and sodium nitroprusside (an endothelium-independent vasodilator agent). The effect of acetylcholine on mesenteric A2 arterioles was impaired by previous application of L- but not D-NMMA to the preparations whereas the vasodilator response to sodium nitroprusside was not altered. The effect of L-NMMA was slow to disappear, unless accelerated by a 3-fold molar excess of L- but not D-arginine. It is suggested that EDRF/NO might be involved in the vasodilator response to endothelium-dependent agents such as acetylcholine at the microcirculatory level and that L-arginine might be the physiological precursor of NO.

Comparison of the effect of endothelin on microvessels and macrovessels in Goldblatt II and deoxycorticosterone acetate-salt hypertensive rats.

The response to endothelin, a novel 21-amino acid peptide, is investigated in isolated aortas with and without endothelium and in mesenteric microvessels in vivo-in situ, in Goldblatt II (GII) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Median effective concentrations and maximal responses to endothelin did not differ in aortas with endothelium isolated from GII, DOCA-salt hypertensive, and control rats. After removal of the endothelium, the potentiation of the aorta responses to endothelin was of the same magnitude in hypertensive and control rats. A closed-circuit television system was used to observe the microvascular bed of the exteriorized mesentery of anesthetized GII, DOCA-salt hypertensive, and control rats. The time necessary to induce a vasoconstrictor response was determined after the topical application of endothelin. Vessel diameters at rest and after endothelin application were also estimated. At the microcirculatory level, a greater reactivity to endothelin was observed in both hypertensive rat groups, whereas higher sensitivity to endothelin was recorded in the GII hypertensive microvessel preparations alone. It is suggested that the increased response to endothelin observed in hypertensive rats might be due to abnormal sensitivity or reactivity of the microvessels of these rats reflecting an alteration of the contractile sequence possibly at the plasma membrane level, or due to both. Endothelial dysfunction at the microcirculatory level, however, cannot be dismissed.

Comparison of the reactivity of micro-and macrovessels to noradrenaline and endothelin in rats with renal (2K1C) hypertension.

The response to noradrenaline and endothelin in isolated aortae in vitro and mesenteric microvessels in vivo - in situ was studied in 4-week 2K1C hypertensive rats. Enhanced reactivity to noradrenaline was observed in aortae with endothelium isolated from hypertensive rats, whereas in aortae without endothelium, noradrenaline induced similar responses in sham-operated control and hypertensive preparations. Endothelin responses were not altered in aortae with or without endothelium isolated from hypertensive rats. In mesenteric microvessels, both noradrenaline and endothelin evoked higher responses in 2K1C than in control animals. It is suggested that the enhanced reactivity observed could be involved in the maintainance of high blood pressure levels in 2K1C hypertension. The altered reactivity could be due to a dysfunction of the endothelial cells.

Indirect evidence for an endothelium-derived contracting factor release in aorta of deoxycorticosterone acetate-salt hypertensive rats.

In order to investigate the involvement of endothelium-derived vasoactive substances in deoxycorticosterone acetate (DOCA)-salt hypertension, the responses to noradrenaline, acetylcholine, sodium nitroprusside and papaverine were studied in the absence and presence of indomethacin. Noradrenaline was equally effective in evoking a constrictor response of aorta, with or without endothelium, isolated from DOCA-salt hypertensive rats, while in controls, noradrenaline induced higher submaximal responses in rubbed than in unrubbed preparations. A decreased response to acetylcholine, an endothelium-dependent vasodilator, was observed in aorta with endothelium which had been precontracted with noradrenaline isolated from hypertensive rats. The relaxant response was lost after removal of the endothelium in both control and DOCA-salt hypertensive groups. The response to sodium nitroprusside, an endothelium-independent agent, in aorta isolated from hypertensive rats as well as the response to papaverine, an agent partially dependent on the endothelium, was not altered. Indomethacin treatment altered the response to noradrenaline only in unrubbed aorta of hypertensive rats. In these preparations, a biphasic response to noradrenaline was observed. At lower concentrations noradrenaline induced the characteristic constrictor response, while at higher concentrations a relaxant response was obtained that was abolished by methylene blue, a guanylate cyclase inhibitor. This could indicate that noradrenaline induced the release of endothelium-derived relaxing factor (EDRF) in aorta of hypertensive rats. Furthermore, indomethacin treatment restored the decreased response to acetylcholine in aorta isolated from DOCA-salt hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin-1 induces potent constriction of lymphatic vessels in situ.

The response of lymph vessels, arterioles and venules in the exteriorized rat mesentery to endothelin-1, vasopressin and norepinephrine was examined with the aid of high-resolution television microscopy. On a molar basis, endothelin-1 was more potent than vasopressin to contract the three types of vessels. Norepinephrine, which could constrict blood microvessels, did not act on lymph vessels. Acetylcholine, sodium-nitroprusside and isoproterenol were ineffective to block the constrictive responses of lymph vessels to endothelin-1 and vasopressin. At the same concentrations, however, acetylcholine and sodium-nitroprusside antagonized the responses of arterioles and venules to endothelin-1 and norepinephrine, whereas the responses of blood microvessels to vasopressin remained unaffected. Isoproterenol, at doses capable of blocking the response of the arterioles and venules to norepinephrine, did not interfere with the constriction induced by endothelin-1 and vasopressin on these vessels. It is suggested that endothelin-1 might play a role in the regulation of lymphatic contractility apart from its vasoconstrictor activity on blood vessels.

The role of endothelium in vascular reactivity.

1. This review describes the role of vascular endothelium in the response induced by different vasoactive agents. 2. The interaction between endothelium, vascular smooth muscle and platelets is discussed. 3. The hormone control as well as physicochemical alterations that interfere with some endothelium-dependent vascular responses are described.