The parasympathetic system and its muscarinic receptors in hypertensive disease.
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Animals↗
Biomedical subjects
M Pfaffendorf
Publications and source records attributed to M Pfaffendorf.
Hemodynamic effects of angiotensin II and the influence of angiotensin receptor antagonists in pithed rabbits.
We investigated the cardiovascular effects of angiotensin II (AII) and the influences of four angiotensin receptor antagonists: losartan, PD123177, BIBS 39, and BIBS 222 in the pithed rabbit preparation. AII (0.03-10 nmol/kg) elicited a dose-dependent increase in blood pressure (BP), left ventricular pressure (LVP), LV end-diastolic pressure (LVEDP), dP/dtmax, and heart rate (HR). The maximal hypertensive effect of AII is comparable to that of norepinephrine (NE), but its effects on LVEDP and HR are weaker than those of NE. On a molar base, AII is approximately 27 times more potent than NE. Propranolol (0.5 mg/kg i.v.) did not significantly influence the AII-induced increase in diastolic BP (DBP) and LVEDP, but it abolished AII-induced positive chronotropic effects over the entire dose range of angiotensin AII studied. Losartan, but not PD123177, shifted the dose-response curves for AII to the right in a parallel manner. BIBS 39 and BIBS 222 also caused rightward shifts of the AII dose-response curve. These experiments indicate that in propranolol-treated pithed rabbits AII causes vasoconstrictor effects in both resistance vessels and in the venous system, which are both mediated by AT1- but not by AT2-receptors. The AII-induced positive chronotropic effect is an indirect action mediated by the stimulation of postsynaptic beta 1-adrenoceptors. BIBS 39 and BIBS 222, two new nonpeptide angiotensin receptor blockers that have affinity for both AT1- and AT2-receptors are also potent antagonists of the cardiovascular effects of AII in pithed rabbits.
Analysis of Variance↗
Influence of the vascular endothelium on angiotensin II-induced contractions in rabbit renal artery.
The influence of vascular endothelium on angiotensin II-induced contraction and the underlying mechanisms in the rabbit renal artery were investigated. In endothelium-intact preparations, angiotensin II (3-100 nM) caused a concentration-dependent increase in tension by maximally (Emax) 0.74 +/- 0.05 g. Removal of the endothelium significantly enhanced the angiotensin II-induced contractions (Emax: 3.91 +/- 0.19 g). Indomethacin (10 microM) did not influence the angiotensin II-induced contractions. Methylene blue (10 microM) and NG-methyl-l-arginine (L-NMMA, 5 microM) significantly enhanced angiotensin II-induced contractions by 418 +/- 29% and 200 +/- 14%, respectively, in endothelium intact preparations, but not in those devoid of endothelium. L-arginine (1 mM), but not D-arginine, reversed the L-NMMA-induced enhancement of the angiotensin II-induced contraction. The present results suggest that angiotensin II-induced contractions in rabbit renal artery are largely subject to the influence of the endothelium. The endothelium-derived relaxant factor (EDRF), rather than cyclo-oxygenase products, appears to be involved in mediating the inhibitory effects of the endothelium. Nitric oxide (NO) derived from endothelium may play a major role in inhibiting angiotensin II-induced contractions in this preparation.
Angiotensin II↗
Effect of Na+ reduction and monensin on ion content and contractile response in normoxic and ischaemic reperfused rat hearts.
