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Biomedical subjects

M Pfaffendorf

Publications and source records attributed to M Pfaffendorf.

At least 109 records · Page 6Linked to original sources
PubMed1994

Antiischemic effects of nifedipine in isolated working heart preparations of healthy, diabetic, and hypertensive rats.

We evaluated the antiischemic effects of nifedipine in isolated working rat hearts from age-matched normotensive Wistar-Kyoto rats (WKY), diabetic WKY, spontaneously hypertensive rats (SHR), and diabetic SHR. Diabetes was induced by streptozotocin. First, we constructed concentration-response curves for the negative inotropic effect of nifedipine in every group. After 15 min of pretreatment with nifedipine (EC60), low-flow ischemia (30 min) was induced by reducing the afterload from 51.5 to 11.0 mm Hg and nifedipine was infused simultaneously. The six measured parameters were left ventricular pressure (LVP), maximum rate of pressure increase (+dP/dtmax), maximum rate of pressure decrease (-dP/dtmax), aortic output (AO), coronary flow (CF), and cardiac output (CO), determined after 15-min equilibration in the working heart mode and at the end of the experiment. From these data, the recovery percentages were calculated. There were no significant differences in sensitivity to nifedipine (as measured by the EC50 concentration) between the four groups with respect to LVP, +dP/dtmax, -dP/dtmax, CF, and CO. However, hearts from SHR were less sensitive to nifedipine than those from diabetic SHR and nondiabetic WKY with regard to AO. In isolated hearts from nondiabetic WKY and SHR, there were no significant differences between vehicle-treated organs and nifedipine-treated preparations. In hearts from diabetic WKY and diabetic SHR, however, the nifedipine-treated group (LVP 87.1 +/- 3.3 and 60.5 +/- 12.1%, respectively) recovered significantly (p < 0.05) better from ischemia as compared with the control group (LVP 35.7 +/- 14.7 and 10.7 +/- 9.8%, respectively) (n = 6 for each group).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Different types of angiotensin II receptor antagonism induced by BIBS 222 in the rat portal vein and rabbit aorta; the influence of receptor reserve.

BIBS 222, a nonpeptide benzimidazole derivative, displayed insurmountable angiotensin II (Ang II) receptor antagonism in the rabbit aorta (pKB = 7.9), whereas it antagonized Ang II-induced phasic contractions in the rat portal vein in a surmountable manner (pA2 = 8.7, slope = 1.02). The mechanism of the different types of antagonism induced by BIBS 222 in vascular preparations was investigated. Using the slowly dissociating Ang II receptor antagonist sarile, we found that the calculated KA values for Ang II in the rat portal vein and in the rabbit aorta were different (6.0 x 10(-8) M vs. 2.0 x 10(-9) M). The estimated receptor reserve at the maximal response for the effect of Ang II in the rat portal vein amounts to 63%, whereas in rabbit aortic rings it is about 9%. In the presence of the disulfide-reducing agent dithiothreitol (0.5 mM), which led to the inactivation of about 70% of the Ang II receptors in the rat portal vein, BIBS 222 (10(-6) M) shifted the concentration-response curve for Ang II to the right and reduced the maximal response by 24 +/- 4.4% (P < .05). In conclusion, rat portal vein possesses a larger receptor reserve for Ang II than rabbit aortic rings. The surmountable Ang II receptor antagonism induced by BIBS 222 may be caused by the large receptor reserve in this preparation. Alternatively, different KA values for Ang II in these tissues may suggest the existence of two subpopulations of Ang II subtype 1 receptors, accounting for the cross-tissue behavior of BIBS 222.

Angiotensin Receptor Antagonists↗
PubMed1993

Cholera toxin but not pertussis toxin inhibits angiotensin II-enhanced contractions in the rat portal vein.

Angiotensin II (Ang II)-enhanced phasic contractions in the rat portal vein were concentration dependently inhibited by cholera toxin (0.1-10 micrograms/ml) and dibutyryl cyclic AMP (0.1-1 mM), but not by pertussis toxin (1 micrograms/ml), which suggests that Gi is not involved in the Ang II signal transduction pathway. It also seems likely that the effect of cholera toxin is due to its ability to increase cyclic AMP production through Gs.

Adenylyl Cyclases↗
PubMed1993

Positive inotropic action of angiotensin II in the pithed rat.

