BACKGROUND: Overall, 75% of patients with acute stroke have elevated mean arterial pressure (MAP). In randomized stroke trials, the indirect NO donor glyceryl trinitrate lowered MAP but improved neither regional cerebral blood flow (rCBF) nor functional outcomes. One probable reason is that the microcirculation cannot bioactivate glyceryl trinitrate. In contrast, the direct NO donor 3-morpholinosydnonimine (SIN-1), not requiring bioactivation, should also release NO in small vessels, where it supports eNOS (endothelial NO synthase)-derived NO in maintaining rCBF in the hypotensive portion of Lassen autoregulatory curve. In a meta-analysis, SIN-1 reduced infarct volume in ischemia models, but the effects of SIN-1 on early pathophysiology are unknown. METHODS: Here, we investigated SIN-1 during a 60-minute bilateral common carotid artery occlusion and reperfusion in forty-eight 12- to 14-week-old Wistar-Kyoto rat (WKY) controls and 48 stroke-prone spontaneously hypertensive rats. We calculated the difference between the median values of each variable in the last 5 minutes of bilateral common carotid artery occlusion and baseline and compared them between treatment (SIN-1/control) and strain (stroke-prone spontaneously hypertensive rat/WKY) using 2-way ANOVA. We proceeded in the same way regarding reperfusion. RESULTS: Strainxintervention interaction was only found for MAP during bilateral common carotid artery occlusion. SIN-1 lowered MAP within stroke-prone spontaneously hypertensive rats (P<0.001) and within WKY (P<0.001), whereas MAP increased only in untreated stroke-prone spontaneously hypertensive rats versus untreated WKY (P=0.038). Across stroke-prone spontaneously hypertensive rat and WKY, SIN-1 increased rCBF (P<0.001), increased spontaneous brain activity (P=0.002), lowered extracellular potassium concentration (P=0.009) and area under the curve of potassium (P=0.025), and reduced the direct current-amplitude (P=0.028) and cumulative direct current-shift duration (P=0.001), consistent with milder ischemia and less severe spreading depolarization load in SIN-1-treated animals. During reperfusion, SIN-1 lowered MAP (P<0.001), decreased the no-reflow area (P=0.002), increased rCBF (P<0.001), increased spontaneous brain activity (P<0.001), and decreased extracellular potassium (P=0.008) and direct current potential (P=0.022) in both strains, consistent with less no-reflow and better recovery in SIN-1-treated animals. CONCLUSIONS: SIN-1 emerges as a promising antihypertensive in acute stroke as it paradoxically increases rCBF in ischemic tissue and reduces no-reflow.