The possibility was explored whether the functional properties of Na+/Ca2+ exchange are altered after ischaemia, thereby contributing to the elevated intracellular (i) Ca2+ levels in ischaemic reperfused hearts. The intracellular Na+, K+ and Ca2+ contents in rat Langendorff heart preparations were determined by atomic absorption spectrometry under normoxic conditions, after ischaemia (30 min) and after ischaemia (30 min) plus reperfusion (30 min). In addition, the influence of modulating the Na+ gradient (Na+o/Na+i) across the sarcolemma was studied with respect to cardiac contractility and intracellular ion content. This was done by either decreasing extracellular (o) Na+ or by increasing Na+i with monensin, both in normoxic and reperfused hearts. Both Na+o reduction and monensin led to an increase in contractility and coronary flow, an effect which was nearly abolished in reperfused hearts. Under normoxic conditions the intracellular ion contents amounted to Na+ = 12.4 +/- 0.4, K+ = 99.0 +/- 3.1 and Ca2+ = 0.64 +/- 0.02 mmol/kg cell (means +/- SEM, n = 7). In normoxic hearts, lowering Na+o reduced and monensin increased Na+i, thereby both leading to a decrease in Na+ gradient; no effect on total Ca2+i content was observed. Na+i increased twofold after ischaemia as compared to the normoxic situation, an effect which was aggravated (4 fold increase) in reperfused hearts. The opposite effects were observed for K+i with a 25% decrease after ischaemia and a 40% decrease in reperfused hearts. Only after ischaemia plus reperfusion was Ca2+i increased (6 fold).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reduced muscarinic cholinoceptor density and sensitivity in various models of experimental cardiac hypertrophy.
1. In the present study we investigated functional and binding characteristics of muscarinic receptors in experimental cardiac hypertrophy. 2. As models of cardiac hypertrophy we used hearts of spontaneously hypertensive rats (SHR) and Wistar rats with surgically induced abdominal aorta stenosis (ASR). Wistar Kyoto rats (WKY) and sham operated Wistar rats were used as respective controls. 3. The hypertrophy was more pronounced in hearts of ASR compared to SHR, although the mean arterial pressure was found to be lower. 4. Isolated, perfused Langendorff heart preparations (paced with 5 Hz) from both groups of hypertrophied hearts were less sensitive to the muscarinic agonists oxotremorin and methacholine (P < 0.05, all n = 6) when compared with control organs. The maximal reduction in contractile force induced by methacholine was 59.3 +/- 4.5% in SHR and 41.6 +/- 3.4% in ASR hearts versus 26.4 +/- 4.1% and 25.0 +/- 2.6% in control organs, respectively. 5. The density (fmol/mg protein-1) of muscarinic receptors in membrane homogenates of hearts from SHR (127.6 +/- 11.5) was unchanged, whereas in hearts from ASR (221.0 +/- 8.9) it was found to be reduced (P < 0.05) when compared to the respective controls (142.5 +/- 14.7 and 308.8 +/- 16.1, respectively, all n = 6). 6. From the present data we conclude that cardiac hypertrophy results in a loss of sensitivity towards muscarinic receptor stimulation. A corresponding reduction of left ventricular receptor density could only be demonstrated in massively hypertrophied hearts of ASR.
Animals↗
Comparative effects of angiotensin II and its degradation products angiotensin III and angiotensin IV in rat aorta.
1. In the present study, the contractile effects of angiotensin III (AIII) and angiotensin IV (AIV) compared with those of angiotensin II (AII) were determined in rat aortic ring preparations. 2. All three peptides caused concentration-dependent contractions with similar maximal responses. AIII proved approximately 4 times less potent than AII, whereas AIV was about 1000 times less active than AII. 3. The selective AT1-receptor antagonist, losartan (10-300 nM) caused parallel rightward shifts of the concentration-response curves (CRC) for all three peptides. The Schild plot slopes for the effect of losartan on AIII curves were significantly lower than unity (P < 0.05). The selective AT2-receptor antagonist, PD123177 did not influence the CRCs for AII and AIV. However, the AIII curves were moderately shifted leftward in the presence of PD123177 (0.1 and 1 microM). 4. Destruction of the endothelium or incubation with the NO-synthesis inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) (0.1 mM) significantly enhanced the contractile responses to all three peptides. 5. Tachyphylaxis was investigated by constructing a second CRC for all three peptides, after an interval of 1 h. The presence of endothelium significantly enhanced the development of tachyphylaxis to all three peptides. However, in endothelium-denuded preparations, the Emax value of the second curve elicited by AII was about 50%, compared with the first one, whereas for AIII and AIV Emax values were as high as 90% and 100%, respectively. 6. Our results indicate that both AIII and AIV are less potent but similarly efficacious vasoconstrictor agents compared with AII. Their contractile effects are also mediated by AT1-receptors and probably modulated by endothelium. Tachyphylaxis induced by AIII and AIV proved weaker than that for AII. Tachyphylaxis appears to be enhanced by the presence of an intact endothelium.