The cardiovascular effects of angiotensin II were examined in aortic blood pressure-controlled and -uncontrolled pithed rats. Angiotensin II induced a dose-dependent increase in diastolic blood pressure, left ventricular pressure (LVP), dP/dt (the first derivative of LVP) and heart rate in pithed rats. The maximal responses for these parameters were similar to those to noradrenaline, except for the rise in diastolic blood pressure, where noradrenaline caused a greater increase than angiotensin II. After treatment with propranolol, the positive chronotropic effect of angiotensin II was abolished. Angiotensin II produced a dose-dependent increase in diastolic blood pressure, which was similar to that of vasopressin, and an increase in dP/dtmax, which proved much greater than that of vasopressin. When aortic blood pressure was controlled and the beta-receptors were blocked by propranolol, angiotensin II caused a dose-dependent increase in dP/dtmax without affecting the left ventricular enddiastolic pressure. The same results were obtained after both beta- and alpha-adrenoceptors were blocked by propranolol and phentolamine. Losartan but not PD123177 caused parallel rightward shifts of the dose-response curve of angiotensin II for dP/dtmax in the aortic blood pressure controlled pithed rat without altering the maximal response. It is concluded that in the pithed rat angiotensin II produced an increase in myocardial contractile force which is not mediated by beta- or alpha-adrenoceptors. The inotropic effect appears to be mediated by angiotensin receptors, of the AT1-subtype.

Adrenergic alpha-Antagonists↗
PubMed1993

Characterization of the angiotensin II-receptor subtype in the longitudinal smooth muscle of the rat portal vein.

The purpose of the present study was to identify the angiotensin II-receptor subtype involved in the enhancement of the amplitude of the phasic contractions by angiotensin II in the isolated rat portal vein preparation. At an extracellular Ca2+ concentration of 0.9 mmol/l and a K+ concentration of 4 mmol/l, angiotensin II induced concentration-dependent increases in the amplitude of the phasic contractions. The enhancement of phasic contraction amplitude caused by angiotensin II was not significantly altered by pretreatment of the rat portal vein with indomethacin 10(-5) mol/l or nitro-L-arginine 10(-4) mol/l, indicating that neither prostaglandins nor the endothelium derived-relaxing factor (NO) are involved. Losartan (DuP 753), a nonpeptide selective AT1-receptor antagonist, concentration-dependently shifted the concentration-response curve for the effect of angiotensin II on the amplitude of the contractions to the right, without reducing the maximal response (pA2 = 8.6, slope = 0.98), thus suggesting competitive antagonism at the level of AT1-receptors. By contrast, PD 123,177, a nonpeptide selective AT2-receptor antagonist, even at 10(-5) mol/l, caused no significant change of the phasic myogenic response to angiotensin II, indicating the absence of AT2-receptor involvement. Dithiothreitol, a disulfide-reducing agent which is known to inactivate AT1-receptors in various tissues, markedly inhibited (3 mmol/l) or even abolished (5 mmol/l) the contractile response of the rat portal vein to angiotensin II, supporting the conclusion that these receptors can be classified as AT1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Effects of manidipine and other calcium antagonists on rat renal arcuate arteries.

We investigated the effect of 1,4-dihydropyridine calcium antagonists (nifedipine, nisoldipine, and manidipine) on serotonin (5-hydroxytryptamine [5-HT])- and KCl (120 mmol/L)-induced contractions of rat isolated renal arcuate arteries. The preparation showed the well-known biphasic response to KCl-induced depolarization. All three calcium antagonists were more potent in inhibiting the second phase (tonic) compared with the first phase (transient) of the effect. The inhibitory concentration of 50% (pIC50) values were 6.92 +/- 0.24/8.51 +/- 0.08 (nifedipine, n = 32), 7.61 +/- 0.10/9.33 +/- 0.03 (nisoldipine, n = 28), and 7.61 +/- 0.13/9.07 +/- 0.06 (manidipine, n = 32) for the suppression of the first and second phases, respectively. In small coronary and renal arteries maximally activated with KCl solution, nifedipine and manidipine concentrations dependently inhibited the calcium concentration response curves. Manidipine was more potent than nifedipine (pIC50 coronary artery: 9.26 +/- 0.14 vs 7.93 +/- 0.22; pIC50 renal artery: 9.14 +/- 0.14 vs 7.77 +/- 0.21), but both compounds showed the same potency in the two different preparations. Furthermore, the influence of the calcium antagonists on the 5-HT concentration-response curve was investigated. Marked differences were found in the ability of the three compounds to inhibit the 5-HT-induced vasoconstriction of isolated renal arteries. For manidipine, a 93% +/- 3% reduction of the maximal 5-HT-induced contraction was observed, which was a significantly stronger inhibition compared with nifedipine (43% +/- 4.12%) or nisoldipine (26% +/- 0.37%). The pIC50 values were 7.96 +/- 0.15 (nifedipine), 8.17 +/- 0.14 (nisoldipine), and 7.84 +/- 0.12 (manidipine).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The influence of high glucose levels and/or hyperosmolarity on rat isolated aorta.