Angiotensin II↗
In vivo characterization of muscarinic receptor subtypes that mediate vasodilatation in patients with essential hypertension.
Attenuated cholinergic vasodilatation has been suggested as an endothelium-related mechanism involved in essential hypertension. We investigated the role of muscarinic (M) receptor subtypes in the forearm resistance vasculature. In eight white men with essential hypertension and eight matched normotensive control subjects (age of both groups, 47 +/- 4 years; mean +/- SEM), we infused the nonselective agonist methacholine in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M1-selective), and AF-DX 116 (M2-selective) into the brachial artery and measured forearm blood flow and forearm vascular resistance using venous occlusion plethysmography. Affinity constants (pKb values) were determined from calculated plasma concentrations of the infused compounds and EC50 values. Sodium nitroprusside was given as an endothelium-independent control, and minimal forearm vascular resistance after 10 minutes of ischemia was used as a marker of structural vascular changes. Hypertensive patients showed higher minimal forearm vascular resistance, indicating structural vascular changes. However, sodium nitro-prusside- and methacholine-induced vasodilatation was similar in both groups, with apparent EC50 values (log moles per liter; mean +/- SEM) of -7.32 +/- 0.13 and -7.51 +/- 0.21 in hypertensive patients and -7.37 +/- 0.13 and -7.45 +/- 0.02 in control subjects, respectively. Atropine, pirenzepine, and AF-DX 116 caused a shift to the right of the concentration-response curve of methacholine, with apparent pKb values of 8.63 +/- 0.08, 6.81 +/- 0.13, and 5.51 +/- 0.29 in hypertensive individuals and 8.62 +/- 0.10, 6.98 +/- 0.08, and 5.49 +/- 0.09 in control subjects, respectively. Again, there were no statistically significant differences in these pharmacological parameters between hypertensive patients and normotensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Atropine↗
Contractile responses to various inotropic agents in isolated hearts obtained from hypertensive diabetic rats.
The profile of the contractile effects of calcium ions, the Ca(2+)-entry promoter Bay K 8644 and two alpha 1-adrenoceptor agonists (cirazoline and ST587) was studied in isolated perfused Langendorff hearts taken from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) with simultaneous diabetes. In both the hypertensive and the diabetic state the isolated hearts showed a tendency to an impaired inotropic response (increase in left ventricular pressure (LVP)) towards an increase of extracellular calcium ions. The impaired inotropic response was most pronounced in hearts of rats with simultaneous diabetes and hypertension. The Ca(2+)-influx promoter Bay K 8644 did not influence the maximally developed LVP in (diabetic) SHR and WKY preparations. The inotropic responses to both cirazoline and ST587 were increased in hearts from diabetic WKY and diabetic SHR, when compared with those from control WKY and SHR. Hypertension, however, blunted the inotropic response to ST587 but not that to cirazoline when compared to hearts from control WKY or diabetic WKY. The present study indicates that the combination of hypertension and diabetes leads to progressive cardiac deterioration, likely to be the result of important changes in calcium homeostasis.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
New insights into the role of endothelial dysfunction in hypertension.
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Animals↗
Endothelium-dependent, nitric oxide-mediated inhibition of angiotensin II-induced contractions in rabbit aorta.
The role of endothelium in angiotensin II-induced contractions of the rabbit aorta and the mechanism involved were investigated. Destruction of the endothelium significantly shifted the concentration-response curve for angiotensin II to the left in a non-parallel manner and enhanced the maximal response. The EC50 and Emax values obtained from the rings with and without functional endothelium were 2.44 +/- 0.13 x 10(-9) M, 4.50 +/- 0.45 g and 1.21 +/- 0.14 x 10(-9) M (n = 8, P < 0.05), 5.73 +/- 0.55 g (n = 8, P < 0.05), respectively. Indomethacin (10(-5) M) did not significantly alter the concentration-dependent response to angiotensin II in the presence of endothelium. Three inhibitors of nitric oxide synthase (NG-monomethyl-L-arginine; NG-nitro-L-arginine, and NG-nitro-L-arginine methyl ester) at 10(-4) M caused a similar endothelium-dependent potentiation of angiotensin II-induced contractions in the aortic rings with, but not in those without endothelium. These effects were reversed by L-arginine (3 x 10(-3) M) but not by D-arginine (3 x 10(-3) M). Angiotensin II in a concentration range of 10(-16) to 10(-6) M did not relax the endothelium-intact rings precontracted with phenylephrine (2 x 10(-7) M). In the presence of endothelium, the angiotensin II subtype 2 receptor antagonist, 1-[(4-amino-3-methylphenyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro- 1H- imidazol[4,5-C]pyridine-6-carboxylic acid (PD 123177), caused neither relaxation of the rings precontracted with phenylephrine nor alteration of the concentration-response curve for angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
A non-competitive type of angiotensin-receptor antagonism by losartan in renal artery preparations.