We investigated the influence of high-glucose levels (30.5 mmol/L) and/or hyperosmolarity on pharmacological responses in aortic ring preparations taken from nondiabetic rats. Moderate changes were observed for the concentration-response curves of noradrenaline and phenylephrine, but not for methoxamine and cirazoline. Maximal active forces of the concentration-response curves of potassium chloride and calcium chloride were significantly reduced by the elevated glucose levels per se, but neither the slopes of the curves nor the -logEC50 values were affected. Concentration-response curves of serotonin and U 46619 were not affected. For angiotensin II, the -logEC50 values and maximal active forces of the concentration-response curves were significantly lower under both hyperglycemic and hyperosmolar conditions. The present study suggests that potential changes in contractile behavior in isolated vessels from diabetic animals cannot be attributed to high glucose levels and/or hyperosmolarity as such, but indeed reflect vascular changes associated with the diabetic state. An exception has to be made for the depolarization of aortic ring preparations of nondiabetic rat; the elevated glucose level leads to an impaired calcium influx via the (slow) L-type calcium channels.

Animals↗
PubMed1993

Similarities and differences between calcium antagonists: pharmacological aspects.

Characteristics of three different calcium antagonist groups: Most important calcium antagonists used to treat cardiovascular disease belong to one of three main groups, phenylalkylamines, dihydropyridines and benzothiazepines. The best known drug in each group is verapamil, nifedipine and diltiazem, respectively. Dihydropyridines are predominantly vasodilators, with little or no primary cardiac activity; the tachycardia caused by these compounds is a reflex phenomenon. Verapamil and related drugs are also vasodilators, with an additional depressant effect on atrioventricular conduction, heart rate and contractility. Diltiazem's pharmacodynamic profile and side effects may be considered as intermediate between those of the dihydropyridines and verapamil. Characteristics of new calcium antagonists: Several new calcium antagonists have been introduced in the last few years, virtually all dihydropyridines. Compared with the older generation of calcium antagonists these newer drugs tend to have (1) a longer duration of action; (2) some selectivity for a specific vascular bed, such as resistance, coronary, renal or cerebral vessels; (3) a potentially useful extra component, such as diuretic or anti-atherogenic activity. Newer calcium antagonists described in this review: The newer compounds briefly characterized in this review are amlodipine, felodipine, isradipine, lacidipine, nimodipine, nisoldipine and nitrendipine. New slow-release formulations are also discussed. There is a particular emphasis on lacidipine and its potential for cardiovascular drug therapy.

Angina Pectoris↗
PubMed1993

Characterization of the muscarinic receptors in the mesenteric vascular bed of spontaneously hypertensive rats.

OBJECTIVE: The nature of the muscarinic (M) receptor subtype mediating endothelium-dependent vasodilation was investigated in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). DESIGN: Characterization of the muscarinic receptor mediating vasodilation and the possible hypertension-induced effects on the nature of this receptor, which have both received little attention in resistance vessels of the SHR. METHODS: After a methoxamine-induced vasoconstriction, the vessels were dilated with acetyl-beta-metacholine (MCh). The MCh-induced vasodilation was analysed by means of the M1-selective antagonist pirenzepine, the M2-selective antagonists AF-DX116 and AQ-RA 741 and the M3-selective antagonists 4-DAMP and p-FHHSiD. The potency of these compounds was quantified by means of pA2 values. Atropine, a non-selective muscarinic antagonist, was used for comparison. RESULTS: The rank order of potency for the muscarinic receptor antagonists in preparations taken from SHR and WKY rats appears to be atropine > 4-DAMP > p-FHHSiD > pirenzepine > AQ-RA 741 > AF-DX 116. This rank order corresponds to that found in isolated conduit arteries. CONCLUSIONS: The pA2 values for the various compounds were not significantly different in SHR and WKY rat preparations, indicating that the nature of this receptor is not influenced by hypertension. The high potency of the M3-selective drugs and the weak activity of pirenzepine and the M2-selective antagonists suggest a major role of M3-receptors in the cholinergic vasodilation in the perfused mesenteric vascular bed both in SHR and WKY rat preparations.

Animals↗
PubMed1993

Cardioprotection by nifedipine in isolated working hearts: a comparative study on three different types of experimental ischemia.

Cardiac ischemia can be provoked by different methods in animal models and in isolated organs. Accordingly, three different procedures were followed to find the most sensitive model for the analysis of the anti-ischemic activity of calcium antagonists. The experiments were performed in the isolated working heart preparation of the rat, paced at the frequency of 5 Hz and perfused with Tyrode solution at 37 degrees C. Global ischemia was achieved by closing off the supply of the perfusion medium and surrounding the heart with Tyrode solution of 37 degrees C gassed with N2; low-flow ischemia was achieved by reducing the cardiac afterload from 51.5 to 11.0 mm Hg; ligation of the left descending coronary artery was performed in order to provoke regional ischemia. Nifedipine was applied in a concentration (EC50) known to reduce the contractile force by one-half of its basal value. The following parameters were determined after 15 min of nifedipine pretreatment and at the end of the experiment: LVP (left ventricular pressure),+dP/dtmax (LVP's first derivative), AO (aortic output), CF (coronary flow), and CO (cardiac output). From the data obtained, the percentages of recovery were calculated. Nifedipine caused a significant improvement in the functional recovery of most of the parameters studied. This improvement, however, was much more pronounced in the model of the low-flow ischemia, which is obviously more sensitive to the anti-ischemic activity of calcium antagonists than the other experimental procedures studied. Low-flow ischemia appears to be preferable to other procedures for the screening of the potential anti-ischemic activity of calcium antagonists and other drugs.

Animals↗
PubMed1993

In vitro effects of nifedipine, nisoldipine, and lacidipine on rat isolated coronary small arteries.

We investigated the effect of 1,4-dihydropyridine calcium antagonists (nifedipine, nisoldipine, and lacidipine) on serotonin (5-HT)- and KCl (120 mM)-induced contractions of rat isolated septal coronary artery. The preparations showed the well-known biphasic response to KCl depolarization. All three calcium antagonists were more potent in inhibiting the second, tonic phase compared to the first, transient phase, with pIC50 values of 7.17 +/- 0.12/8.27 +/- 0.07 (nifedipine), 7.93 +/- 0.21/8.96 +/- 0.06 (nisoldipine), and 8.28 +/- 0.07/9.79 +/- 0.04 (lacidipine) for suppressing the first and the second phase, respectively. Furthermore, the influence of the calcium antagonists on the 5-HT concentration-response curve was investigated. Nifedipine, nisoldipine, and lacidipine concentration dependently depressed the maximum effect of 5-HT on the coronary artery preparations without influencing the pEC50 of the 5-HT concentration-response curve. In conclusion, all three dihydropyridine calcium antagonists are potent and effective inhibitors of depolarization- or 5-HT-induced coronary artery contractions. Lacidipine, a new lipophilic compound, was the most potent one in inhibiting the depolarization-induced contraction, thereby showing a marked selectivity for the tonic phase compared to the initial phasic response.

Animals↗
PubMed1993

Hemodynamic and antiischemic effects of nifedipine, lacidipine, and nisoldipine in rat isolated working heart.

We compared two newer dihydropyridine-calcium antagonists (lacidipine and nisoldipine) with the classic prototype of this group, nifedipine, in the rat working heart preparation. The hearts were paced at a frequency of 5 Hz and perfused with Tyrode's solution of 37 degrees C. The following five parameters were determined: left ventricular pressure (LVP), maximal rate of pressure increase (+dP/dtmax), aortic output (AO), coronary blood flow (CBF), and cardiac output (CO). First, dose-response curves were constructed; from these data the EC50 concentration for the three calcium antagonists was calculated. Subsequently, washout from the cardiac tissue for these three compounds was determined. The effects of lacidipine did not diminish during < or = 90-min washout, whereas the effects of nifedipine disappeared completely in 10 min. The effects of nisoldipine, however, disappeared partly in 10 min. In separate experiments, the antiischemic activity of the three calcium antagonists was analyzed, using low-flow ischemia. The calcium antagonists were used in a concentration that produced a 60% reduction in contractile force (EC60). Nifedipine and nisoldipine caused significant improvement in functional recovery. The antiischemic properties of lacidipine could not be shown because of its slow kinetic properties with accumulation in the membrane phase and slow kinetics with the channel. Nisoldipine and lacidipine appear to be more potent calcium antagonists as compared with nifedipine, whereas lacidipine displays a clearly different kinetic pattern in comparison to nifedipine and nisoldipine. In particular, the extremely slow onset and very long duration of action of lacidipine are of interest.