In rabbit isolated renal artery preparations angiotensin II (1-100 nM) induced concentration-dependent vasoconstriction. Losartan at lower concentrations (3-100 nM) concentration dependently depressed the maximal responses to angiotensin II. At higher concentrations (0.3 and 1 microM) lasartan only shifted the concentration-response curves for angiotensin II to the right without further reducing the maximal responses. PD123177 (1 microM) did not influence angiotensin II-induced contractions. In rabbit renal artery, AT1 but not AT2 receptors appear to mediate the responses to angiotensin II. However, losartan antagonized the AT1 receptors in both an insurmountable and a surmountable manner, possibly involving two subpopulations of AT1 receptors.
Angiotensin II↗
Effects of aging and hypertension on the reactivity of isolated conduit and resistance vessels.
We have studied the effects of hypertension and aging on the concentration-response curves for alpha 1-adrenoceptor-mediated vasoconstriction and methacholine-induced endothelium-dependent relaxation. The experiments were performed in aortic rings and in perfused mesenteric vascular bed preparations taken from WKY rats, from SHR of 16-18, 28-30, and 58-60 weeks, and from 16- to 18-week-old SHRSP rats, respectively. The influence of aging and/or hypertension caused no alterations of the alpha 1-agonist response provoked by phenylephrine in aortic rings. Mesenteric vascular bed preparations showed an increase in maximal response to methoxamine when taken from hypertensive animals. Age per se did not change the contraction in the mesenteric arteries. Hypertension in combination with age caused a decrease in endothelium-dependent vasodilation induced by methacholine in aortic rings, but not in mesenteric arteries. However, the sensitivity to methacholine decreased age-dependently in the mesenteric vascular bed preparation taken from the WKY and SHR. The endothelium-independent relaxation induced by sodium nitroprusside showed a decrease in sensitivity in aortic rings taken from 58- to 60-week-old SHR when compared with the age-matched WKY. These findings suggest that the mechanisms beyond the endothelium involved in vasodilation are not responsible for the decreased methacholine-induced relaxation in aortic rings. It is concluded that (1) the responsiveness of resistance arteries to adrenoceptor stimulation only changes with elevated blood pressure and (2) hypertension in combination with aging induces an endothelial dysfunction in conduit arteries but not in resistance vessels.
Aging↗
Inhibitory effect of dithiothreitol on angiotensin II-induced contractions mediated by AT1-receptors in rat portal vein and rabbit aorta.
The disulfide-reducing agent dithiothreitol (DTT) has been shown to reduce angiotensin II (Ang II) subtype 1 receptor (AT1) binding sites in various tissues. Its effect on Ang II-induced contractions was studied in the rat portal vein and rabbit aorta. In the isolated rat portal vein, DTT shifted the concentration-response curve for Ang II to the right (DTT 0.5-3 mmol/l) and depressed the maximal response (DTT 1-3 mmol/l). DTT 5 mmol/l almost abolished the effect of Ang II. In the isolated rabbit aorta, the inhibitory effect of DTT was more pronounced and its pattern of effect was different, since DTT 0.3 and 0.5 mmol/l caused a progressive flattening of the concentration-response curve of Ang II. DTT (1 mmol/l) fully suppressed the effect of Ang II. A biphasic curve consisting of a high sensitivity component and a component of low sensitivity for Ang II was observed after pretreatment with DTT 1 mmol/l in the rat portal vein but not in the rabbit aorta. In the presence of DTT 1 mmol/l, the AT1-receptor antagonist losartan antagonized the high sensitivity response to Ang II in a competitive manner with a pA2 value very similar to that obtained in the absence of DTT, suggesting that this response to Ang II is mediated by those AT1-receptors which were not inactivated by DTT. The biphasic curve may be explained by the occurrence of a single AT1-receptor subtype existing in two different states. Another possibility might be the involvement of two AT1-receptor subpopulations.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Calcium dependency of the AT1-receptor mediated effects in the rat portal vein: influence of calcium antagonists.