Animals↗
PubMed1993

Differential response of hypertrophied rat hearts to various alpha 1-adrenoceptor agonists.

With respect to the heart, the prolonged existence of hypertension, both in man and in experimental animals is predominantly characterized by an increase in left ventricular myocardial mass. In this process, the autonomic nervous system plays an important role. Although endogenous catecholamine stimulation of the heart is mainly exerted via the beta-adrenoceptors, in several mammalian species, the stimulation of cardiac alpha 1-adrenoceptors also mediates positive inotropic actions. We investigated the functional responses of isolated hypertrophied hearts taken from spontaneously hypertensive rats (SHR) and rats with an induced aortic stenosis (ASR) to various alpha 1-adrenoceptor agonists and compared them with those from age matched Wistar Kyoto (WKY) and "sham" operated controls. Accordingly, we studied the functional response to: methoxamine (alpha 1), cirazoline (alpha 1) and phenylephrine (alpha 1 > beta 1). The inotropic response to the alpha 1-adrenoceptor agonists cirazoline and methoxamine proved to be significantly weaker in hypertrophied hearts from SHR and ASR than in non-hypertrophied hearts from WHY and "sham" operated controls (p < 0.05). The inotropic response to phenylephrine remained intact in hypertrophied myocardial tissue. However, it was significantly reduced when the hearts were pre-treated with the intracellular Ca(2+)-antagonists ryanodine and TMB-8. These findings show that the mechanism of sarcolemmal Ca2+ release, activated by phenylephrine, is still intact in the hypertrophied myocardial cell. In conclusion, these data show that cardiac hypertrophy, be it of genetical or mechanical origin, leads to a reduced response of the isolated heart to alpha 1-adrenoceptor stimulation.

Adrenergic alpha-Agonists↗
PubMed1993

Mediation by the same muscarinic receptor subtype of phasic and tonic contractile activities in the rat isolated portal vein.

1. The effects of several agonists on the phasic and tonic contractile responses to muscarinic receptor stimulation have been investigated in the rat portal vein in vitro. 2. Neither chemical denervation with 6-hydroxydopamine nor the presence of the alpha 1-adrenoceptor antagonist, prazosin, influenced the spontaneous or the stimulated myogenic activity of the portal vein. 3. Indomethacin and NG-nitro-L-arginine were used to investigate the influence of vasoactive factors in this preparation. They slightly increased the frequency and the amplitude of the spontaneous myogenic activity of the portal vein, respectively. NG-nitro-L-arginine but not indomethacin enhanced the maximal phasic response to carbachol. Both indomethacin and NG-nitro-L-arginine failed to influence the tonic response to carbachol. 4. Muscarinic agonists increased phasic activity according to the rank order of potency: acetylcholine > muscarine > methacholine > carbachol > aceclidine > bethanechol. These effects were superimposed on a sustained contracture at higher concentrations. Oxotremorine was more potent than arecoline in increasing the mechanical phasic activity, without inducing a sustained contracture. Pilocarpine and McN A343 were weak agonists, producing submaximal effects only on phasic activity. 5. The muscarinic antagonists AF-DX116, 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), P-fluorohexahydrosiladiphenidol (pFHHSiD) and pirenzepine antagonized the phasic and tonic mechanical responses to carbachol. Although the tonic contracture was slightly more sensitive to all antagonists studied, the rank order of potency: 4-DAMP > pFHHSiD > pirenzepine > AF-DX 116 was the same for both types of responses, which is indicative of a M3-receptor subtype. 6. The tonic contractile response of the rat portal vein to carbachol was more susceptible to partial receptor inactivation with propylbenzilylcholine mustard than the phasic contractile response. The dissociation constants (KA) obtained from an analysis according to Furchgott & Bursztyn (1967) were found to be 4.32 +/- 0.31 1AM for the phasic and 3.56 +/- 0.21 1AM for the tonic type of carbachol-induced response, respectively. Since the EC50-values for both carbachol-induced effects were different (phasic0.232 +/- 0.02 1AM; tonic 2.75 +/- 0.1 1AM) the phasic type of response appears to involve a large receptor reserve.