The calcium dependency of AT1-receptor mediated contractions was studied in isolated rat portal vein preparations. The spontaneous phasic contractile force of the rat portal vein was increased (ED50 = 1.76 mmol/l) and the frequency of contractions decreased by raising the extracellular calcium concentration. The Ang II-induced rise in phasic contractile force (mediated by AT1-receptors, Zhang et al. 1993) proved most pronounced at 0.9 mmol/l of calcium chloride, but it was weaker at either lower or higher calcium concentrations. The maximal increases in the phasic contractile force induced by Ang II were 2.4 +/- 0.4, 14.8 +/- 0.9 and 5 +/- 0.5 mN at calcium concentrations of 0.5, 0.9 and 2.5 mmol/l, respectively. Calcium antagonists reduced at the lower and abolished at the higher concentrations (nifedipine 2 x 10(-8) or 10(-7) mol/l; verapamil 10(-7) or 5 x 10(-7) mol/l; diltiazem 3 x 10(-7) or 10(-6) mol/l) the spontaneous contractile force. All of these calcium antagonists caused a strong inhibition or suppression of the phasic contractions induced by Ang II. The rank order of potency was nifedipine > verapamil > diltiazem. Ang II (10(-6) mol/l) elicited a tonic contraction which was abolished by the AT1-receptor antagonist losartan 10(-6) mol/l but not by the AT2-receptor antagonist PD 123177 (10(-5) mol/l). Very high concentrations of nifedipine (10(-6) mol/l), verapamil (5 x 10(-6) mol/l) and diltiazem (5 x 10(-6) mol/l) almost suppressed the tonic effect evoked by the activation of AT1-receptors. In a nominally Ca2+ "free", EGTA-containing solution, a single supra-maximal concentration of Ang II (10(-6) mol/l) caused a transient contraction, also mediated by AT1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin I↗
Streptozotocin-induced diabetes mellitus in spontaneously hypertensive rats: a pathophysiological model for the combined effects of hypertension and diabetes.
The present study was undertaken to investigate the combined effects of hypertension and streptozotocin-induced diabetes mellitus in the rat. Accordingly, four groups of rats were studied: Wistar Kyoto rats (WKY), diabetic WKY, spontaneously hypertensive rats (SHR) and diabetic SHR, respectively. The mean arterial blood pressure was increased in hypertensive animals compared to normotensive animals. The base excess in the diabetic rats was higher than that of normoglycemic animals. An elevated glucose concentration was found in the blood and urine of streptozotocin-treated rats. Ketone bodies were detected in the urine and blood of the diabetic rats. Mortality rates after treatment were not different among the four groups. In separate experiments, isolated working hearts of the various groups were set up and analyzed. For the maximal left ventricular pressure (mm Hg) the following values were formed: 110.0 +/- 2.6, 93.6 +/- 2.7, 93.4 +/- 3.0, and 87.5 +/- 2.4, respectively. The wet heart weights, dry heart weights, and body weights of the diabetic rats were lower than those of normoglycemic animals. The wet heart weight/body weight ratio, however, was increased by diabetes and hypertension (0.43 +/- 0.01, 0.47 +/- 0.01, 0.47 +/- 0.01, and 0.54 +/- 0.02, respectively). There were no significant differences between the water content of the hearts from the four different groups. Pathologic examination of the hearts showed myocardial hypertrophy and medial hypertrophy of coronary arteries in diabetic and hypertensive animals. There was no difference in relative collagen content in the hearts of the four groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of various angiotensin receptor antagonists on cardiovascular responses to angiotensin II in pithed rats.
The effects of four nonpeptide angiotensin receptor antagonists, i.e., losartan (AT1) PD123177 (AT2), and 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl]biphenyl-carboxylic acid (BIBS 39; AT1 and AT2), and 2-n-butyl-1-[4-(6-carboxy-2,5-di-chlorbenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222; AT1 and AT2) on cardiovascular responses to angiotensin II (AII) were investigated in propranolol-pretreated pithed rats. AII (0.01-10 nmol/kg intravenously, i.v.) induced a dose-dependent increase in diastolic blood pressure (DBP), the rate of increase in left ventricular pressure (LVdP/dtmax), cardiac output (CO), and total peripheral resistance (TPR) without changing LV end-diastolic pressure (LVEDP) or heart rate (HR). Losartan 3 and 10 mg/kg i.v. caused dose-dependent parallel rightward shifts of the dose-response curves (DBP and LVdP/dtmax) without altering the maximal responses to AII. PD123177 (100 mg/kg i.v.) did not influence the dose-response curves for AII significantly. BIBS 39 (1, 3, and 10 mg/kg i.v.) and BIBS 222 (1, 3, and 10 mg/kg, i.v.) shifted the dose-response curves (DBP and LVdP/dtmax) for AII to the right. Although these two compounds (BIBS 39 1, 3, and 10 mg/kg and BIBS 222 1 and 3 mg/kg) did not alter the maximal increase in DBP to angiotensin AII, they decreased the maximal increase in LVdP/dtmax by approximately 35%. BIBS 39 (3 and 10 mg/kg) significantly reduced the increase in CO caused by AII and therefore mean arterial pressure (MAP), whereas the AII-induced increase in TPR remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
The influence of coarctation hypertension on the pharmacodynamic behaviour of rat isolated conduit vessels.
We have studied the effects of coarctation hypertension on the reactivity of the aorta with respect to alpha 1-adrenoceptor mediated vasoconstriction and methacholine-induced endothelium-dependent vasodilation. The experiments were performed in aortic rings taken from rats that had been subjected to banding of the abdominal aorta, aortic stenosis rats (ASR), and from SHAM operated control rats. As expected, the thoracic aorta was subjected to elevated blood pressure, whereas the pressure in the abdominal aorta region was much lower. Concomitantly, the thoracic and abdominal aorta regions were studied separately as isolated vessels. Both the thoracic and abdominal aortic rings taken from ASR were more sensitive to phenylephrine than those obtained from control rats. The increase in sensitivity cannot be explained by elevated pressure alone and neurohormonal factors are likely to play a role. The maximal relaxation induced by methacholine in thoracic aortic rings obtained from ASR was significantly less when compared with that in preparation taken from SHAM rats. No changes in maximal relaxation were observed in the abdominal aortic rings. It is concluded that i) the enhanced responsiveness of the rat aorta to alpha 1-adrenoceptor stimulation cannot be explained by elevated blood pressure alone and ii) coarctation hypertension impairs the endothelium-dependent relaxation of the aortic region exposed to high blood pressure.
Animals↗
Drug-induced endothelium-dependent and -independent relaxations in isolated resistance vessels taken from simultaneously hypertensive and streptozotocin-diabetic rats.
Hypertension and diabetes mellitus often co-exist and both conditions may be expected to cause synergistic vascular damage. Our group has introduced an animal model for simultaneously occurring hypertension and diabetes mellitus by treating spontaneously hypertensive rats with streptozotocin (STZ). We investigated the drug-induced endothelium-independent and -dependent relaxation in isolated mesenteric small arteries (resistance vessels). Concerning the influence of hypertension, the responses to sodium nitroprusside, methacholine, histamine and nifedipine proved unchanged, the vasodilator response to bradykinin was diminished, whereas that to the K(+)-channel opener cromakalim was enhanced. With respect to the influence of STZ-induced diabetes we found that the responses to sodium nitroprusside, methacholine and nifedipine were unchanged, and that to cromakalim was enhanced, also when the preparations were pretreated with glibenclamide. The responses to histamine (STZ WKY versus control WKY) and bradykinin (STZ SHR versus control SHR) proved enhanced in the isolated vessels taken from diabetic animals. These findings suggest that the influence of the diabetic state is more pronounced than that of hypertension. However, our findings do not indicate that either hypertension or diabetes is associated with generalised endothelial damage in the resistance arteries.
Animals↗