Animals↗
PubMed1993

The effect of muscarinic receptor alkylation on endothelium-dependent vasodilation in SHR.

Possible hypertension-related alterations in the nature- and receptor reserve of the muscarinic (M) receptors mediating endothelium-dependent vasodilation remain to be elucidated. Therefore we used 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine (4-DAMPmustard), an irreversible M3-receptor antagonist, to estimate the receptor reserve for the methacholine (MCh)-induced endothelium-dependent vasodilation in perfused mesenteric vascular bed preparations obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats, respectively. The concentration-response curve parameters for the MCh-induced vasodilation were similar in both types of preparations. 4-DAMPmustard concentration-dependently decreased the maximal effect (Emax) of MCh without altering (N.S.) the pD2 in either type of preparation. The Emax was decreased to the same extent (N.S.) in both types of preparations. The dissociation constants of MCh for the response to muscarinic stimulation were comparable in preparations from SHR and WKY rats. The receptor reserve for this response, which is relatively low, does not appear to differ between vessels from SHR and WKY. It is concluded that an endothelial dysfunction does not seem to occur in perfused mesenteric resistance vessels from SHR. Also, the nature- and M-receptor reserves to not appear to differ. Therefore there are no important hypertension-related alterations in the M-receptor mediating endothelium-dependent vasodilation, at least in the experimental model used.

Alkylating Agents↗
PubMed1993

The effects of hypertension and diabetes mellitus on the vascular reactivity of resistance arteries.

We have studied the effects of both hypertension and streptozotocin-induced diabetes mellitus on alpha 1-adrenoceptor mediated vasoconstriction, endothelium-dependent and endothelium-independent vasodilation. The experiments were performed in perfused mesenteric vascular bed preparations taken from age-matched SHR, WKY, diabetic SHR and diabetic WKY. For the alpha 1-adrenoceptor agonist methoxamine, the mesenteric preparations from SHR and diabetic SHR yielded significantly (p < 0.05) stronger maximal responses than preparations taken from WKY and diabetic WKY, respectively. The diabetic state significantly (p < 0.05) decreased the responsiveness to methoxamine in arteries from SHR and WKY. Hypertension does not significantly change the concentration response-curves for (acetyl-beta) methacholine, histamine, adenosine diphosphate and sodium-nitroprusside. However, the sensitivity to endothelium-dependent vasodilation decreased in preparations from diabetic animals (< 0.05). It is concluded that mesenteric resistance arteries from SHR and diabetic SHR are more reactive to alpha 1-adrenoceptor stimulation, whereas diabetes reduces the responsiveness to methoxamine in WKY and SHR. Hypertension does not affect the endothelium-dependent relaxation in mesenteric arteries. However, diabetes decreases the sensitivity to endothelium-dependent relaxation without altering the sensitivity to sodium-nitroprusside. These findings are indicative of a diabetes-induced endothelial dysfunction in mesenteric resistance arteries. In preparations from diabetic hypertensive rats the reduced response to methoxamine and the endothelial dysfunction seem to run parallel.

Animals↗
PubMed1993

The role of nitric oxide and potassium channels in endothelium-dependent vasodilation in SHR.

We have investigated the effects of L-NG-nitro arginine (L-NOARG), glibenclamide, ouabain, tetraethylammonium and 4-aminopyridine on the methacholine-induced endothelium-dependent vasodilation in perfused resistance arteries from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Since the concentration-response curves of MCh were similar in both types of preparations there does not seem to exist an endothelial dysfunction in mesenteric arteries of SHR. L-NOARG only partially inhibited the maximal methacholine-induced response in preparations taken from SHR and WKY rats. Ouabain decreased the maximal effect of methacholine without altering the potency (pD2). Preparations from SHR were more susceptible to ouabain. 4-aminopyridine and tetraethylammonium decreased the pD2 for methacholine without reducing the maximal effect (Emax). The WKY rat preparations were more affected by these compounds. An important role of ATP-sensitive potassium channels may be ruled out since glibenclamide was without effect on the methacholine-induced vasodilation. It is concluded that endothelium-derived relaxing factor is only partially responsible for the endothelium-dependent vasodilation. Indirect arguments point toward a role of endothelium-derived hyperpolarizing factor, since ouabain, tetraethylammonium and 4-aminopyridine inhibited the methacholine-induced response. Although hypertension related differences for these compounds were observed high blood pressure does not seem to alter the functional response to muscarinic stimulation.

4-Aminopyridine↗